Sleisenger and Fordtran's Gastrointestinal and Liver Disease [11 ed.] 9780323609623, 9780323760782, 9780323760775, 2020934045

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Sleisenger and Fordtran’s

11

TH EDITION

Gastrointestinal and Liver Disease PATHOPHYSIOLOGY | DIAGNOSIS | MANAGEMENT EDITORS

ASSOCIATE EDITORS

MARK FELDMAN, MD

RAYMOND T. CHUNG, MD

Chairman of Internal Medicine Texas Health Presbyterian Hospital Dallas Clinical Professor of Internal Medicine University of Texas Southwestern Medical School Dallas, Texas

Director of Hepatology, Vice Chief, Gastroenterology Division of Gastroenterology Massachusetts General Hospital and Harvard Medical School Associate Member, Broad Institute Boston, Massachusetts

LAWRENCE S. FRIEDMAN, MD

DAVID T. RUBIN, MD

Professor of Medicine Harvard Medical School Professor of Medicine Tufts University School of Medicine Boston, Massachusetts The Anton R. Fried, MD, Chair Department of Medicine Newton-Wellesley Hospital Newton, Massachusetts Assistant Chief of Medicine Massachusetts General Hospital Boston, Massachusetts

Joseph B. Kirsner Professor of Medicine Chief, Section of Gastroenterology, Hepatology, and Nutrition Department of Medicine University of Chicago Chicago, Illinois

LAWRENCE J. BRANDT, MD Professor of Medicine and Surgery Albert Einstein College of Medicine Emeritus Chief Division of Gastroenterology Montefiore Medical Center Bronx, New York

C. MEL WILCOX, MD, MSPH Division of Gastroenterology and Hepatology University of Alabama at Birmingham Birmingham, Alabama

Elsevier 1600 John F. Kennedy Blvd. Ste 1800 Philadelphia, PA 19103-2899 SLEISENGER AND FORDTRAN’S GASTROINTESTINAL AND LIVER DISEASE, ELEVENTH EDITION

ISBN: 978-0-323-60962-3 Volume 1: 978-0-323-76078-2 Volume 2: 978-0-323-76077-5

Copyright © 2021 by Elsevier, Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).

Notice Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds or experiments described herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made. To the fullest extent of the law, no responsibility is assumed by Elsevier, authors, editors or ­contributors for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Previous editions copyrighted 2016, 2010, 2006, 2002, 1998, 1993, 1989, 1983, 1978, and 1973. Library of Congress Control Number: 2020934045

Senior Content Strategist: Nancy Duffy Senior Content Development Specialist: Dee Simpson Publishing Services Manager: Julie Eddy Senior Project Manager: Cindy Thoms Design Direction: Patrick Ferguson

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We dedicate this 11th edition to you, our readers, as you were always central in our thoughts as we wrote, edited, and produced this textbook. We hope our book meets your educational needs.

Contributors Nezam H. Afdhal, MD, DSc

Senior Physician in Hepatology Department of Gastroenterology Beth Israel Deaconess Medical Center Boston, Massachusetts, United States Rakesh Aggarwal, MD, DM

Director Jawaharlal Institute of Postgraduate Medical Education and Research Puducherry, India Taymeyah Al-Toubah, MPH

Gastroenterology and Oncology H. Lee Moffitt Cancer Center Tampa, Florida, United States Jaime Almandoz, MD

Assistant Professor Department of Internal Medicine, ­Division of Endocrinology University of Texas Southwestern Dallas, Texas, United States Ashwin N. Ananthakrishnan, MD, MPH

Associate Professor of Medicine Harvard Medical School Division of Gastroenterology Massachusetts General Hospital Boston, Massachusetts, United States Karin L. Andersson, MD, MPH

Assistant Professor of Medicine Harvard Medical School Hepatologist Division of Gastroenterology Massachusetts General Hospital Boston, Massachusetts, United States Farshid Araghizadeh, MD, MBA

Colon and Rectal Surgeon Texas Digestive Disease Consultants (TDDC) and The GI Alliance (TGIA) Dallas–Fort Worth, Texas, United States Louis J. Aronne, MD

Sanford I. Weill Professor of Metabolic Research Department of Medicine Weill Cornell Medicine New York, New York, United States Fernando Azpiroz, MD, PhD

Chief Department of Gastroenterology University Hospital Vall d’Hebron Professor of Medicine Universitat Autònoma de Barcelona Barcelona, Spain

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Bruce R. Bacon, MD

Professor of Internal Medicine Division of Gastroenterology and Hepatology Saint Louis University School of Medicine St. Louis, Missouri, United States William F. Balistreri, MD

Director, Pediatric Liver Care Center Gastroenterology, Hepatology, and Nutrition Cincinnati Children’s Hospital Medical Center Cincinnati, Ohio, United States

William Bernal, MD

Professor Liver Intensive Therapy Unit King’s College Hospital London, United Kingdom

Adil E. Bharucha, MBBS, MD

Professor of Medicine Division of Gastroenterology and Hepatology Mayo Clinic Rochester, Minnesota, United States

Taft P. Bhuket, MD

Professor of Medicine Division of Gastroenterology and Hepatology University of North Carolina Chapel Hill, North Carolina, United States

Associate Clinical Professor of Medicine Division of Gastroenterology University of California, San Francisco San Francisco, California Chief of Gastroenterology and ­Hepatology Director of Endoscopy Alameda Health System Oakland, California, United States

Bradley A. Barth, MD, MPH

Yangzom D. Bhutia, DVM, PhD

Todd H. Baron, MD

Professor Department of Pediatrics University of Texas Southwestern Dallas, Texas, United States Lee M. Bass, MD

Associate Professor of Pediatrics Gastroenterology, Hepatology, and Nutrition Ann and Robert H. Lurie Children’s Hospital of Chicago Northwestern University Feinberg School of Medicine Chicago, Illinois, United States Alex S. Befeler, MD

Professor of Internal Medicine Medical Director of Liver Transplantation Department of Internal Medicine Saint Louis University St. Louis, Missouri, United States Mark Benson, MD

Associate Professor of Medicine Section of Gastroenterology and Hepatology University of Wisconsin School of Medicine and Public Health Madison, Wisconsin, United States

Assistant Professor Cell Biology and Biochemistry Texas Tech University Health Sciences Center Lubbock, Texas, United States

J. Andrew Bird, MD

Associate Professor Pediatrics, Division of Allergy and Immunology University of Texas Southwestern Medical Center Director Food Allergy Center Children’s Medical Center Dallas, Texas, United States

Boris Blechacz, MD, PhD

Clinical Associate Professor of Internal Medicine Gastroenterology and Hepatology Palmetto Health—University of South Carolina Columbia, South Carolina, United States

Diego V. Bohórquez, PhD

Assistant Professor Departments of Medicine and Neurobiology Duke University Medical Center Durham, North Carolina, United States

Contributors

Jan Bornschein, MD

Translational Gastroenterology Unit John Radcliffe Hospital Oxford University Hospitals Oxford, United Kingdom

Christopher L. Bowlus, MD

Professor and Chief Division of Gastroenterology and Hepatology University of California Davis Sacramento, California, United States

Lawrence J. Brandt, MD

Professor of Medicine and Surgery Albert Einstein College of Medicine Emeritus Chief Division of Gastroenterology Montefiore Medical Center Bronx, New York, United States

Robert Scott Bresalier, MD

Professor of Medicine Lydia and Birdie J Resoft Distinguished Professor in GI ­Oncology Gastroenterology, Hepatology, and Nutrition The University of Texas MD Anderson Cancer Center Houston, Texas, United States

Simon J.H. Brookes, PhD

Professor Human Physiology College of Medicine, Flinders University Adelaide, South Australia, Australia

Alan L. Buchman, MD, MSPH

Professor of Clinical Surgery University of Illinois at Chicago Medical Director Intestinal Rehabilitation and Transplant Center Chicago, Illinois, United States

Ezra Burstein, MD, PhD

Professor Departments of Internal Medicine and Molecular Biology UT Southwestern Medical Center Dallas, Texas, United States

Andres F. Carrion, MD

Assistant Professor of Clinical Medicine Program Director, Transplant Hepatology Fellowship Division of Gastroenterology and Hepatology University of Miami Miami, Florida, United States

Scott Celinski, MD

Surgical Oncologist Department of Surgery Baylor University Medical Center Dallas, Texas, United States

Francis K.L. Chan, MBChB(Hons), MD, DSc

Professor of Medicine Department of Medicine and Therapeutics Chinese University of Hong Kong Hong Kong, China

Eugene B. Chang, MD

Martin Boyer Professor Department of Medicine University of Chicago Chicago, Illinois, United States Joseph G. Cheatham, MD

Associate Professor of Medicine Department of Medicine Uniformed Services University Bethesda, Maryland Program Director Gastroenterology Fellowship Naval Medical Center San Diego San Diego, California, United States Shivakumar Chitturi, MD

Associate Professor Australian National University Senior Staff Hepatologist The Canberra Hospital Australian Capital Territory, Australia Daniel C. Chung, MD

Associate Professor of Medicine Harvard Medical School Division of Gastroenterology Massachusetts General Hospital Medical Co-Director Center for Cancer Risk Analysis Massachusetts General Hospital Cancer Center Boston, Massachusetts, United States Raymond T. Chung, MD

Director of Hepatology, Vice Chief, Gastroenterology Division of Gastroenterology Massachusetts General Hospital and Harvard Medical School Associate Member, Broad Institute Boston, Massachusetts, United States

Paul A. Dawson, PhD

Professor Pediatrics— Gastroenterology, Hepatology, and ­Nutrition Emory University Atlanta, Georgia, United States Gregory de Prisco, MD

Diagnostic Radiologist Department of Radiology Baylor University Medical Center Director of Medical Education American Radiology Associates Dallas, Texas, United States Jill K. Deutsch, MD

Clinical Fellow Department of Internal Medicine Section of Digestive Diseases Yale New Haven Hospital—Yale University School of Medicine New Haven, Connecticut, United States Kenneth R. DeVault, MD

Professor of Medicine Mayo Clinic College of Medicine Jacksonville, Florida, United States Adrian M. Di Bisceglie, MD

Professor of Internal Medicine Department of Internal Medicine Saint Louis University St. Louis, Missouri, United States John K. DiBaise, MD

Professor of Medicine Division of Gastroenterology and Hepatology Mayo Clinic Scottsdale, Arizona, United States Philip G. Dinning, PhD

Marcello Costa, MD

Flinders Medical Centre Human Physiology Flinders University Adelaide, South Australia, Australia

Thomas G. Cotter, MD

Program Director Colon and Rectal Surgery Texas Health Resources Clinical Professor of Surgery Colon and Rectal Surgery University of Texas Southwestern Medical School Dallas, Texas, United States

Matthew Flinders Distinguished Professor and Professor of Neurophysiology Physiology Flinders University Adelaide, South Australia, Australia Gastroenterology Fellow Section of Gastroenterology, Hepatology, and Nutrition University of Chicago Medicine Chicago, Illinois, United States Albert J. Czaja, MD

Professor Emeritus of Medicine Gastroenterology and Hepatology Mayo Clinic College of Medicine and Science Rochester, Minnesota, United States Brian G. Czito, MD

Professor Radiation Oncology Duke University Medical Center Durham, North Carolina, United States

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J. Marcus Downs, MD

Douglas A. Drossman, MD

Professor Emeritus of Medicine and Psychiatry Division of Digestive Disease and Nutrition University of North Carolina President Center for Education and Practice of Biopsychosocial Care Chapel Hill, North Carolina President Drossman Gastroenterology PLLC Durham, North Carolina, United States



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Contributors

Kerry B. Dunbar, MD, PhD

Section Chief, VA Gastroenterology Section Department of Medicine– Gastroenterology and Hepatology VA North Texas Healthcare System– Dallas VA Medical Center Associate Professor of Medicine Department of Medicine–Division of Gastroenterology and Hepatology University of Texas Southwestern Medical School Dallas, Texas, United States John E. Eaton, MD

Assistant Professor of Medicine Department of Internal Medicine Division of Gastroenterology and Hepatology Mayo Clinic Rochester, Minnesota, United States Steven A. Edmundowicz, MD

Professor of Medicine Interim Director, Division of Gastroenterology and Hepatology University of Colorado Anschutz Medical Campus Aurora, Colorado, United States David E. Elliott, MD, PhD

University of Iowa Carver College of Medicine Department of Internal Medicine Division of Gastroenterology and Hepatology Iowa City VAHCS Department of Internal Medicine Veterans Administration Health Care System Iowa City, Iowa, United States

Michael B. Fallon, MD

Alexander C. Ford, MBChB, MD

Geoffrey C. Farrell, MD

John S. Fordtran, MD

Professor of Medicine Gastroenterology, Hepatology, and Nutrition University of Arizona Chair Department of Internal Medicine University of Arizona—Phoenix Phoenix, Arizona, United States Professor, Hepatic Medicine Australian National University Senior Staff Hepatologist The Canberra Hospital Australian Capital Territory, Australia Jordan J. Feld, MD, MPH

Associate Professor of Medicine University of Toronto Research Director Toronto Centre for Liver Disease Senior Scientist Sandra Rotman Centre for Global Health Toronto General Hospital Toronto, Ontario, Canada

Lawrence S. Friedman, MD

Scott Fung, MD

Charles O. Elson, MD

Grace H. Elta, MD

Professor and Chief Division of Gastroenterology, Hepatology, and Nutrition University of Florida Gainesville, Florida, United States

Nielsen Q. Fernandez-Becker, MD

Mark Feldman, MD

Attending Physician Gastroenterology Gastroenterology Center of Connecticut Hamden, Connecticut Assistant Clinical Professor of Medicine Gastroenterology Yale University School of Medicine New Haven, Connecticut, United States

Professor Emeritus Formerly the H. Marvin Pollard Collegiate Professor Division of Gastroenterology University of Michigan Ann Arbor, Michigan, United States

Chris E. Forsmark, MD

Chairman of Internal Medicine Texas Health Presbyterian Hospital Dallas Clinical Professor of Internal Medicine University of Texas Southwestern Medical School Dallas, Texas, United States

B. Joseph Elmunzer, MD, MSc

Professor of Medicine and Microbiology Basil I. Hirschowitz Chair in Gastroenterology University of Alabama at Birmingham Birmingham, Alabama, United States

Internal Medicine, Division of Gastroenterology Baylor University Medical Center Dallas, Texas, United States

Professor of Medicine Harvard Medical School Professor of Medicine Tufts University School of Medicine Boston, Massachusetts The Anton R. Fried, MD, Chair Department of Medicine Newton-Wellesley Hospital Newton, Massachusetts Assistant Chief of Medicine Massachusetts General Hospital Boston, Massachusetts, United States

Clinical Associate Professor of Medicine Division of Gastroenterology and Hepatology Stanford University Redwood City, California, United States

Peter B. Cotton Professor of Medicine and Endoscopic ­Innovation Division of Gastroenterology and Hepatology Medical University of South Carolina, Charleston Charleston, South Carolina, United States

Professor of Gastroenterology and Honorary Consultant ­Gastroenterologist Leeds Institute of Medical Research St. James’s University of Leeds Leeds Gastroenterology Institute Leeds Teaching Hospitals Trust Leeds, West Yorkshire, United Kingdom

Paul Feuerstadt, MD

Peter Fickert, Prof

Division of Gastroenterology and Hepatology Medical University of Graz Graz, Austria Robert E. Fleming, MD

Professor of Pediatrics Saint Louis University School of Medicine St. Louis, Missouri, United States

Associate Professor Department of Medicine University of Toronto Staff Hepatologist University Health Network Toronto General Hospital Toronto, Ontario, Canada

Vadivel Ganapathy, PhD

Professor Cell Biology and Biochemistry Texas Tech University Health Sciences Center Lubbock, Texas, United States

John J. Garber, MD

Instructor in Medicine Harvard Medical School Assistant in Medicine Division of Gastroenterology Massachusetts General Hospital Boston, Massachusetts, United States

Praveen Ramakrishnan Geethakumari, MD, MS

Assistant Professor Division of Medical Oncology Department of Internal Medicine University of Texas Southwestern Medical Center Dallas, Texas, United States

Contributors

Marc G. Ghany, MD, MHSc

David J. Hass, MD

Liver Diseases Branch National Institute of Diabetes and Digestive and Kidney ­Diseases National Institutes of Health Bethesda, Maryland, United States

Associate Clinical Professor of Medicine Division of Digestive Diseases Yale University School of Medicine New Haven, Connecticut, United States

Pere Ginès, MD, PhD

Member Clinical Research Fred Hutchinson Cancer Research Center Professor of Medicine Division of Gastroenterology University of Washington Seattle, Washington, United States

Chairman Liver Unit Hospital Clinic Barcelona Full Professor of Medicine University of Barcelona Principal Investigator Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS) Barcelona, Spain

Robert E. Glasgow, MD

Professor and Vice Chairman Surgery University of Utah Salt Lake City, Utah, United States

Gregory J. Gores, MD

Executive Dean for Research, Professor of Medicine Division of Gastroenterology and Hepatology Mayo Clinic Rochester, Minnesota, United States

David M. Hockenbery, MD

Christoph Högenauer, MD

Associate Professor of Medicine Department of Internal Medicine Medical University of Graz Graz, Austria Jacinta A. Holmes, MBBS, PhD

Division of Gastroenterology Massachusetts General Hospital Boston, Massachusetts, United States Gastroenterology St. Vincent’s Hospital University of Melbourne Fitzroy, Victoria, Australia Colin W. Howden, MD

Peter H.R. Green, MD

Phyllis and Ivan Seidenberg Professor of Medicine Columbia University Medical Center New York, New York, United States

Hyman Professor of Medicine Division of Gastroenterology University of Tennessee Health Science Center Memphis, Tennessee, United States

David A. Greenwald, MD

Patrick A. Hughes, PhD

Director of Clinical Gastroenterology and Endoscopy Division of Gastroenterology Mount Sinai Hospital New York, New York, United States

C. Prakash Gyawali, MD, MRCP

Professor of Medicine Division of Gastroenterology Department of Medicine Washington University in St. Louis St. Louis, Missouri, United States

Hazem Hammad, MD

Assistant Professor of Medicine Division of Gastroenterology and Hepatology University of Colorado Anschutz Medical Campus Aurora, Colorado, United States

Heinz F. Hammer, MD

Associate Professor of Medicine Department of Internal Medicine Medical University Graz, Austria

Stephen A. Harrison, MD

Visiting Professor of Hepatology Radcliffe Department of Medicine University of Oxford Oxford, United Kingdom

Centre for Nutrition and Gastrointestinal Diseases Adelaide Medical School University of Adelaide South Australian Health and Medical Research Institute Nutrition and Metabolism Adelaide, South Australia, Australia Sohail Z. Husain, MD

Professor of Pediatrics Division of Gastroenterology, Hepatology, and Nutrition Stanford University School of Medicine Stanford, California, United States Christopher D. Huston, MD

Professor Medicine, Microbiology, and Molecular Genetics University of Vermont College of Medicine Attending Physician Medicine and Infectious Diseases Fletcher Allen Health Care Burlington, Vermont, United States

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M. Nedim Ince, MD

University of Iowa Carver College of Medicine Iowa City, Iowa, United States Department of Internal Medicine Division of Gastroenterology and Hepatology Iowa City VAHCS Department of Internal Medicine Veterans Administration Health Care System Iowa City, Iowa, United States Rachel B. Issaka, MD, MAS

Assistant Member Clinical Research and Public Health Science Divisions Fred Hutchinson Cancer Research Center Assistant Professor Department of Medicine, Division of Gastroenterology University of Washington Seattle, Washington, United States Johanna C. Iturrino, MD

Assistant Professor of Medicine Harvard Medical School Beth Israel Deaconess Medical Center Boston, Massachusetts, United States Theodore W. James, MD

Fellow Division of Gastroenterology University of North Carolina Chapel Hill, North Carolina, United States Harry L.A. Janssen, MD, PhD

Professor of Medicine Gastroenterology and Hepatology University of Toronto Toronto, Ontario, Canada Dennis M. Jensen, MD

Professor of Medicine Professor of Medicine–Gastrointestinal David Geffen School of Medicine at UCLA Staff Physician Medicine-Gastrointestinal VA Greater Los Angeles Healthcare System Key Investigator Director, Human Studies Core and Gastrointestinal Hemostasis Research Unit CURE Digestive Diseases Research Center Los Angeles, California, United States Pamela J. Jensen, MD

Department of Pathology Texas Health Presbyterian Hospital Dallas Dallas, Texas, United States



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Contributors

D. Rohan Jeyarajah, MD

Chair of Surgery Assistant Chair of Clinical Sciences Head of Surgery TCU and UNTHSC School of Medicine Fort Worth, Texas Director, Gastrointestinal Services Methodist Richardson Medical Center Director, HPB/UGI Fellowship Associate Program Director, General Surgery Residency Program Methodist Richardson Medical Center Richardson, Texas, United States Peter J. Kahrilas, MD

Gilbert H. Marquardt Professor of Medicine Feinberg School of Medicine Northwestern University Gastroenterology and Hepatology Northwestern Medicine Chicago, Illinois, United States Vishal Kaila, BS, MD

Resident Internal Medicine Texas Health Presbyterian Dallas, Texas, United States Patrick S. Kamath, MD

Professor of Medicine Division of Gastroenterology and Hepatology Consultant Gastroenterology and Hepatology Mayo Clinic College of Medicine and Science Rochester, Minnesota, United States Gilaad G. Kaplan, MD, MPH

Professor of Medicine University of Calgary Calgary, Alberta, Canada Purna Kashyap, MBBS

Associate Professor of Medicine Physiology and Biomedical Engineering Mayo Clinic Rochester, Minnesota, United States Jennifer Katz, MD

Assistant Professor of Medicine Division of Gastroenterology Montefiore Medical Center Bronx, New York, United States David A. Katzka, MD

Professor of and Consultant in Medicine Gastroenterology Mayo Clinic Rochester, Minnesota, United States Debra K. Katzman, MD, FRCPC

Professor of Pediatrics Department of Pediatrics The Hospital for Sick Children and University of Toronto Toronto, Ontario, Canada

Jonathan D. Kaunitz, MD

Professor of Medicine and Surgery UCLA School of Medicine Attending Gastroenterologist West Los Angeles Veterans Affairs Medical Center Los Angeles, California, United States Laurie Keefer, PhD

Professor Medicine and Psychiatry Icahn School of Medicine at Mount Sinai New York, New York, United States Ciarán P. Kelly, MD

Professor of Medicine Gastroenterology Harvard Medical School Fellowship Program Director Gastroenterology Beth Israel Deaconess Medical Center Boston, Massachusetts, United States Sahil Khanna, MBBS, MS

Associate Professor of Medicine Gastroenterology and Hepatology Mayo Clinic Rochester, Minnesota, United States Arthur Y. Kim, MD

Associate Professor of Medicine Harvard Medical School Division of Infectious Diseases Massachusetts General Hospital Boston, Massachusetts, United States Kenneth L. Koch, MD

Professor of Medicine Department of Medicine Section on Gastroenterology and Hepatology Wake Forest University School of Medicine Winston-Salem, North Carolina, United States Benjamin Kulow, MD

Colon and Rectal Surgeon Saint Luke’s Health System Kansas City, Missouri, United States Rekha B. Kumar, MD, MS

Assistant Professor of Medicine Endocrinology, Diabetes, and Metabolism Weill Cornell Medical College Attending Physician Endocrinology, Diabetes, and Metabolism New York Presbyterian Hospital New York, New York, United States Vidhya Kunnathur, MD

Assistant Professor Division of Digestive Diseases University of Cincinnati Cincinnati, Ohio, United States Joann Kwah, MD

Assistant Professor of Medicine Albert Einstein College of Medicine Gastroenterology Montefiore Medical Center Bronx, New York, United States

Brian E. Lacy, MD, PhD

Senior Associate Consultant Division of Gastroenterology Mayo Clinic Jacksonville, Florida, United States

Anne M. Larson, MD

Professor of Medicine Division of Gastroenterology/ Hepatology University of Washington Seattle, Washington, United States

James Y.W. Lau, MD

Professor of Surgery Department of Surgery The Chinese University of Hong Kong Director Endoscopy Centre Prince of Wales Hospital Hong Kong, China

Ryan Law, DO

Assistant Professor Division of Gastroenterology University of Michigan Ann Arbor, Michigan, United States

Benjamin Lebwohl, MD, MS

Assistant Professor of Medicine and Epidemiology Columbia University Medical Center New York, New York, United States

Anthony J. Lembo, MD

Professor of Medicine Department of Medicine Beth Israel Deaconess Medical Center Boston, Massachusetts, United States

Cynthia Levy, MD

Professor of Medicine Division of Hepatology University of Miami Miami, Florida, United States

Blair Lewis, MD

Medical Director Carnegie Hill Endoscopy Clinical Professor of Medicine Mount Sinai Medical Center New York, New York, United States

James H. Lewis, MD

Professor of Medicine Director of Hepatology Division of Gastroenterology Georgetown University Medical Center Washington, DC, United States

Rodger A. Liddle, MD

Professor of Medicine Department of Medicine Duke University Medical Center Durham, North Carolina, United States

Steven D. Lidofsky, MD, PhD

Professor of Medicine University of Vermont Director of Hepatology University of Vermont Medical Center Burlington, Vermont, United States

Contributors

Keith D. Lindor, MD

Senior Advisor and Professor Office of the University Provost Arizona State University Medicine Gastroenterology and Hepatology Mayo Clinic Hospital Phoenix, Arizona, United States

Mark E. Lowe, MD, PhD

Harvey R. Colton Professor of Pediatric Science and Vice Chair Department of Pediatrics Washington University School of Medicine St. Louis, Missouri, United States

Cara L. Mack, MD

Professor of Pediatrics University of Colorado School of Medicine Children’s Hospital Colorado Aurora, Colorado, United States

Ryan D. Madanick, MD

Assistant Professor of Medicine Division of Gastroenterology and Hepatology University of North Carolina School of Medicine Chapel Hill, North Carolina, United States

Willis C. Maddrey, MD

Special Assistant to the President Professor of Internal Medicine Arnold N. and Carol S. Ablon Professorship in Biomedical Science Adelyn and Edmund M. Hoffman Distinguished Chair in Medical Science University of Texas Southwestern Medical Center Dallas, Texas, United States

Matthias Maiwald, MD, PhD

Senior Consultant in Microbiology Department of Pathology and Laboratory Medicine KK Women’s and Children’s Hospital, Singapore Adjunct Associate Professor Department of Microbiology and Immunology Yong Loo Lin School of Medicine National University of Singapore Adjunct Associate Professor Duke-NUS Graduate Medical School Singapore, Singapore

Ricard Masia, MD, PhD

Associate Director, Translational Pathology Surface Oncology Cambridge, Massachusetts, United States Joel B. Mason, MD

Professor of Medicine and Nutrition Divisions of Gastroenterology and Clinical Nutrition Tufts University Director Vitamins and Carcinogenesis Laboratory USDA Human Nutrition Research Center at Tufts University Boston, Massachusetts, United States Jeffrey B. Matthews, MD

Dallas B. Phemister Professor and Chairman Department of Surgery The University of Chicago Medicine Chicago, Illinois, United States Craig J. McClain, MD

Professor of Medicine and Pharmacology and Toxicology Vice President for Health Affairs and Research University of Louisville Director Gastroenterology Robley Rex VA Medical Center Louisville, Kentucky, United States

Ginat W. Mirowski, DMD, MD

Adjunct Clinical Professor Department of Oral Pathology, Medicine, and Radiology Indiana University School of Dentistry Professor of Clinical Dermatology (Clinical Track) Department of Dermatology Indiana University School of Medicine Indianapolis, Indiana, United States Joseph Misdraji, MD

Associate Professor of Pathology Harvard Medical School Associate Pathologist Massachusetts General Hospital Boston, Massachusetts, United States Daniel S. Mishkin, MD, CM

Chief of Gastroenterology Atrius Health Boston, Massachusetts, United States Bijal Modi, MD

Stephen A. McClave, MD

Shilpa Mehra, MD

Vice Chair for Quality Department of Surgery Chief Bariatric and Minimally Invasive Surgery Yale School of Medicine Department of Surgery New Haven, Connecticut, United States

Professor and Director of Clinical Nutrition Department of Medicine University of Louisville School of Medicine Louisville, Kentucky, United States Assistant Professor of Medicine Department of Medicine Division of Gastroenterology Albert Einstein College of Medicine Bronx, New York, United States Megha S. Mehta, MD

Assistant Professor of Pediatrics University of Texas Southwestern Medical Center Dallas, Texas, United States Shivang S. Mehta, MD

Lawrence A. Mark, MD, PhD

Paul Martin, MD, FRCP, FRCPI

Assistant Professor of Medicine Johns Hopkins University School of Medicine Baltimore, Maryland, United States

Chief, Division of Gastroenterology and Hepatology University of Miami Miami, Florida, United States

Frederick H. Millham, MD, MBA

Chair, Surgery South Shore Hospital Weymouth, Massachusetts Associate Professor of Surgery (Part Time) Harvard Medical School Boston, Massachusetts, United States

Department of Internal Medicine Division of Hematology and Oncology Texas Health Presbyterian Hospital Dallas Dallas, Texas, United States

Pediatric Gastroenterology Fellow Department of Pediatric Gastroenterology University of Texas Southwestern Medical Center Dallas, Texas, United States

Associate Professor of Clinical Dermatology Department of Dermatology Indiana University School of Medicine Indianapolis, Indiana, United States

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Joanna M.P. Melia, MD

John Magaña Morton, MD, MPH, MHA

William Conan Mustain, MD

Assistant Professor of Surgery Division of Colon and Rectal Surgery University of Arkansas for Medical Sciences Little Rock, Arkansas, United States Filipe Gaio Nery, MD

Physician Departamento de Anestesiologia, Cuidados Intensivos e Emergência Centro Hospitalar do Porto–Hospital Santo António, Porto Researcher, EPIUnit Instituto de Saúde Pública, Universidade do Porto, Porto Researcher, Ciências Médicas Instituto de Ciências Biomédicas de Abel Salazar Porto, Portugal



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Contributors

Siew C. Ng, MBBS (Lond), PhD (Lond)

Patrick R. Pfau, MD

Christopher K. Rayner, MBBS, PhD

Professor of Medicine Department of Medicine and Therapeutics State Key Laboratory of Digestive Disease LKS Institute of Health Science The Chinese University of Hong Kong Hong Kong, China

Professor, Chief of Clinical Gastroenterology Section of Gastroenterology and Hepatology University of Wisconsin School of Medicine and Public Health Madison, Wisconsin, United States

Mark L. Norris, BSc (Hon), MD

Clinical Assistant Professor Gastroenterology, Hepatology, and Nutrition University of Florida Gainesville, Florida, United States

Ahsan Raza, MD

Kimberly L. Pham, MD

Chair and Professor of Medicine Department of Gastroenterology and Hepatology Cleveland Clinic, Digestive Disease and Surgery Institute Cleveland, Ohio, United States

Associate Professor of Pediatrics Pediatrics Children’s Hospital of Eastern Ontario University of Ottawa Ottawa, Ontario, Canada John O’Grady, MD, FRCPI

Professor Institute of Liver Studies King’s College Hospital London, United Kingdom Manisha Palta, MD

Associate Professor Radiation Oncology Duke University Durham, North Carolina, United States

Angela K. Pham, MD

St. George’s University Grenada West Indies, Grenada Daniel S. Pratt, MD

Clinical Director, Liver Transplantation Division of Gastroenterology Massachusetts General Hospital Assistant Professor of Medicine Harvard Medical School Boston, Massachusetts, United States David O. Prichard, MB, BCh, PhD

Stephen J. Pandol, MD

Gastroenterologist Gastroenterology and Hepatology Mayo Clinic Rochester, Minnesota

John E. Pandolfino, MD, MSCI

Technische Universität München II Medizinische Klinik Klinikum rechts der Isar München, Germany

Professor Medicine Cedars-Sinai Medical Center Los Angeles, California, United States Hans Popper Professor of Medicine Feinberg School of Medicine Northwestern University Division Chief Gastroenterology and Hepatology Northwestern Medicine Chicago, Illinois, United States Darrell S. Pardi, MD, MS

Vice Chair Division of Gastroenterology and Hepatology Associate Dean Mayo School of Graduate Medical Education Mayo Clinic Rochester, Minnesota, United States Michelle Pearlman, MD

Professor of Medicine Department of Internal Medicine, Division of Digestive and Liver Diseases University of Texas Southwestern Dallas, Texas, United States Vyjeyanthi S. Periyakoil, MD

Director, Palliative Care Education and Training Department of Medicine Stanford University School of Medicine Stanford, California, United States

Michael Quante, PD, Dr

Eamonn M.M. Quigley, MD

Professor of Medicine and Chief, Gastroenterology and Hepatology David M. and Lynda K. Underwood Center for Digestive Disorders Houston Methodist Hospital Weill Cornell Medical College Houston, Texas, United States Balakrishnan S. Ramakrishna, MBBS, MD, DM, PhD

Head Institute of Gastroenterology SRM Institutes for Medical Science Chennai, Tamil Nadu, India Mrinalini C. Rao, PhD

Professor Department of Physiology and Biophysics University of Illinois at Chicago Chicago, Illinois, United States Satish S.C. Rao, MD, PhD

Professor of Medicine Harold J. Harrison, MD, Distinguished University Chair in Gastroenterology Medicine-Gastroenterology/Hepatology Augusta University Augusta, Georgia, United States

Professor Adelaide Medical School University of Adelaide Consultant Gastroenterologist Department of Gastroenterology and Hepatology Royal Adelaide Hospital Adelaide, South Australia, Australia General and Colorectal Surgery Rapides Surgical Specialists Alexandria, Louisiana, United States

Miguel D. Regueiro, MD

John F. Reinus, MD

Professor of Medicine Department of Medicine Albert Einstein College of Medicine Medical Director of Liver Transplantation Montefiore-Einstein Center for Transplantation Montefiore Medical Center Bronx, New York, United States

David A. Relman, MD

Thomas C. and Joan M. Merigan Professor Departments of Medicine and Microbiology and Immunology Stanford University Stanford, California Chief of Infectious Diseases Veterans Affairs Palo Alto Health Care System Palo Alto, California, United States

Arvind Rengarajan, MD

Barnes-Jewish Hospital Department of Internal Medicine Washington University in St. Louis St. Louis, Missouri, United States

Joel E. Richter, MD

Professor and Director Division of Digestive Diseases and Nutrition University of South Florida Director Joy McCann Culverhouse Center for Swallowing Disorders University of South Florida Tampa, Florida, United States

Sumera H. Rizvi, MD

Assistant Professor of Medicine Division of Gastroenterology and Hepatology Mayo Clinic Rochester, Minnesota, United States

Contributors

Syed Mujtaba Rizvi, MD

Assistant Professor Division of Medical Oncology Department of Internal Medicine UT Southwestern Medical Center Dallas, Texas, United States

Eve A. Roberts, MD, PhD

Adjunct Professor Pediatrics, Medicine, and Pharmacology and Toxicology University of Toronto Adjunct Scientist Genetics and Genome Biology Program Hospital for Sick Children Research Institute Associate Division of Gastroenterology, Hepatology, and Nutrition The Hospital for Sick Children Toronto, Ontario, Canada Associate Fellow History of Science and Technology Program University of King’s College Halifax, Nova Scotia, Canada

Martin D. Rosenthal, MD

Assistant Professor Surgery University of Florida Gainesville, Florida, United States

Marc E. Rothenberg, MD, PhD

Professor of Pediatrics Cincinnati Children’s Hospital Medical Center Cincinnati, Ohio, United States

Jayanta Roy-Chowdhury, MBBS

Professor Departments of Medicine and Genetics Director, Genetic Engineering and Gene Therapy Core Facility Albert Einstein College of Medicine New York, New York, United States

Namita Roy-Chowdhury, PhD

Professor Departments of Medicine and Genetics Albert Einstein College of Medicine New York, New York, United States

David T. Rubin, MD

Joseph B. Kirsner Professor of Medicine Chief, Section of Gastroenterology, Hepatology, and Nutrition Department of Medicine University of Chicago Chicago, Illinois, United States

Jayashree Sarathy, PhD

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Vijay H. Shah, MD

Associate Professor Department of Biological Sciences Program Director of Master of Science in Integrative Physiology Benedictine University Lisle, Illinois Visiting Research ­Professor Department of Physiology and ­Biophysics University of Illinois at Chicago Chicago, Illinois, United States

Professor Medicine, Physiology, and Cancer Cell Biology Chair Division of Gastroenterology and Hepatology Associate Chair of Research Medicine Mayo Clinic College of Medicine and Science Rochester, Minnesota, United States

George S. Sarosi Jr., MD

John P. Thompson Chair Surgical Services Texas Health Presbyterian Hospital Dallas Dallas, Texas, United States

Robert H. Hux MD Professor and Vice Chairman for Education Department of Surgery University of Florida College of Medicine Staff Surgeon Surgical Service NF/SG VAMC Gainesville, Florida, United States Thomas J. Savides, MD

Professor of Clinical Medicine Division of Gastroenterology University of California San Diego La Jolla, California, United States Lawrence R. Schiller, MD

Attending Physician Gastroenterology Division Baylor University Medical Center Dallas, Texas, United States Mitchell L. Schubert, MD

Professor of Medicine and Physiology Virginia Commonwealth University Health System Chief, Division of Gastroenterology, Hepatology, and Nutrition McGuire Veterans Affairs Medical Center Richmond, Virginia, United States Cynthia L. Sears, MD

Professor of Medicine and Oncology Johns Hopkins University School of Medicine Baltimore, Maryland, United States Joseph H. Sellin, MD

Professor Emeritus Division of Gastroenterology Baylor College of Medicine Chief of Gastroenterology Ben Taub General Hospital Houston, Texas, United States M. Gaith Semrin, MD, MBBS

Associate Professor Pediatric Gastroenterology and Nutrition UT Southwestern Medical Center Children Medical Center Dallas Dallas, Texas, United States

G. Thomas Shires, MD

Maria H. Sjogren, MD, MPH

Senior Hepatologist Department of Medicine Walter Reed National Medical Center Bethesda, Maryland, United States Phillip D. Smith, MD

Professor of Medicine and Microbiology University of Alabama at Birmingham Birmingham, Alabama, United States Elsa Solà, MD, PhD

Liver Unit Hospital Clinic Associate Professor University of Barcelona Researcher Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS) Barcelona, Spain Rhonda F. Souza, MD

Co-Director, Center for Esophageal Diseases Department of Medicine Baylor University Medical Center Co-Director, Center for Esophageal Research Baylor Scott and White Research Institute Dallas, Texas, United States Cedric W. Spak, MD, MPH

Clinical Assistant Professor Infectious Diseases Baylor University Medical Center Staff Physician Infectious Diseases Texas Centers for Infectious Disease Associates Dallas, Texas, United States Stuart Jon Spechler, MD

Chief, Division of Gastroenterology Co-Director, Center for Esophageal Research Department of Medicine Baylor University Medical Center at Dallas Co-Director, Center for Esophageal Research Baylor Scott and White Research Institute Dallas, Texas, United States



xiv

Contributors

James E. Squires, MD, MS

Assistant Professor Department of Pediatrics UPMC Children’s Hospital of Pittsburgh Pittsburgh, Pennsylvania, United States Neil H. Stollman, MD

Associate Clinical Professor Department of Medicine, Division of Gastroenterology University of California San Francisco San Francisco, California Chief Division of Gastroenterology Alta Bates Summit Medical Center Oakland, California, United States Sarah E. Streett, MD

Clinical Associate Professor Director IBD Education Division of Gastroenterology and Hepatology Stanford University Redwood City, California, United States Jonathan R. Strosberg, MD

Associate Professor Gastrointestinal Oncology Moffitt Cancer Center Tampa, Florida, United States Frederick J. Suchy, MD

Children’s Hospital Colorado Professor of Pediatrics and Associate Dean for Child Health Research Pediatrics University of Colorado School of Medicine Aurora, Colorado, United States Aravind Sugumar, MD

Instructor Gastroenterology and Hepatology Cleveland Clinic Foundation Cleveland, Ohio, United States Shelby Sullivan, MD

Associate Professor of Medicine Director, Gastroenterology Metabolic and Bariatric Program Division of Gastroenterology and Hepatology University of Colorado Anschutz Medical Campus Aurora, Colorado, United States Gyongyi Szabo, MD, PhD

Mitchell T. Rabkin, MD Chair Chief Academic Officer Beth Israel Deaconess Medical Center and Beth Israel Lahey Health Faculty Dean for Academic Affairs Harvard Medical School Boston, Massachusetts, United States

Jan Tack, MD, PhD

Head, Division of Gastroenterology and Hepatology Leuven University Hospitals Professor of Medicine Translational Research Center for Gastrointestinal Disorders (TARGID) Department of Clinical and Experimental Medicine University of Leuven Leuven, Belgium Nicholas J. Talley, MD, PhD

Distinguished Laureate Professor Faculty of Health and Medicine University of Newcastle, Australia Newcastle, New South Wales, Australia Jarred P. Tanksley, MD, PhD

Resident Radiation Oncology Duke University Durham, North Carolina, United States Narci C. Teoh, MD

Professor of Medicine Australian National University Senior Staff Hepatologist The Canberra Hospital Australian Capital Territory, Australia Dawn M. Torres, MD

Program Director GI Fellowship Department of Medicine Walter Reed National Military Medical Center Associate Professor of Medicine Department of Medicine Uniformed Services University of the Health Sciences Bethesda, Maryland, United States Kiran Turaga, MD, MPH

Associate Professor Department of Surgery The University of Chicago Chicago, Illinois, United States Richard H. Turnage, MD

Executive Associate Dean for Clinical Affairs Professor of Surgery University of Arkansas for Medical Sciences Medical Center University of Arkansas for Medical Sciences Little Rock, Arkansas, United States Michael F. Vaezi, MD, PhD, MS

Professor of Medicine and ­Otolaryngology Division of Gastroenterology and ­Hepatology Vanderbilt University Director Center for Swallowing and Esophageal Disorders Vanderbilt University Medical Center Director Clinical Research Vanderbilt University Medical Center Nashville, Tennessee, United States

Dominique Charles Valla, MD

Professor of Hepatology Liver Unit Hôpital Beaujon, APHP, Clichy-la-Garenne France CRI, UMR1149 Inserm and Université de Paris Paris, France

John J. Vargo II, MD, MPH

Associate Professor of Medicine Gastroenterology and Hepatology Cleveland Clinic Cleveland, Ohio, United States

Santhi Swaroop Vege, MD

Professor of Medicine and Director Pancreas Group Gastroenterology and Hepatology Mayo Clinic Rochester, Minnesota, United States

Axel von Herbay, MD

Professor of Pathology Faculty of Medicine University of Heidelberg Heidelberg Hans Pathologie Hamburg, Germany

Margaret von Mehren, MD

Professor Department of Hematology/Oncology Fox Chase Cancer Center Philadelphia, Pennsylvania, United States

David Q.-H. Wang, MD, PhD

Professor of Medicine Departments of Medicine and Genetics Director, Molecular Biology and Next Generation Technology Core Marion Bessin Liver Research Center Albert Einstein College of Medicine Bronx, New York, United States

Sachin Wani, MD

Associate Professor of Medicine Division of Gastroenterology and Hepatology University of Colorado Anschutz Medical Campus Aurora, Colorado, United States

Frederick Weber, MD

Clinical Professor Division of Gastroenterology and Hepatology University of Alabama Birmingham Birmingham, Alabama, United States

Barry K. Wershil, MD

Professor Pediatrics Northwestern University Feinberg School of Medicine Chief, Division of Gastroenterology, Hepatology, and Nutrition Pediatrics Ann & Robert H. Lurie Children’s Hospital of Chicago Chicago, Illinois, United States

Contributors

David C. Whitcomb, MD, PhD

Christopher G. Willett, MD

Professor Medicine, Cell Biology and Molecular Physiology, and Human Genetics University of Pittsburgh and UPMC Pittsburgh, Pennsylvania, United States

Professor and Chairman Radiation Oncology Duke University Durham, North Carolina, United States

C. Mel Wilcox, MD, MSPH

Assistant Professor of Medicine Harvard Medical School Associate Physician Division of Gastroenterology Massachusetts General Hospital Boston, Massachusetts, United States

Division of Gastroenterology and ­Hepatology University of Alabama at Birmingham Birmingham, Alabama, United States

Joseph C. Yarze, MD

xv

Anahit A. Zeynalyan, MD

Resident Internal Medicine Baylor University Medical Center Dallas, Texas, United States



Foreword Even attempting to write a Foreword for the 11th edition of Sleisenger and Fordtran’s Gastrointestinal and Liver Disease: Pathophysiology/Diagnosis/Management, a textbook that has served for many decades to prepare readers to respond to challenges presented by patients with gastrointestinal and liver disease, is a daunting task and yet a great pleasure. Just having achieved an 11th edition of a textbook is, in and of itself, a remarkable accomplishment. Generations of gastroenterologists and hepatologists have relied on Sleisenger and Fordtran to provide comprehensive, up-to-date, reliable information. The 11th edition is a welcome addition to the previous editions, which have been widely acclaimed as important go-to sources of information regarding the broad array of disorders affecting the gastrointestinal tract and the liver. Over the past half century, these volumes have been mainstays in the libraries of those engaged in these fields. Since its inception 10 editions ago, this now classic textbook has tracked the evolution of thinking in multiple areas and has served readers well. These days, there are everexpanding ways for those of us interested in gastroenterology and hepatology to be stimulated, informed, educated, and refreshed. Lectures, conversations with colleagues, and attendance at local, regional, and national meetings have their roles, and we all learn from our patients. Perusal of relevant articles in medical journals is increasingly difficult in an era in which the number of available journals has increased remarkably. The practicing clinician, given present-day time constraints, will more than ever find this textbook reliable, informative, and useful. In these two volumes are overviews of what is known now and glimpses of what the future is likely to bring. A blend of skill, knowledge, practical experience, and the ability to teach is required of the authors in order to achieve these goals. Overall, these efforts have been successful in presenting accurate and comprehensive updates in our fields of interest and serve us well as a look to our past, provide reflections regarding our present, and delineate problems yet to be solved. We are fortunate to live in exciting and rapidly changing times in gastroenterology and hepatology. The sheer volume of new ideas presented in multiple journals is stimulating and often overwhelming. Each of us must evaluate and assimilate new information while making efforts to appropriately incorporate the new advances into our practices. To stay up to date and achieve our goals requires considerable effort and dedication (Even COVID-19 is mentioned several times throughout the book.). There is comfort in having available a reliable and trusted guide to refresh and stimulate us. The 11th edition of Sleisenger and Fordtran provides a firm, authoritative platform regarding what is established knowledge and identifies where progress is being made to prepare us to be better armed for the foreseeable future. We all need to be informed of the likely validity and usefulness of new observations. It is vital that we recognize the degree of certainty of the data that led to our conclusions. There have been (and will be) definite game-changing advances and also many seemingly good ideas and approaches that turn out to be sidesteps. New concepts must be recognized, double-checked, processed, and then incorporated into our thinking, subsequently affecting our actions. The breadth of subjects covered in depth in these two volumes is impressive. I had the honor to write the Foreword to the 9th edition published in 2010. When comparing the expansion of knowledge from then to now, one can appreciate where we have

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been in the recent past and what we hope (and expect) to achieve in the future. A trusted book provides a helpful guide that is readily available at moments of uncertainty. A comparison of an individual chapter from a past edition and what we have now further validates the conclusion that progress is being made, and the future of our specialty is encouraging. The three senior editors and three associate editors of the 11th edition are foremost authorities and widely recognized for their abilities to identify topics of interest and to persuade experts in these areas to share their knowledge. To write an updated review of one’s field can be a Herculean task that requires not only knowledge but also courage. The editors have surely succeeded. The careful selection of authors of individual chapters allows each to bring his or her own style regarding what to emphasize; to lay out what we know, as well as what we need to know, to diagnose and effectively treat specific problems; and to provide suggestions and guidance as to how to manage patients while integrating new observations into practice. With regard to the liver section, the current state of knowledge about hepatitis-inducing viruses and drug-induced liver diseases and the tsunami of interest in the many consequences of the effects of excessive fat in the liver in the causation of chronic liver diseases are breathtaking. These achievements have been wellchronicled journeys with opportunities (and hope) for even more effective therapeutic agents in the near future. Just one edition ago, we were on the threshold of having effective, widely applicable treatments for the several types of viral hepatitis; much of what we hoped for has been achieved. It is now likely that there will be discovery of therapeutic approaches that will favorably affect the broad array of fat-related liver injuries, including their association with cardiovascular disorders. Widely available access to advanced endoscopy has changed the approach to the evaluation and treatment of many disorders of the gastrointestinal tract, bile ducts, and pancreas. Furthermore, who could have foreseen just a few years ago how advances in biological therapies and minimally invasive surgery would so redirect our treatments of a broad array of disorders or how important the gut microbiome would be in the pathogenesis of many disorders. Once we understand how to favorably alter the gut microbiome, major leaps forward can be expected. What is next? Gene editing and an understanding of intestinal microbiota, now in their infancy, will receive much deserved attention in the next few years. With each passing year, advances in manipulation of the human genome and intestinal microbiota are becoming more precise and require constant, thoughtful oversight to ensure that we do what we should do and not just what we can do. In this edition, we have blueprints and predictions of the future for many aspects of our specialty. It is important to discard old ideas that have not proved effective while constantly re-examining the basis for what we think we know and appropriately altering what we do. We all marvel when we see what has been (and is) happening in medicine and the effects of these advances in gastroenterology and hepatology. Surely, the best is yet to come, and we all hope that what we are learning and applying now will stimulate us to create an even better future. Willis C. Maddrey, MD Dallas, Texas

The Sleisenger and Fordtran Editors

Mark Feldman, MD

Lawrence S. Friedman, MD

Lawrence J. Brandt, MD

Editions 5-11

Editions 7-11

Editions 8-11

Raymond T. Chung, MD

David T. Rubin, MD

C. Mel Wilcox, MD

Edition 11

Edition 11

Edition 11

Marvin H. Sleisenger, MD

John S. Fordtran, MD

Bruce F. Scharschmidt, MD

Editions 1-7

Editions 1-5

Editions 5-6

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Preface Nearly a half century ago, in the summer of 1971, Drs. Marvin H. Sleisenger in San Francisco and John S. Fordtran in Dallas embarked on a new venture: planning, writing, and editing the inaugural edition of a new textbook for gastroenterologists. The book received widespread praise for incorporating stateof-the-art descriptions of the pathophysiology of the d ­ isorders ­discussed—a first for a medical textbook. Since the a­ uspicious debut of Gastrointestinal Disease: Pathophysiology/Diagnosis/ Management, subsequent editions have been published every 4 to 5 years, and we are pleased that the 11th edition of this venerable textbook continues the tradition and standards set by the founding editors. To be sure, innumerable enhancements have been made since the 1st edition, such as the addition of chapters on liver diseases, the availability of the book online and on hand-held devices, the introduction of monthly updates to bring attention to important new developments that occur between editions, the incorporation of videos of new diagnostic and therapeutic procedures, and the participation of authors from around the world to give the book a truly international flavor. In the summer of 2017, the current editors met with the publisher and reviewed the prior (10th) edition of the book in great detail. Most importantly, the core group of 3 senior editors invited 3 associate editors (Drs. Raymond T. Chung, David T. Rubin, and C. Mel Wilcox) to join them in order to facilitate critical review of the chapters, to help select the most expert authors, and to provide greater content expertise. Each associate editor worked closely with a senior editor. The result, we hope, is an easily readable, carefully edited, highly accurate, and thorough review of the state of the art of gastrointestinal and liver disease. The target audience is primarily practicing gastroenterologists and hepatologists (adult and pediatric) and trainees in gastroenterology. We hope the book will also be useful to general internists, other specialists, and students at all levels.

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As one looks back 50 years, the advances made in our field as a result of rigorous basic science and clinical research have been truly remarkable, and the future holds even greater promise of discovery. Featured advances discussed in the 11th edition include improved diagnosis and treatment of chronic hepatitis B and C; evolution in the diagnosis and treatment of Helicobacter pylori infection and the resulting benefits on the prevention and treatment of peptic ulcer disease and gastric neoplasia; improvements in the prevention of colorectal cancer through screening and surveillance; new approaches to the recognition and treatment of Barrett esophagus and consequent prevention of esophageal adenocarcinoma; the expanding use of biologic agents and novel small molecules to treat and prevent recurrences of IBD; recognition of an increasing number of immune and autoimmune diseases affecting not only the stomach and hepatobiliary system but also the pancreas and intestine; improvements in the ability to risk stratify and treat patients with GI bleeding; and continuing progress in hepatic, pancreatic, and small bowel transplantation. There have been remarkable advances in our understanding the gut microbiome, which is becoming the focus of interest in diverse fields, such as IBS, IBD, obesity, hepatic encephalopathy, and others, including non-GI disorders. We are particularly pleased to have completely redesigned the section on IBD by reorganizing and updating the discussions of pathophysiology, clinical presentation, and management, all of which are evolving rapidly. Sadly, the original co-founder of this textbook, Dr. Marvin H. Sleisenger, passed away on October 19, 2017, at the age of 93. Marvin will be greatly missed, and we trust that this 11th edition would have met with his approval and commendation. Mark Feldman, MD Lawrence S. Friedman, MD Lawrence J. Brandt, MD

Acknowledgments The editors and associate editors of the 11th edition of Sleisenger & Fordtran’s Gastrointestinal and Liver Disease are most grateful to the more than 230 authors from countries in North America, Europe, Asia, and Australia who contributed their knowledge, expertise, and wisdom to the pages of the book. We are also appreciative of the talented staff at Elsevier who helped bring this book to life, particularly Nancy Duffy, Dolores Meloni, and Deidre Simpson. A special call out goes to Cindy Thoms, who oversaw production of the book. We are most thankful to our assistants, Sherie Strang, Alison Sholock, Amy Nash, and Amy Majkowski, for outstanding secretarial support. We want to

thank Dr. Willis C. Maddrey of the University of Texas Southwestern for his eloquent Foreword, the second time he has been called on to do this honor for Sleisenger & Fordtran. We remember with affection Dr. Marvin H. Sleisenger, who passed away as the 11th edition of the book he co-­created was being prepared, and pay tribute to Dr. John S. Fordtran for his continuing inspiration and contributions. We are deeply appreciative of the love and support of our spouses: Barbara Feldman, Mary Jo Cappuccilli, Lois Brandt, Kim Wilcox, Diane Abraczinskas, and Rebecca Rubin. Finally, we thank our readers, to whom the book is dedicated, for their confidence and trust in this textbook.

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Abbreviation List AASLD  American Association for the Study of Liver Diseases ACG  American College of Gastroenterology ACTH Corticotropin AE Angioectasia AFP  Alpha fetoprotein AGA  American Gastroenterological Association AIDS  Acquired immunodeficiency syndrome ALF  Acute liver failure ALT  Alanine aminotransferase AMA  Antimitochondrial antibodies ANA  Antinuclear antibodies ANCA  Antineutrophil cytoplasmic antibodies APACHE  Acute physiology and chronic health ­examination APC  Argon plasma coagulation ASGE  American Society for Gastrointestinal Endoscopy AST  Aspartate aminotransferase ATP  Adenosine triphosphate BICAP  Bipolar electrocoagulation BMI  Body mass index BRBPR  Bright red blood per rectum CBC  Complete blood count CCK Cholecystokinin CEA  Carcinoembryonic antigen CDI Clostridioides difficile infection CF  Cystic fibrosis CFTR  Cystic fibrosis transmembrane conductance ­regulator CMV Cytomegalovirus CNS  Central nervous system CO2  Carbon dioxide COX Cyclooxygenase CT  Computed tomography CTA  Computed tomography angiography DAA  Direct-acting antiviral agent DIC  Disseminated intravascular coagulation DILI  Drug-induced liver injury DNA  Deoxyribonucleic acid DU  Duodenal ulcer DVT  Deep vein thrombosis EBV  Epstein-Barr virus EGD Esophagogastroduodenoscopy EGF  Epidermal growth factor EMG Electromyography ERCP  Endoscopic retrograde cholangiopancreatography  

ESR  Erythrocyte sedimentation rate EUS  Endoscopic ultrasonography FDA  U.S. Food and Drug Administration FNA  Fine-needle aspiration GAVE  Gastric antral vascular ectasia GERD  Gastroesophageal reflux disease GGTP  Gamma glutamyl transpeptidase GI Gastrointestinal GIST  GI stromal tumor GU  Gastric ulcer H & E  Hematoxylin and eosin H2RA  Histamine-2 receptor antagonist HAV  Hepatitis A virus HBV  Hepatitis B virus HCC  Hepatocellular carcinoma HCG  Human chorionic gonadotropin HCV  Hepatitis C virus HDL  High-density lipoprotein HDV  Hepatitis D virus HELLP  Hemolysis, elevated liver enzymes, low platelets HEV  Hepatitis E virus Hgb Hemoglobin HHT  Hereditary hemorrhagic telangiectasia HIV  Human immunodeficiency virus HLA  Human leukocyte antigen HPV  Human papillomavirus HSV  Herpes simplex virus Hp Helicobacter pylori IBD  Inflammatory bowel disease IBS  Irritable bowel syndrome ICU  Intensive care unit IMA  Inferior mesenteric artery IMT  Intestinal microbiota transplantation INR  International normalized ratio IV Intravenous IVIG  Intravenous immunoglobulin LDH  Lactate dehydrogenase LDL  Low-density lipoprotein LGI  Lower gastrointestinal LGIB  Lower gastrointestinal bleed LLQ  Left lower quadrant LT  Liver transplantation LUQ  Left upper quadrant MELD  Model for end-stage liver disease MEN  Multiple endocrine neoplasia  

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Abbreviation List

MHC  Major histocompatibility complex MRA  Magnetic resonance angiography MRCP  Magnetic resonance cholangiopancreatography MRI  Magnetic resonance imaging NAFLD  Nonalcoholic fatty liver disease NASH  Nonalcoholic steatohepatitis NG Nasogastric NPO  Nil per os (nothing by mouth) NSAID(s)  Nonsteroidal anti-inflammatory drug(s) O2 Oxygen PBC  Primary biliary cholangitis PCR  Polymerase chain reaction PET  Positron emission tomography PPI  Proton pump inhibitor PSC  Primary sclerosing cholangitis PSE  Portosystemic encephalopathy PUD  Peptic ulcer disease RA  Rheumatoid arthritis RLQ  Right lower quadrant RNA  Ribonucleic acid RUQ  Right upper quadrant SBO  Small bowel obstruction

SBP  Spontaneous bacterial peritonitis SIBO  Small intestinal bacterial overgrowth SLE  Systemic lupus erythematosus SOD  Sphincter of Oddi dysfunction TB Tuberculosis TG Triglyceride(s) TIPS  Transjugular intraheptic portosystemic shunt TNF  Tumor necrosis factor TNM  Tumor node metastasis TPN  Total parenteral nutrition UC  Ulcerative colitis UDCA  Ursodeoxycholic acid UGI  Upper gastrointestinal UGIB  Upper gastrointestinal bleed UGIS  Upper gastrointestinal series UNOS  United Network for Organ Sharing US Ultrasonography USA  United States of America VLDL  Very-low-density lipoprotein WBC  White blood cell WHO  World Health Organization ZES  Zollinger-Ellison syndrome

PART I

1

Biology of the Gastrointestinal Tract

Cellular Growth and Neoplasia Ezra Burstein

CHAPTER OUTLINE MECHANISMS OF NORMAL TISSUE HOMEOSTASIS . . . . . . . 1 Cellular Proliferation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Apoptosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Senescence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Signaling Pathways That Regulate Cellular Growth . . . . . . . 3 INTESTINAL TUMOR DEVELOPMENT . . . . . . . . . . . . . . . . . . . 5 Multistep Formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Clonal Expansion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Cancer Stem Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Epithelial-Mesenchymal Transition . . . . . . . . . . . . . . . . . . . 5 NEOPLASIA-ASSOCIATED GENES . . . . . . . . . . . . . . . . . . . . . 6 Oncogenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Oncogenic Growth Factors and Growth Factor Receptors . . . 7 Nuclear Oncogenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Tumor Suppressor Genes . . . . . . . . . . . . . . . . . . . . . . . . . . 8 DNA Repair Genes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 Noncoding RNAs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 Oncogenic Signaling Pathways . . . . . . . . . . . . . . . . . . . . . 10 TUMOR MICROENVIRONMENT . . . . . . . . . . . . . . . . . . . . . . . 10 TUMOR METABOLISM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 Inflammation and Cancer . . . . . . . . . . . . . . . . . . . . . . . . . 10 Microbiome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 BIOLOGICAL FEATURES OF TUMOR METASTASIS . . . . . . . . 11 Angiogenesis and Lymphangiogenesis . . . . . . . . . . . . . . . 11 ENVIRONMENTAL INFLUENCES . . . . . . . . . . . . . . . . . . . . . . 11 Chemical Carcinogenesis . . . . . . . . . . . . . . . . . . . . . . . . . 11 Dietary Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 MOLECULAR MEDICINE: CURRENT AND FUTURE APPROACHES IN GASTROINTESTINAL ONCOLOGY . . . . . . . 12 Next Generation Sequencing . . . . . . . . . . . . . . . . . . . . . . . 12 Molecular Diagnostics . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 Normal cellular proliferation and differentiation are essential to tissue homeostasis in all organs, including the digestive tract. The neoplastic process involves a fundamental disruption of these mechanisms, which can give rise to cancer development and metastasis with the additional acquisition of other hallmarks of cancer. As a group, malignancies of the GI tract are the leading cause of cancerassociated mortality, and it is therefore essential to understand the underlying biology that gives rise to tumor formation. This chapter reviews mechanisms of normal cell growth and the fundamental cellular and molecular alterations that facilitate malignant transformation. The basic concepts discussed in this chapter provide the framework for discussion of specific GI neoplasms in later chapters.

MECHANISMS OF NORMAL TISSUE HOMEOSTASIS Cellular Proliferation Tissue homeostasis is maintained by the delicate balance of cellular proliferation and differentiation, which provide new cellular elements to replace dying cells as part of normal tissue function or during tissue repair. At a fundamental level, neoplasia arises when cell proliferation escapes the homeostatic mechanisms that maintain this process in balance with senescence and programmed cell death. Cell proliferation occurs as cells divide, a process that occurs through an orderly set of steps referred to as the cell cycle (Fig. 1.1). In preparation for cell division, there is a period of biosynthetic activity called the G1 phase that is typically associated with an increase of cell size. This phase is followed by precise duplication of the genome, designated the S phase. After an intervening gap period designated as the G2 phase, mitosis occurs during the M phase. The commitment to proceed to DNA replication occurs at the G1/S checkpoint or restriction (R) point. Cells may exit this cycle of active proliferation before reaching the R point and enter a quiescent phase known as G0. Cells can subsequently reenter the cell cycle from the G0 state (see Fig. 1.1). Another checkpoint exists at the boundary between the G2 and M phases. The G2/M checkpoint ensures that mitosis does not proceed prior to the repair of any damaged DNA after genome replication. Impaired function of these checkpoints is frequently observed in cancers. Regulation of cell cycle progression is achieved principally by a set of proteins known as cyclins and cyclin-dependent kinases (CDKs). These proteins are expressed in specific parts of the cell cycle and regulate the G1/S and G2/M checkpoints. During the G1 phase, cyclins D and E are most active.1 Overexpression of cyclin D1 in fibroblasts results in more rapid entry of cells into the S phase, and, consistent with a role in cancer, cyclin D1 is frequently overexpressed in a number of GI and non-GI malignancies.2 During the S phase, cyclin A is predominantly expressed, and by the G2 phase cyclin B is the main regulator (see Fig. 1.1). Each cyclin forms a complex with a CDK and function as catalysts for CDK activity in a cell cycle–dependent fashion (see Fig. 1.1). The cyclin-CDK complexes regulate cell cycle progression through phosphorylation of key target proteins. For example, cyclin D1–dependent progression from G1 to S phase is the result of cyclin D1/CDK4 phosphorylation of the tumor suppression pRb, the product of the retinoblastoma gene, as well as the Rb family members p130 and p107.3 These proteins sequester E2F transcription factors that promote expression of factors required for S phase, and their phosphorylation by CDK4 leads to their functional inhibition. Thus, loss of Rb expression also accomplishes more rapid progression to S phase and is another genetic lesion seen in many tumors. An analogous circuit is found in the G2/M transition, where cyclin A/CDK2 mediates the activation of another transcriptional regulator, FoxM1, required for the expression of factors involved in mitosis.4

1

2

PART I  Biology of the Gastrointestinal Tract

CDK4

Ink4A

Cyclin D1

E2F

P pRb

pRb

P P

G1/S checkpoint E2F

G0

G1

S Cyclin D/E

Cyclin A

Cyclin B G2

M

P P

FoxM1 G2 /M checkpoint P P

FoxM1

FoxM1 Cyclin A

Cip/Kip

CDK2

Fig. 1.1  Regulation of the cell cycle by (cycs), cyclin-dependent kinases (cdks), and cdk inhibitors. In the normal cell cycle, DNA synthesis (in which chromosomal DNA is duplicated) occurs in the S phase, whereas mitosis (in which nuclei first divide to form a pair of new nuclei, followed by actual cellular division to form a pair of daughter cells) takes place in the M phase. The S and M phases are separated by two gap phases: the G1 phase after mitosis and before DNA synthesis, and the G2 phase following the S phase. During these gap phases, the cell is synthesizing proteins and metabolites, increasing its mass, and preparing for the S phase and M phase. Cell cycle progression is regulated primarily at two points, the G2/M and G1/S checkpoints, through the coordinated activities of cyclins and CDKs, which in turn are negatively regulated by CDK inhibitors (Ink4 and Cip/Kip families).

The cell cycle is also regulated by multiple CDK inhibitors, which are classified into various classes and are referred by multiple names.5 CDK4 and CDK6 are inhibited by members of the Ink4 family of inhibitors known as p16INK4a (encoded by the Cdkn2a gene), p15INK4b (Cdkn2b), p18INK4c (Cdkn2c), and p19INK4d (Cdkn2d)].6 Thus these factors also impinge on Cyclin D1/CDK4 regulation of pRb, and consequent E2F activity and S phase entry. p16INK4A loss in cancer results in greater activation of CDK4 and is frequently inactivated in GI cancers, a finding consistent with its function as a tumor suppressor gene.7,8 Members of the Cip/Kip family of CDK inhibitors are known as p21Cip1 (Cdkn1a), p27Kip1 (Cdkn1b), and p57Kip2 (Cdkn1c)] and are more promiscuous and interfere with multiple cyclin/CDK complexes, including CDK2. 

Apoptosis Apoptosis is a form of programmed cell death that is genetically programmed and executed by specific proteases known as caspases.9 Similar to other protease cascades, such as the coagulation system, caspases become active upon cleavage of an inactive pro-form, typically through the action of another caspase or as a result of focal accumulation of inactive caspases. Apoptosis is an important mechanism that counterbalances cell proliferation; thus, escape from normal apoptotic mechanisms plays a critical role in oncogenesis. Morphologically, apoptosis is characterized by distinctive features that include chromatin compaction, condensation of the cytoplasm, nuclear fragmentation, and marked alterations at the plasma membrane, resulting

CHAPTER 1  Cellular Growth and Neoplasia

3

Death Receptors

1

(TNFR1, Fas, etc.)

Bax

Cyto c

Caspase-8

Bak

Cellular Stress

(Radiation, chemotherapy, etc.)

Caspase-9

Apaf-1

Bcl-2 Bcl-xL

Mitochondria

Mcl-1

Executioner Caspases (Casp-3, Casp-7)

Downstream Targets leading to Cell Death

Fig. 1.2  Apoptosis (programmed cell death) counterbalances cellular proliferation to regulate overall tissue growth. A complex interplay of proapoptotic and antiapoptotic molecules results in downstream activation of caspases that mediate cell death. Some of these signals are initiated through cellular stress that can destabilize mitochondrial membranes, and some are initiated through death receptors, including TNFR1 and Fas. The mitochondrial step is regulated by the interplay between proapoptotic (Bax, Bak) and antiapoptotic (Bcl-2, Bcl-xL) molecules. Upon mitochondrial permeabilization, cytochrome c release promotes the formation of the apoptosome complex (APAF1, caspase 9, and cytochrome c). Activation of caspase-8 (downstream of death receptor) or of caspase-9 (as a result of apoptosome formation), leads to activation of executioner caspases (3 and 7) which are responsible for targeting downstream targets that are responsible for cell death.

in compacted apoptotic bodies that are eventually phagocytosed and eliminated. Apoptosis may be triggered by internal or external stimuli. Internal stimuli of apoptosis may include nutrient deprivation, hypoxia, DNA damage, or other stressors, including specific toxins, chemical signals, and pathogens. Apoptosis routinely occurs during normal development to facilitate tissue patterning. Similarly, a number of stress situations, including tissue inflammation, can trigger apoptosis. Apoptosis may also be stimulated by specific cell surface receptors belonging to the tumor necrosis factor receptor superfamily, including tumor necrosis factor R1 and Fas, which are referred to as death receptors (Fig. 1.2). At the intracellular level, the last common event in all forms of apoptosis is the activation of so-called executioner caspases, caspase 3 and 7, which mediate the cleavage of a large number of downstream targets that eventually precipitate cell death. Proapoptotic signals frequently converge at the level of the mitochondria, where they destabilize the mitochondrial membrane and collapse the electrical gradient required for aerobic respiration (see Fig. 1.2). Besides the effects that result in cellular energetics, this process leads to the release into the cytosol of proteins normally present in the intermembrane space of the mitochondria, including cytochrome c, a component of the respiratory chain. In the cytosol, cytochrome c helps in the assembly of a multiprotein complex known as the apoptosome, which contains Apaf1 and facilitates the activation of caspase 9, which can directly activate caspases 3 and 7. On the other hand, death receptors activate executioner caspases through receptor initiated intracellular signaling events that result in the upstream activation of caspase 8. The mitochondrial membrane permeabilization events that lead to apoptosome formation are controlled by proteins of the Bcl-2 family. On the one hand, Bax and Bak help form the pore, whereas Bcl-2, Bcl-xL, and Mcl-1 inhibit pore formation. The stoichiometric ratio between proapoptotic and antiapoptotic members of the Bcl-2 family can determine the balance between cell survival and cell death.10 In cancer, alterations in the balance of proapoptotic and antiapoptotic factors, including member of the Bcl-2 family, are common events. 

Senescence Senescence is the process by which cells permanently lose their ability to divide. Senescence may occur in response to the stress induced by activation of oncogenes or DNA damage or after a fixed number of cellular divisions (replicative senescence). Associated with the exit from the cell cycle, senescence is associated with a secretory phenotype that includes a variety of proinflammatory factors. As a physiologic event, senescence limits dysregulated or excessive proliferation. However, when dysregulated, senescence can also contribute to aging and depletion of stem cells.11 During carcinogenesis, senescence is frequently bypassed or lost. Replicative senescence is triggered shortening of telomeres, repetitive sequences at the end of chromosomes that protect genomic integrity. Telomeres shorten with each cell division, and when they reach a critically short length, they initiate DNA damage signaling and cellular senescence. This phenomenon can be routinely seen in vitro when primary cells undergo repeated rounds of replication, eventually acquiring critically short telomeres.12 To prevent senescence from being triggered by sustained replication, cancer cells activate the telomerase enzyme, which adds additional telomeres to the end of chromosomes.13 

Signaling Pathways That Regulate Cellular Growth Cellular proliferation is achieved through transition of cells from G0 arrest into the active cell cycle (see Fig. 1.1). Although progression through the cell cycle is controlled by the regulatory mechanisms just described, overall proliferation is also modulated by external stimuli. Growth factors that bind to specific transmembrane receptors on the cell surface are especially important. Also acting through transmembrane cell surface receptors, extracellular matrix and cell-cell adhesion molecules (i.e., integrins, cadherins, selectins, proteoglycans) can also have a significant impact on cell proliferation. Alterations in cell-matrix or cellcell interactions are particularly important in contributing to the invasive phenotype of malignant cells. After ligand binding, the cytoplasmic tails of these transmembrane receptor proteins activate intracellular signaling cascades

4

PART I  Biology of the Gastrointestinal Tract

that alter gene transcription and protein expression. Based on the nature of the intracellular signaling cascades that these receptors initiate, they can be classified into three major categories: (1) tyrosine kinases, (2) serine and threonine kinases, and (3) G protein–coupled receptors (GPCRs). The receptors for many peptide growth factors contain intrinsic tyrosine kinase activity within their intracellular tail. After ligand binding, tyrosine kinase activity is stimulated, leading to phosphorylation of tyrosine residues in target proteins within the cell. Most receptors also autophosphorylate tyrosine residues present in the receptors themselves to magnify signaling, and, in some cases, this also causes attenuation of their own activity to effect an intramolecular feedback regulatory mechanism. The receptors for many peptide growth factors, including the receptor for EGF and related growth factors, belong to this receptor class. Other receptors on the cell surface possess kinase activity directed toward serine or threonine residues rather than tyrosine. These receptors also phosphorylate a variety of cellular proteins, leading to a cascade of biological responses. Multiple sites of serine and threonine phosphorylation are present on many growth factor receptors, including the tyrosine kinase receptors, suggesting the existence of significant interactions among various receptors present on a single cell.14 The transforming growth factor (TGF)-α receptor complex is one important example of a serinethreonine kinase–containing transmembrane receptor.

Many receptors are members of the so-called 7-membrane– spanning receptor family. These receptors are coupled to guanine nucleotide binding proteins, also known as G proteins, and thus, the receptors are referred to as G protein–coupled receptors. G proteins undergo a conformational change that is dependent on the presence of guanosine phosphates.15 Activation of G proteins can trigger a variety of intracellular signals, including stimulation of phospholipase C and the generation of phosphoinositides (most importantly, inositol 1,4,5-triphosphate) and diacylglycerol through hydrolysis of membrane phospholipids, as well as modulation of the second messengers cyclic adenosine monophosphate and guanosine monophosphate.16 Somatostatin receptors exemplify a GPCR prevalent in the GI tract. Binding of growth factors and cytokines to cell surface receptors typically produces alterations in a variety of cellular functions that influence growth. These functions include ion transport, nutrient uptake, and protein synthesis. However, the ligandreceptor interaction must ultimately modify one or more of the homeostatic mechanisms discussed to affect cellular proliferation. The Wnt pathway is one important example of a signaling pathway that regulates a diverse number of homeostatic mechanisms to control proliferation of intestinal epithelial cells (Fig. 1.3). Evolutionarily conserved among several species, Wnt signaling, as a rule, regulates proliferation in the stem cell niche and is essential for epithelial homeostasis in the GI tract. From a Wnt

Frizzled Receptor

Plasma Membrane

β-catenin Pi

GSK-3β

GSK-3β Axin

Axin APC

Pi

APC

Dishevelled

Cytosolic β-catenin

Proteosome

Nucleus

c-Myc Cyclin D1 VEGF Tcf4

Fig. 1.3 The Wnt signaling pathway is an important regulator of intestinal epithelial cell proliferation and tumorigenesis. In the absence of a Wnt signal (left top), cytosolic β-catenin is regulated by the destruction complex, consisting of APC, Axin, and glycogen synthase kinase-3β (GSK-3β). The destruction complex phosphorylates α-catenin and targets it for degradation via the ubiquitin-proteosome pathway. In the presence of an active Wnt signal (right top), α-catenin degradation is prevented and the protein is stabilized, leading to excess cytoplasmic α-catenin which is translocated to the nucleus. Nuclear α-catenin interacts with the Tcf-4 transcription factor to regulate the expression of many key target genes. APC, Adenomatous polyposis coli; P, phosphate group; Ub, ubiquitin; VEGF, vascular endothelial growth factor.  

CHAPTER 1  Cellular Growth and Neoplasia

signaling perspective, its actions are largely the result of the accumulation of α-catenin in the nucleus, where it binds with the transcription factor Tcf-4 to activate a set of target genes.17 In normal cells, α-catenin is largely associated with adherens junctions, and the cytoplasmic pool of this protein is rapidly degraded through a phosphorylation and ubiquitination pathway. This is mediated by the so-called destruction complex, which includes the tumor suppressor APC. When secreted Wnt ligands bind to cell surface receptors of the Frizzled family, the constitutive degradation of α-catenin is inhibited (disheveled) which results in the nuclear accumulation of this factor, and the subsequent transcriptional activation of genes that promote cell proliferation. Inhibition of the Wnt signal in mice can be achieved by deletion of Tcf-4 or overexpression of the Wnt inhibitor Dickkopf1, which results in dramatic hypoproliferation of the intestinal epithelium.18,19 Wnt signaling is most active in the base of the crypt, and as differentiation ensues, tissue homeostasis is maintained by growth-inhibiting signals that counterbalance proliferative signals and promote differentiation, including members of the TGF-α family such as BMP4.20 Specific members of this family have unique functions is tissue homeostasis, including promoting a differentiated and fibrogenic phenotype of mesenchymal cells, induction of specific T cell subtypes, and myriad other activities. In broad terms, the effects of TGF-α family members are mediated intracellularly through the Smad family of proteins, which are transcription factors that are activated in response to ligand-receptor binding.21 TGF-α induces transcription of the cell cycle inhibitors p15INK4B and p21CIP1/WAF1 and is a potent growth-inhibiting factor that mediates arrest of the cell cycle at the G1 phase. Furthermore, it also enhances the inhibitory activity of p27KIP1 on the cyclin E/ CDK2 complex.22 

INTESTINAL TUMOR DEVELOPMENT Multistep Formation Multiple sequential genetic alterations are required for the transformation of normal intestinal epithelium to neoplasia. This multistep nature of tumorigenesis is most directly illustrated by the changes that accrue in the development of colonic neoplasia (see Chapter 127). The progression from normal epithelium through adenomatous polyps to malignant neoplasia is paralleled by the accumulation of genetic alterations that change key pathways that control proliferation and tissue homeostasis. Studies on the molecular pathogenesis of colon cancer have served as a paradigm for the elucidation of genetic alterations in other GI cancers, including gastric and pancreatic cancer. Genomic instability is observed in almost all cancers in the GI tract. This genetically unstable environment promotes the accumulation of the multiple alterations that characterize GI cancers. Instability of the genome may result from several mechanisms, including changes in the genome DNA sequence or through modifications of the nucleotides to alter their functionality, a process called epigenetic change. In colon cancer, there are now 3 wellrecognized forms of genetic/epigenetic instability that promote carcinogenesis (Fig. 1.4), and they have been termed chromosomal instability, microsatellite instability (MSI), and CpG island methylator phenotype (CIMP).23,24 Chromosomal instability refers to alterations in chromosomal structure resulting in large chromosomal deletions, duplications, and translocations, which in aggregate result in a state of aneuploidy. In contrast, MSI refers to frequent alterations in tracts of repetitive DNA sequences (referred to microsatellite DNA) and are often diploid or near-diploid on a chromosomal level (see later discussion on DNA repair). CIMP refers to the accumulation of an epigenetic modification, methylation of guanine residues in so-called CpG-islands, areas rich in cytidine and guanine in gene promoter sites. This modification has a potent effect on gene transcription and results in gene

5

silencing. Other forms of epigenetic change involve the chemical modification of the histone proteins that are required for the assembly of the nucleosome and that control chromatin compaction and DNA access. Although mutations in histones themselves are rare in cancer, mutations in the enzymes that modify histones are emerging as an important group of tumor-associated mutations. It is important to note that involvement by these pathways is not mutually exclusive. 

Clonal Expansion Clonal expansion is essential to tumor development.25 The acquisition of a mutation that may provide a growth or survival advantage to a cell is followed by clonal expansion of these mutated cells. As this population grows, and particularly with the acquisition of genetic/epigenetic instability, a second round of clonal expansion occurs as a cell within this population sustains still another genetic alteration that further enhances its growth properties. This iterative process of selection, with accumulating genetic alterations, results in malignancy. Because of the nature of the clonal expansion process, once frank malignancy has developed, it is often the case that multiple clones are present in the same tumor, with a different catalog of mutations harbored among various cancer cells. Referred to as tumor heterogeneity, this ongoing process may give certain cells selection advantages.26 Metastasis may be facilitated by the evolution of a subset of tumor cells that acquire the capability of traversing the circulatory system and thriving in a new environment. 

Cancer Stem Cells Recognition of tumor heterogeneity has led to the cancer stem cell (CSC) hypothesis, which asserts that there exists a subset of tumor cells that have stem cell–like properties. CSCs are believed to be the tumor-initiating cells from which clonal expansion occurs. Moreover, it is hypothesized that eradication of these cells is a key therapeutic goal because failure to do so may result in relapse of disease. Within this CSC hypothesis, there are 2 models.27 The first is a hierarchical model in which CSCs serve as progenitors for all cells in in a given tumor, whereas other cells have limited long-term reproductive potential. The basic evidence for this model is the finding that only cells with specific surface markers can repopulate the tumor in xenotransplantation experiments. In the GI tract, analysis of putative CSCs demonstrate transcriptional programs and markers shared with normal intestinal stem cells, such as Lgr5 and EphB2, which identify and purify colon CSCs.28 The second stochastic model posits that each cancer cell has the same potential to be a CSC, but this determination is stochastically based on internal factors in addition to external environmental cues. 

Epithelial-Mesenchymal Transition It has been noted that within tumors of epithelial origin, some cells acquire features of mesenchymal cells. A similar process occurs during normal embryogenesis, when polarized epithelial cells no longer recognize the boundaries imposed by adjacent epithelial cells or their basement membrane and adopt features of migratory mesenchymal cells. This phenomenon, designated epithelial-mesenchymal transition (EMT), endows cells with the ability to move through tissue planes that normally serve as boundaries for epithelial cells, such as the basement membrane, a dense matrix of collagen, glycoproteins, and proteoglycans. The transmigration of tumor cells through the basement membrane likely involves production of key proteolytic activities. Alternatively, the tumor cell may produce factors capable of activating proenzymes present in the extracellular matrix. For example, the tumor may produce urokinase, itself a protease, or plasminogen

1

6

PART I  Biology of the Gastrointestinal Tract 7-10 years Chromosomal instability

Hyperproliferative epithelium

Normal

APC

Microsatellite instability

COX2 overexpression

Hyperproliferative epithelium

Normal

Early Adenoma

Late Adenoma

KRAS

Carcinoma

TP53

2-3 years Early Serrated Polyp

Late Sessile Serrated Adenoma

Mutations in genes with polynucleotide tracks IGF2R, BAX, TGFB2R, etc.

Germline mutations in MMR genes followed 'second hit' (˜5%)

Carcinoma

TP53

MLH1 promoter methylation and silencing (˜10%)

Unclear duration CIMP

Hyperproliferative epithelium

Normal

Early Serrated Polyp

KRAS or BRAF mutations

Late Sessile Serrated Adenoma

CpG island methylation and silencing of tumor suppressor genes

Carcinoma

TP53

Fig. 1.4 Multistep models of colorectal cancer based on underlying genetic instability. As shown on the left, there are 3 major pathways: chromosomal instability (top pathway), microsatellite instability (middle pathway), and the CpG island methylation, or CIMP (lower pathway). The progression from normal colonic epithelium to carcinoma is associated with the acquisition of several genetic and epigenetic alterations. In the chromosomal instability pathway (top pathway), these alterations include the early loss of APC, followed by activation of oncogenes (e.g., KRAS) through a point mutation and inactivation of tumor suppressor genes (e.g., APC, TP53) through a point mutation or deletion. An increasing aggregate number of mutations can be correlated with progression from early benign adenoma to cancer, as reflected by analysis of polyps by size. In the microsatellite instability model (middle pathway), mutations in DNA mismatch repair (MMR) genes create a mutator phenotype in which mutations accumulate in specific target genes (see section on DNA mismatch repair). Tumors develop much more rapidly through this pathway than through the chromosomal instability pathway (2-3 years compared to 7-10 years). Germline mutations in MMR genes account for 5% of all colorectal tumors. In the CIMP pathway (lower pathway), the initiating event is hypothesized to be a BRAF or KRAS activating mutation that somehow triggers extensive CpG island methylation, particularly of gene promoters, resulting in gene silencing. Among the potential gene targets is MLH1, a component of the MMR pathway, and when silenced as part of the CIMP pathway, the tumor evolves along a similar molecular as microsatellite unstable cancers (MSI-H). Sporadic MLH1 methylation and silencing accounts for nearly 10% of sporadic colorectal cancers. Alternatively, serrated adenomas arising in the CIMP pathway can undergo a pathway similar to that of chromosomal instability to become microsatellite stable tumors.  

activator. Having gained access to the interstitial stromal compartment, tumor cells can then enter lymphatic and blood vessels and metastasize. In addition to these properties, it has been recognized that cells that undergo EMT acquire not only invasive features but also CSC-like features.29 One key feature of EMT is the loss of adherens junctions that normally maintain epithelial cell–cell interactions. The molecular correlate of this phenomenon is the loss of expression of E-cadherin, a critical component of the adherens junction.30 Mutations in E-cadherin are common in many GI cancers, particularly gastric cancer, where germline mutations in E-cadherin are also linked to hereditary diffuse gastric cancer. 

NEOPLASIA-ASSOCIATED GENES Genes that become altered during the neoplastic process belong to two distinct groups: (1) oncogenes, which actively confer a growth-promoting property, or (2) tumor suppressor genes, the products of which normally restrain growth or proliferation. An important category within tumor suppressor genes includes

DNA repair genes, which prevent accumulation of new mutations. Activation of oncogenes or inactivation of tumor suppressor genes contributes to malignant transformation. Although most of these genes encode for proteins, many cancer-promoting genes that harbor oncogenic and tumor suppressive functions do not encode for proteins but rather for RNAs that modulate genomic function, so-called noncoding RNAs.

Oncogenes According to the Catalog of Somatic Mutations in Cancer (COSMIC),31 there are close to 80 oncogenes with strong evidence of involvement in cancer. Genes that encode a normal cellular protein, whose function may promote the neoplastic process (e.g., antiapoptotic function, cell proliferation stimulation, etc.), may function as oncogenes when they are expressed at inappropriately high levels. A typical mechanism for this phenomenon is gene amplification, when tumors acquire multiple copies of a normal gene resulting in a dosage effect that leads to increased gene expression. In other cases, a variety of mutations may lead to inappropriately high activity of a normal gene, leading to cancer-promoting

CHAPTER 1  Cellular Growth and Neoplasia

activities. Point mutations or large gene rearrangements resulting in fusion proteins are examples of mutations that can lead to oncogene activation. For example, several genes that encode tyrosine kinase–containing growth factor receptors become oncogenes after a mutation results in unregulated tyrosine kinase activity that is no longer dependent on the presence of the appropriate ligand (e.g., EGF). Because of their tumor-promoting activity, these mutations tend to be recurrent among specific cancer classes. The normal cellular genes from which the oncogenes derive are designated proto-oncogenes. Most of these genes are widely expressed in many different types of tumor cells. Finally, another source of oncogenes are virally encoded proteins that may affect cellular growth or survival.32 These factors, while evolved to favor the viral cycle, may in some instances favor neoplastic development and this is the reason why specific viruses are associated with increased cancer risk. In addition, in the case of retroviruses, the ability of the viral genome to insert itself in the genome of the host can lead to disruptions in the expression of genes in the vicinity of insertion sites, which at times, may have oncogenic activities. The proteins encoded by oncogenes may affect any of the hallmarks of cancer, such as stimulate growth factor pathways, promote tumor invasion, prevent cell death, or have other tumorpromoting actions. With regards to promoting growth factor pathways, oncogenes may encode for (1) growth factors or their receptors, or for (2) intracellular signal transduction molecules downstream of the receptor itself, including transcription factors that mediate the actions of the growth factor at the level of the nucleus. 

Oncogenic Growth Factors and Growth Factor Receptors The transforming effects of enhanced expression of a variety of growth factors have been demonstrated both in vitro and in vivo. Several growth factor–related proteins encoded by oncogenes have now been recognized, including the family of Wnt and Sis proteins, which encodes the α chain of platelet-derived growth factor. Cancer cells may engage in autocrine signaling to promote their growth, or coax the adjacent stroma to hypersecrete such growth-stimulating factors. More frequently, a variety of receptors are upregulated in expression or dysregulated leading to constitutive action. Among them, are receptor tyrosine kinases of the EGF receptor family (ERBB1-4), which are frequently upregulated in a variety of GI cancers.

Signal Transduction–Related Oncogenes Intermediate steps that effectively translate ligand-receptor binding to an intracellular signal are essential in mediating functional responses of the cell. Mutations in genes that encode key proteins that participate in signal transduction can also lead to cellular transformation (Fig. 1.5). In this regard, the largest family of oncogenes encodes proteins with protein kinase activity. Many members of this large oncogene group are expressed by neoplasms of the GI tract, and these include the Src nonreceptor tyrosine kinase that associates with the inner surface of the plasma membrane. G proteins regulate signaling of the large family of GPCRs through the exchange of guanosine triphosphate with guanosine diphosphate. In this regard, the ras family of genes, which encodes a family of proteins related to the G proteins, are among the most commonly detected oncogenes in GI tract cancers. The ras family contains 3 genes: H-ras, K-ras, and N-ras. These factors are essential to transduce signals from various growth receptor signaling cascades and point mutations that result in activating amino acid substitutions at critical hot spot positions convert the normal gene into an oncogene.

7

Growth factor receptors

1

K-ras

PI3K

B-raf

AKT

MEK

mTOR

ERK

Cell growth Proliferation Survival

Fig. 1.5  Signal transduction downstream of growth factor receptors, where K-ras plays a major role. Oncogenic K-ras can activate multiple signaling pathways. Molecules that are frequently mutated in colorectal cancer are noted by a red arrow and include K-ras (40%), B-raf (10%), and PI3K (15%). AKT, Cellular homolog of v-Akt oncogene; ERK, extracellular signal regulated kinase; MEK, MAPK/ERK kinase; mTOR, mammalian target of rapamycin; PI3K; phosphoinositide-3 kinase.

To date, almost all ras mutations in GI malignancies occur in the K-ras oncogene. The highest mutation frequency is found in tumors of the exocrine pancreas (>90%).33 Ras genes activated through point mutation have been identified in approximately 50% of colonic cancers as well as a subset of serrated tumors (see Fig. 1.4).34 Most oncogenic mutations in ras cause biochemical changes that maintain it in the active, guanosine triphosphate–bound state by reducing guanosine triphosphatase activity or by destabilizing the inactive guanosine diphosphate–bound form. However, several ras mutants retain significant guanosine triphosphatase activity; therefore, other mechanisms that convert ras to a transforming protein may be involved.35 A functional consequence of ras activation is the phosphorylation and activation of key downstream serine/threonine kinases. One important target of ras is B-raf. In colon cancers without an identifiable K-ras mutation, 20% possess an activating B-raf mutation,36 consistent with the concept that activation of an oncogenic pathway can be achieved through an alteration in any of several sequential components of a particular pathway (see Fig. 1.5). 

Nuclear Oncogenes Many cellular oncogenes encode proteins that localize to the nucleus. In essence, these nuclear oncogene products are the final mediators of signal transduction pathways that are also affected by cytoplasmic and plasma membrane–bound oncoproteins, because they act as transcription factors that regulate expression of certain genes that enhance cellular proliferation and suppress normal differentiation.

8

PART I  Biology of the Gastrointestinal Tract

The role of nuclear oncogenes is illustrated by the myc family. The c-Myc protein product is involved in critical cellular functions like proliferation, differentiation, apoptosis, transformation, and transcriptional activation of key genes.37 Frequently, c-Myc is overexpressed or amplified in many GI cancers. c-Myc has been found to be a transcriptional target of the α-catenin/TCF-4 complex in colorectal cancers (see Fig. 1.3), which may explain the overexpression of c-Myc observed in this cancer type.38 

Tumor Suppressor Genes Mutations of tumor suppressor genes are associated with all GI cancers, and a number of these genes and their products have been identified and characterized (Table 1.1). Unlike gain-offunction mutations, which are characteristic of oncogenes, mutations in tumor suppressor genes are loss-of-function mutations and are therefore biallelic. Initial recognition of the existence of tumor suppressor genes was derived from genetic analyses of cancer-prone families. In the GI tract, hereditary colon cancer, gastric cancer, and pancreatic cancer syndromes are the best described and are discussed elsewhere in this text (see Chapters 54, 60, and 127). In these syndromes, there is a marked increase in risk for a particular tumor in the absence of other predisposing environmental factors. Tumors arise typically at a younger age than they do in the general population, and multiple primary tumors may develop within the target tissue. From a genetic standpoint, cancer genetic syndromes most often have an autosomal dominant mode of mendelian inheritance. Based on observations in hereditary retinoblastoma, Knudson proposed the “2-hit” hypothesis,39 which explains the relationship between sporadic and familial forms of cancer. Whereas sporadic tumors are initiated by somatic biallelic inactivating mutations of a tumor suppressor gene, tumors in familial cancer syndromes are accelerated by the inheritance of a monoallelic mutation of a tumor suppressor gene present in all cells in affected family members. When this germline mutation is followed by a somatic mutation in the remaining normal allele of the tumor suppressor gene, this gives rise to the development of a neoplastic clone that eventually gives rise to a tumor (Fig. 1.6). Because of the germline mutation, the likelihood of full inactivation of the tumor suppressor is diminished substantially because TABLE 1.1  Mutations Associated with Hereditary Gastrointestinal Cancer Syndromes Disorder

Gene(s) Mutated

FAP, AFAP, Gardner syndrome

APC

Lynch syndrome (HNPCC)

MLH1, MSH2, PMS2, MSH6, EPCAM (through disruption of the neighboring MSH2 gene)

MAP

MUTYH

Peutz-Jeghers syndrome

STK11

Cowden’s disease

PTEN

Juvenile polyposis

SMAD4, BMPR1A

Hereditary diffuse gastric cancer

CDH1

Hereditary pancreatic cancer

ATM, BRCA1, BRCA2, PALB2, PALLD, CDKN2A, PRSS1, SPINK1, PRSS2, CTRC, CFTR

MEN1

Menin

  

AFAP, Attenuated FAP; APC, adenomatous polyposis coli; FAP, familial adenomatous polyposis; HNPCC, hereditary nonpolyposis colorectal cancer; MAP, MUTYH-associated polyposis; MEN1, multiple endocrine neoplasia, type 1; MUTYH, mutY homolog.   

only one additional hit is required, leading to the younger age of onset and the potential for tumor multiplicity that accompanies these syndromes. Although this 2-hit model has been generally observed, there are exceptions. Some tumor suppressors may function to increase cancer risk when only one allele is mutated. Moreover, some cancer genetic syndromes display somatic recessive mode of inheritance because genetic risk is conferred only when biallelic inactivating mutations are present. Another important feature of tumor suppressor genes is that they do not function identically in every tissue type. Consequently, inactivation of a particular tumor suppressor gene is tumorigenic only in certain tissues. For example, the tumor suppressor genes RB1 and VHL play crucial roles in retinoblastomas and renal cell cancer, respectively, but are rarely mutated in GI malignancies. Tumor suppressor genes shown to have a critical role in the pathogenesis of GI malignancies, APC, TP53, and SMAD4, are described later. Furthermore, we will discuss DNA repair pathways that, when lost, can give rise to neoplasia and therefore function as tumor suppressor factors.

Adenomatous Polyposis Coli Gene Genetic linkage analysis revealed markers on chromosome 5q21 that were tightly linked to polyp development in affected members of kindreds with familial adenomatous polyposis (FAP) and Gardner’s syndrome.40 Further work led to identification of the gene responsible for FAP, the APC gene.41-43 The full spectrum of adenomatous polyposis syndromes attributable to APC is discussed in detail in Chapter 126. Somatic mutations in APC have also been found in most sporadic colon polyps and cancers.44,45 Mutations in APC are characteristically identified in the earliest adenomas, indicating that APC plays a critical role as the gatekeeper in the multistep progression from normal epithelial cell to colon cancer (see Fig. 1.4). The APC gene comprises 15 exons and encodes a predicted protein of 2843 amino acids, or approximately 310 kDa. Most germline and somatic APC gene mutations result in a premature stop codon and therefore a truncated APC protein product and loss of function. As discussed earlier, APC is a negative regulator of the Wnt signaling pathway and its inactivation results in a state that resembles constitutive activation of Wnt. Intracellularly, Acquired somatic mutation

Germline mutation Inherited cancer syndrome

TSG

X

Tumor Acquired somatic mutation

Second somatic mutation X

X

Sporadic cancer

Tumor

Time , Tumor suppressor gene. Fig. 1.6  Knudson’s 2-hit hypothesis. In an inherited cancer syndrome, one chromosome has an inactive tumor suppressor gene (TSG) locus because of a germline mutation. The counterpart TSG on the remaining paired chromosome is subsequently inactivated by a somatic mutation, leading to tumor formation. In contrast, in a sporadic cancer, the two alleles of the TSG need to become inactivated through two independent somatic mutations, an event that is less likely to occur within a single cell.

CHAPTER 1  Cellular Growth and Neoplasia

this is manifested by stabilization of α-catenin, which mediates the transcriptional effects of Wnt activation and the subsequent oncogenic phenotype (see Fig. 1.3). Interestingly, another mechanism to achieve this signaling outcome are mutations in α-catenin itself that render the protein impervious to APC-dependent degradation. 

TP53 Gene This is the most commonly mutated gene in human cancer,46 and point mutations in TP53 are found with high frequency in all cancers of the GI tract.47 In fact, point mutations in TP53 have been identified in as many as 50% to 70% of sporadic colon cancers (see Fig. 1.4). Interestingly, these mutations arise relatively late in the oncogenic process as the gene is mutated in only a small subset of colonic adenomas.48 Named for a 53-kDa-sized gene product, p53 is a nuclear phosphoprotein that plays a key role in cell cycle regulation and apoptosis.47 In the nucleus, p53 functions as a transcription factor which can be induced by conditions of cellular stress, such as ionizing radiation, growth factor withdrawal, or cytotoxic therapy. Induction of p53 arrests cells at the G1 phase to facilitate DNA repair, senescence, or trigger apoptosis. These responses are mediated in part by its transcriptional targets such as the p21CIP1/WAF1 inhibitor of the cell cycle or the proapoptotic gene, PUMA.49 Interestingly, it is often the case that TP53 mutations occur as the combination of a genomic deletion encompassing one allele, together with a missense mutation in the second allele that targets specific hotspots within the protein. Recent evidence indicates that the genomic deletions function not only by removing TP53 but through the loss of adjacent genes with tumor suppressive activities.50 Furthermore, the second type of mutations, resulting in specific missense mutations are thought to contribute gain-of-function tumorigenic activities.51 In addition to the TP53 point mutations in sporadic cancers, germline TP53 mutations have been observed in the Li-Fraumeni syndrome, an autosomal dominant familial disorder in which breast carcinoma, soft tissue sarcoma, osteosarcoma, leukemia, brain tumor, colon cancer, and adrenocortical carcinoma can develop in affected persons.52 

SMAD4 Gene SMAD4 is a tumor suppressor gene located on chromosome 18q and is deleted or mutated in most pancreatic adenocarcinomas and a subset of colon cancers. Smad4, the protein encoded by this gene is an essential intracellular mediator of factors belonging to the TGF-α superfamily. Smad4 functions as a transcription factor and is an obligate partner of other members of the Smad protein family.53 Mutant Smad4 lacks these properties and among other effects, leads to loss of TGF-α inhibition of proliferation. Germline mutations in SMAD4 result in the juvenile polyposis syndrome (see Chapter 126). 

DNA Repair Genes DNA replication itself and various types of DNA damaging agents can introduce errors into the genome. These errors include spontaneous mismatching of nucleotides during normal DNA replication, oxidative damage of nucleotides, and complete double-strand breaks. Therefore, a variety of cellular mechanisms have evolved to prevent or correct DNA errors. One type of error that develops during replication may occur in repetitive mononucleotide or dinucleotide stretches of DNA, so-called microsatellite regions.54 These repetitive regions are prone to DNA mismatches, which if not resolved, can result in short insertions or deletions. The cellular machinery devoted to correct these errors is referred to the mismatch repair system. The enzymes bind mismatched DNA, cut the DNA strand with the mismatched nucleotide, unwind the

9

DNA fragment, fill in the gap with the correct nucleotide, and finally reseal the remaining nick. The family of DNA mismatch repair genes includes two basic molecular components, a mismatch recognition complex composed of MSH2 and MSH6, and an excision inducing complex composed of MLH1 and PMS2. Mutations in any of these genes result in defective mismatch repair, and when inherited due to a germline mutation, they give rise to Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer.55,56 Complete loss of a mismatch repair factor leads to very high rates of DNA mutations, and mismatch repair defective tumors accumulate a high burden of cancer somatic mutations, typically over 2000 somatic mutations, resulting in a large number of tumor-specific neoantigens.57 Affected cells are called replication error positive, in contrast to the replication error– negative phenotype.58,59 Because microsatellite DNA sequences are primarily affected by this type of genetic instability, the tumor cells display insertions or deletions in these stretches of DNA when compared to nontumor tissue, a phenomenon referred to as microsatellite instability. Mechanistically, the absence of DNA repair does not directly cause cancer but creates a milieu that permits accumulation of mutations in a variety of genes that contain repetitive DNA sequences, such as the TGF-α type II receptor, IGF type II receptor, BAX, and E2F-4, among others. Loss of mismatch repair genes represents an important mechanism for the accumulation of mutations within a tumor (see Fig. 1.4). While 5% of colon cancer are due to Lynch syndrome, i.e., germline mutations in the mismatch repair system, twice as many tumors (10%) display similar molecular characteristics without a germline mutation in any of the mismatch repair genes. These tumors are most often driven by somatic loss of function in this system, most often as a result of silencing of MLH1 gene expression as a result of an epigenetic change in the promoter region of this gene called DNA methylation. MLH1 promoter hypermethylation is most often observed in lesions that are serrated adenomas by histology and that also carry B-Raf mutations (see Fig. 1.4). Finally, it has been recognized that another mechanism that can lead to a state of high mutation burden is the loss of exonuclease proofreading activity of the replicative DNA polymerase Pol-ε or Πολ–δ, through a variety of missense mutations.60 Another important DNA repair pathway involved in carcinogenesis is mediated by the MUTYH gene. It encodes a DNA glycosylase that participates in the repair of oxidized guanine nucleotides, such as 8-oxoguanine residues, that may inappropriately pair with adenines, ultimately leading to somatic G:C→T:A mutations if uncorrected. Biallelic mutations in MUTYH results in an adenomatous polyposis syndrome that resembles FAP, except that its mode of inheritance is autosomal recessive (see Chapter 126).61,62 Interestingly, G:C→T:A mutations in the APC gene were almost universally found in the polyps of patients with germline MUTYH mutations, indicating that there are important similarities in the molecular pathogenesis of polyps in the MUTYH and FAP syndromes. 

Noncoding RNAs Our genomes harbor a variety of genes whose products are RNAs that do not encode for a protein. The RNA products, termed noncoding RNAs, consist of a broad category of active RNA molecules that can mediate a variety of effects. The categories of noncoding RNAs are rapidly expanding and include so-called microRNAs and long noncoding RNAs, which are frequently dysregulated in cancers. The microRNAs play a critical role in silencing of other RNA transcripts via RNA degradation or translational inhibition and typically regulate dozens of target RNAs at a time. Their biogenesis involves conventional gene transcription, followed by processing of the resulting RNA by a variety of nuclease cleavage events, resulting ultimately in the generation of small interfering

1

10

PART I  Biology of the Gastrointestinal Tract

RNAs (siRNAs) by the protein Dicer. These siRNAs bind to complementary mRNA sequences, and this binding determines the specificity for RNA targets. Long noncoding RNAs may perform diverse functions like gene silencing, splicing, and extension of telomeres. 

Oncogenic Signaling Pathways Individual oncogenes or tumor suppressor genes do not necessarily induce cellular transformation directly but typically function in concert with one another as components of larger oncogenic signaling pathways already discussed. Some of the pathways that are particularly relevant for GI tumorigenesis include the Wnt and Ras signaling pathways. These are pathways that regulate normal tissue homeostasis but become oncogenic when the signals are transduced in an aberrant or amplified manner. The key features of Wnt signaling are illustrated in Fig. 1.3. α-Catenin is translocated from the inner plasma membrane to the cytoplasm. There, it forms a macromolecular complex with the APC protein Axin and glycogen synthase kinase-3α. Phosphorylation of α-catenin by glycogen synthase kinase-3α triggers its degradation. In the presence of an active Wnt signal, α-catenin is stabilized and enters the nucleus, where it interacts with the transcription factor Tcf-4 to up-regulate a number of key target genes, including c-Myc, cyclin D1, and vascular endothelial growth factor (VEGF). As discussed earlier, Wnt signaling is essential for regulating proliferation of normal intestinal epithelium, and dysregulated Wnt signaling is an almost universal feature of all colorectal cancers. The latter can result from a mutation in the APC, Axin, or α-catenin genes, although alterations in the APC tumor suppressor gene are the most common. An alteration in just one of these components is sufficient to activate the entire pathway. Thus, it is essential to consider individual genetic alterations in the context of the overall signaling pathway in which they function. Because pathways are typically not linear, additional levels of complexity arise. There is frequent overlap among pathways, and the distinction between pathways can be somewhat arbitrary. For example, mutations in the K-ras oncogene result in activation of multiple distinct signaling pathways, including Raf/ERK/MAPK, PI3K/Akt, and nuclear factor-κB, all of which play an important role in tumorigenesis (see Fig. 1.5). Crosstalk between these effector pathways serves to modulate the cellular responses further. For example, Akt, a target of PI3K, can phosphorylate Raf and thereby regulate signaling through the MAPK pathway.63 Finally, each of these signaling pathways regulates multiple biological processes related to tumorigenesis,64 including cell cycle progression, apoptosis, senescence, angiogenesis, and invasion. Another pathway that plays a particularly important role in GI tumors is the cyclooxygenase-2 (COX-2) pathway. The enzyme COX-2 is a key regulator of prostaglandin synthesis that is induced in inflammation and neoplasia. Although no mutations of COX-2 have been described, overexpression of COX-2 in colonic adenomas and cancers is associated with tumor progression and angiogenesis (see Fig. 1.4), primarily through induction of prostaglandin E2 synthesis. Inhibition of COX-2 with a variety of agents (aspirin, nonsteroidal anti-inflammatory drugs, or COX-2 selective inhibitors such as celecoxib) is associated with a reduced risk of colorectal adenomas and cancer.65 

its mesenchymal cells, its vasculature, a variety of immune cells recruited to the tumor and particularly in tumors of the intestinal tract, and tumor-associated microbiota which contribute significantly to the tumor microenvironment. In addition, these elements acting in concert lead to a metabolic environment, such as the oxygen and nutrient supply of the tumor, that often plays a significant role in the evolution of the tumor at the primary site and its potential for distant metastasis. 

TUMOR METABOLISM Tumor cells exhibit abnormal metabolic profiles to facilitate their growth and anabolic needs. Observations in 1924 from Nobel Laureate Otto Heinrich Warburg revealed that tumor cells displayed dramatic increases in aerobic glycolysis and diminished mitochondrial respiration. This metabolic state, known as the Warburg effect, has been validated and is a hallmark feature of most malignancies.66 It is becoming increasingly clear that integration of the genetic lesions that characterize cancer formation is responsible for the changes in cellular metabolism that accompany cellular transformation. Many of the genes implicated in GI cancers (p53, K-Ras, PI3K, mTOR, HIF, Myc) can in fact regulate metabolic pathways. Moreover, germline mutations in metabolic regulators (e.g., subunits of succinate dehydrogenase) that are not classical oncogenes or tumor suppressor genes have been associated with a high risk of tumorigenesis (pheochromocytoma and paraganglioma).67,68 The selection advantage of increased glycolysis in cancer cells may include greater tolerance to hypoxic environments and shunting of metabolic byproducts (e.g., lactate) to other biosynthetic pathways. These altered metabolic pathways are promising new targets for therapy.

Inflammation and Cancer Immune cells recruited to the tumor microenvironment can result in a variety of effects. On the one hand, tumor immune surveillance is well recognized and immunosuppressed states increase the risk of cancer development. On the other hand, a number of cellular elements of hematopoietic origin can promote primary tumor growth, prevent effective immune surveillance, or promote the acquisition of features of neoplastic cells that facilitate metastasis. Myeloid cells with immature characteristics, so-called myeloid-derived suppressor cells, are an important example of this phenomenon.69 In addition, a number of chronic inflammatory conditions increase the site-specific risk of cancer; examples of this include ulcerative colitis (see Chapter 115), chronic gastritis (see Chapter 52), chronic pancreatitis (see Chapter 59), Barrett’s esophagus (see Chapter 47), and chronic viral hepatitis (see Chapters 79 and 80). The influences of inflammation on the development of neoplasia are multifaceted and complex. Cytokines produced by inflammatory cells can lead to activation of antiapoptotic and pro-proliferative signals in tumor cells mediated by transcription factors such as nuclear factor-κB and STAT3.70,71 Immune cells may also promote remodeling of the vascular network and promote angiogenesis (discussed later). Inflammation may also induce DNA damage from cytokine-stimulated production of reactive oxygen species. 

TUMOR MICROENVIRONMENT

Microbiome

Cancer is ultimately a complex tissue consisting not only of neoplastic cells harboring a number of genetic lesions, as outlined previously, but the composite of a number of cellular components that endow the tumor with all of its properties. Indeed, the contribution of non-neoplastic cells to the behavior and evolution of a tumor is increasingly recognized. Cellular elements with recognized contributions to the behavior of the tumor include

The human body possesses over 100 trillion microbes and the largest concentration of these organisms are present in the GI tract. The interaction between these organisms and the host is an area of great interest, particularly for a broad range of autoimmune, metabolic, and neoplastic disorders.72 Interestingly, colonic tumors are associated with specific subsets of bacteria, and the tumor associated microbial species have the capacity of inducing

CHAPTER 1  Cellular Growth and Neoplasia

colonic tumors in specified animal models.73 Fusobacterium nucleatum, an organism typically found in the oral cavity, is an example of this behavior as it can be found in association with colon tumors and, when introduced into colon cancer models driven by germline APC mutations, can drive colon tumorigenesis.74 

BIOLOGICAL FEATURES OF TUMOR METASTASIS The establishment of distant metastases requires multiple processes, many of which involve alterations in interactions between tumor cells and normal host cells. To metastasize, a cell or group of cells must detach from the primary tumor, gain access to the lymphatic or vascular space, adhere to the endothelial surface at a distant site, penetrate the vessel wall to invade the second tissue site, and finally proliferate as a second tumor focus. Angiogenesis is necessary for proliferation of the primary tumor and tumor metastases. Tumor cells must also overcome host immune cell killing. As a result, few circulating tumor cells (CD4 monocytes NK cells

192-194,200

CCL28 (MEC)

CCR3 CCR10

Colon IEC

CD4 Tm eosinophils

200

CCL22 (MDC)

CCR4

Colon IEC

CD4 Th1

195

CCL20 (MIP3α)

CCR6

IEC

DCs CD4 Tm

196-199

CXCL12

CXCR4 CXCR7

IEC

CD4 Th1 CD45RO+ Plasma cells

201-205

CXCL8 (IL-8)

CXCR1>CXCR2

IEC Mϕ Neutrophils

Neutrophils

206

2

  

DC, Dendritic cell; IEC, intestinal epithelial cell; Mϕ, macrophage; NK, natural killer.   

The chemokine macrophage inflammatory protein-3α (MIP3, CCL20) is unique in its ability to specifically attract immature DCs as well as memory CD4+ T lymphocytes.196-198 CCL20 is also expressed and produced by human small intestinal ECs (mainly in the follicle-associated epithelium) and by colonic IECs and may be the mediator of lymphocyte adhesion to the α4β7 ligand MAdCAM-1.196 MIP3α expression and secretion is increased in colonic IECs derived from IBD patients.199 Mucosal memory T cells, as well as IECs, express CCR6, the cognate receptor for MIP3α. Mucosal defenses, including microbiota itself, provide protection from intestinal pathogens. The microbiota competes with, and provides resistance to, colonization by transient bacteria and pathogens in food and water. Some enteric pathogens induce host inflammation that in turn kills anaerobes in the gut, thus opening a niche for the aerotolerant pathogen. Certain bacteria

are pathogens because they have evolved mechanisms to breach the mucosal barrier. In healthy mucosa, resident macrophages potently phagocytose and kill such microbes in a non-inflammatory manner, but in disease conditions, the mechanism(s) responsible for inflammation anergy are disrupted allowing the macrophages to retain the pro-inflammatory profile of their monocyte progenitors. However, once IECs are invaded, they produce large amounts of chemokines such as IL-8, which attract neutrophils and monocytes from the blood into the gut at the site of infection. Such phagocytes are inflammatory and produce more chemokines, as well as other cytokines, rapidly acquiring a critical mass and killing the invading bacteria, thus resolving the infection. Full references for this chapter can be found on www.expertconsult.com

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3

The Enteric Microbiota Eugene B. Chang, Purna Kashyap

CHAPTER OUTLINE CHARACTERISTICS OF THE HUMAN INTESTINAL MICROBIOME�������������������������������������������������������������������� 24 Spatial Variation in the Intestinal Microbiome������������������ 24 Temporal Changes and Resilience of the Intestinal Microbiome���������������������������������������������������������������� 25 FACTORS AFFECTING INTESTINAL MICROBIOME VARIABILITY AND RESILIENCE ���������������������������������������� 25 Age�������������������������������������������������������������������������������� 25 Sex�������������������������������������������������������������������������������� 25 Genetics������������������������������������������������������������������������ 27 Geography and Diet�������������������������������������������������������� 27 Exercise ������������������������������������������������������������������������ 28 Medications ������������������������������������������������������������������ 28 Other Lifestyle Factors���������������������������������������������������� 29 Microbe-Microbe Signaling�������������������������������������������� 29 THE EFFECT OF HOST–INTESTINAL MICROBIOME INTERACTIONS ON HOST PHYSIOLOGY���������������������������� 29 Interactions Between the Intestinal Microbiome and Immune System �������������������������������������������������������� 29 Interactions Between the Intestinal Microbiome and Gastrointestinal Tract�������������������������������������������������� 29 The Microbiome-Gut-Brain Axis�������������������������������������� 30 THE ROLE OF THE INTESTINAL MICROBIOME IN HUMAN DISEASE���������������������������������������������������������������������������� 30 Metabolic Function�������������������������������������������������������� 30 INFLAMMATORY DISEASES���������������������������������������������� 30 CANCER���������������������������������������������������������������������������� 31 FUNCTIONAL GASTROINTESTINAL DISORDERS ���������������������������������������������������������������������� 31 THE ROLE OF THE INTESTINAL MICROBIOME IN MODULATION OF DRUG RESPONSE���������������������������������� 31 THERAPEUTIC MODULATION OF THE INTESTINAL MICROBIOME�������������������������������������������������������������������� 32 NONBACTERIAL MEMBERS OF THE INTESTINAL MICROBIOME�������������������������������������������������������������������� 32 FUTURE DIRECTIONS�������������������������������������������������������� 33

CHARACTERISTICS OF THE HUMAN INTESTINAL MICROBIOME The intestinal microbiome is a diverse ecosystem comprising microorganisms (bacteria, archaea, fungi, and viruses including bacteriophages), their genomes (i.e., genes), and the surrounding environmental conditions. The population of microorganisms alone in a particular niche is referred to as microbiota (Box 3.1) and is often used interchangeably with microbiome, which includes the genomes

24

of the microorganisms. Each of these contributes to the stability of the ecosystem and drives specific interactions with the host. We are making advances in understanding the role of each of these components, although our primary focus has been on bacteria. We have made big strides in our ability to characterize the microbiome and its impact on the host following the advent of next-generation sequencing (NGS) and advanced experimental tools (Box 3.2). Composition of the intestinal microbiota varies significantly among individuals, and so it is not surprising that it has been difficult to identify a universal “healthy” intestinal microbiota in terms of specific microbial members. This variation primarily reflects differences in the relative abundance of the 4 dominant phyla: Bacteroidetes, Firmicutes, Proteobacteria, and Actinobacteria.4, 5 In contrast to composition, a subset of microbial functional properties does appear to be conserved among individuals, including central metabolic pathways and nutrient metabolism, of, for example, carbohydrates and proteins. There are still significant inter-individual differences in the microbial functions, however, such as in drug metabolism, pathogenicity islands, and nutrient transporters. There are several factors that shape the intestinal microbiome (Fig. 3.1), but there is no 1 crucial factor. Diet appears to have the most prominent effects, but the membership and functions of the intestine microbiome result from complex interplay among the different factors.

Spatial Variation in the Intestinal Microbiome The microbiota composition varies along the gastrointestinal (GI) tract, from mouth to anus through both its longitudinal and radial axes.6 There are several factors that determine the localization of bacteria within different niches in the intestine, including oxidation-reduction potential, chemical and nutrient gradients, host immune activity, and the mucus layer (Fig. 3.2).7 The highest bacterial density, perhaps due to increased nutrient availability and slower transit, is in the colon (see Fig. 3.1). In contrast, the harsh chemical environment and relatively rapid transit through the small intestine contribute to lower abundance and diversity of microbiota. In addition, contact between bacteria and the surface epithelium differs between the colon and small intestine. Colonic mucus has 2 layers: the inner layer is devoid of bacteria, whereas the looser outer layer is populated by bacteria.8 In contrast, the small intestine has a single, incomplete mucus layer. Here, antimicrobial factors (e.g., REGIIIγ) appear to be more important than the mucus in segregating microbes from the epithelium.9,10 The radial gradient of oxygen from the mucosa to the lumen results in differences in taxonomic membership, genetics, and function between mucosa-associated microbes and lumen-associated microbes.11 There is an increased proportion of oxygentolerant organisms within the Proteobacteria and Actinobacteria phyla in the mucosa, highlighting the effect of oxygen availability. In addition, groups of bacteria that primarily use amino acids12 are associated with the mucus layer, which is a nutrient source driving differences across the intestine. The majority of studies characterizing the intestinal microbiota analyze stool samples, treating fecal microbes as surrogates for those present in the colon. Although this approach is simpler and more accessible to a wider scientific community, it only allows insight into the microbial side of host-microbe interactions. A more regionally targeted sampling approach is needed to

CHAPTER 3  The Enteric Microbiota

BOX 3.1 Glossary of Terms Used to Describe Relationships Among Individual Organisms Within the Microbiota and Between the Microbiota and Host Allochthonous: Organisms found in a place other than their origin. Autochthonous: Organisms that are indigenous to their present location. Commensal: Strictly speaking, the term commensal (derived from cum mensa, “to share a table”) describes a relationship between 2 organisms in which 1 organism benefits and the other is unaffected. In most instances, however, the term commensal is used to describe the in situ microbes colonizing a particular niche without doing harm, but may include organisms that provide a benefit to each other or to the host. Microbiome: The microorganisms, their genomes (i.e., genes), and the surrounding environmental conditions.181 Microbiota: The population of microorganisms (bacteria, archaea, lower and higher eukaryotes, and viruses) organisms in a particular niche.180 Pathobiont: Usually refers to an organism that is a potential pathogen, but only causes disease under a given set of circumstances such as when the microbiome is perturbed. An example is Clostridioides difficile, which can be carried in the intestine of healthy individuals, but usually only causes a problem after antibiotic treatment. Pathogen: Any pathologic (disease-causing) organism. Pharmabiotic: Any biological entity mined from human microbiota and with a proven biological effect. These entities could include live or dead microbes, cell wall components, purified proteins or lipids, individual metabolites (e.g., neurotransmitters), or active enzymes. Prebiotic: A nondigestible compound that, through its metabolization by microorganisms in the intestine, modulates functional capacity of the microbial community, thus conferring a beneficial physiological effect on the host.182 Probiotic: Live microorganisms that when administered in adequate amounts confer a health benefit on the host. Symbiont: Any organism participating in a symbiotic (mutually beneficial) relationship. Synbiotic: A nondigestible compound that contains both prebiotics and probiotics and combines nutrients appropriate to stimulate the specific beneficial microbe in the synbiotic.

understand the microbial effects in regulating host metabolism, digestion and absorption, local immune systems, and in causing or contributing to diseases such as IBD, IBS, food allergy, celiac disease, and colon cancer.11 

Temporal Changes and Resilience of the Intestinal Microbiome A healthy stable state is characterized by a diverse intestinal microbiota that develops from compositional and functional changes in the early years of life. There is such significant interpersonal variation, however, that a “healthy” state is difficult to define. Perhaps the best approximation for this definition would be one that promotes health by providing critical functions essential to the host.13 The concept of enterotypes based on metagenomics sequencing that stratifies healthy communities into 3 groups (Bacteroides, Prevotella, or Ruminococcus) does not hold up when expanded to larger “healthy” populations where it becomes clear that the range of inter-personal variability is a continuous spectrum of stable configurations.13 The intestinal microbial ecosystem is generally stable over time, i.e., intestinal microbiota

25

composition in samples obtained longitudinally from an individual is more similar to each other than to those obtained from a different individual. Thus although relative abundances of individual microbes can change, the overall community function and membership community remain intact. Similarly, an unfavorable microbial community can also be stable and contribute to chronic disease or states of poor health. Resilience is a key property of microbial community states, and is defined as the amount of stress or perturbation a microbial community can tolerate before it shifts to a different steady state (see Fig. 3.1). A high degree of resilience is desirable to maintain healthy states, but not in an unhealthy condition. The competition among microbes and positive and negative feedback to maintain levels of individual microbes further contributes to stability.13 Certain perturbations such as with short courses of antibiotics can result in a transiently disrupted microbial community structure (see Fig. 3.1), which often returns to the original state.14 A persistent perturbation such as long-term change in diet/antibiotic administration (see Fig. 3.1), or perturbation during a vulnerable phase such as early childhood or the peripartum period,15, 16 can result in disordered assembly with a shift to a disease-promoting state that is resistant to change. 

FACTORS AFFECTING INTESTINAL MICROBIOME VARIABILITY AND RESILIENCE Age The most dramatic and influential changes in intestinal microbiota composition occur during the first years of life. Although there is some evidence suggesting that microbes are acquired in utero, most microbial acquisitions start at the time of birth when an infant’s intestine is seeded with microbes from mother’s vagina.17 By contrast, the intestines of infants delivered by cesarean section are colonized by their mothers’ skin bacteria.17 Mode of feeding is also linked to differences in microbiota composition, with formula feeding linked to a decreased abundance of Bifidobacteria relative to that found in breastfed infants.18 The infant continues to acquire microbes both from the environment and from different body sites of the mother; interestingly, microbes acquired from the mother are more persistent and better adapted to infant intestine.19 Early development of the intestinal microbiome is critical in educating the mucosal20, 21 and systemic immune response.22-24 Disturbance of host-microbe interactions when the immune system is maturing, i.e., with antibiotic exposure in infancy, is linked to a higher risk of conditions such as asthma, type I diabetes, and obesity later in life.17 The intestinal microbiota composition and function continues to change throughout life. By 3 years of age, an individual’s microbiome more or less resembles that of an adult,25, 26 although the pre-adolescent intestinal microbiome is enriched in functions such as vitamin synthesis that support development.27 In general, microbial membership and functional diversity increase with age,4 although older adults living in long-term care facilities often harbor intestinal microbiomes that are distinct from and less diverse than those of persons living in the community.28 

Sex Women display higher levels of microbiota diversity and functional richness than men,4 and a decreased abundance of Bacteroides and Prevotella species.29 Although the implications of these differences remain unclear, animal studies have provided some clues. Colonization with commensal bacteria prevents development of diabetes in male but not female mice predisposed to developing type 1 diabetes.30, 31 This protective effect is dependent on androgen receptor activity and can be transferred to female mice by transplanting intestinal microbes from adult male to immature

3

BOX 3.2 Techniques to Assess Microbiota Composition and Functionality 26 PART I  Biology of the Gastrointestinal Tract MICROBIOTA COMPOSITION Microbial Culture Early studies dissecting the microbiota composition were technologically limited by culture-based techniques, which in turn relied on specialized growth media under varying conditions to identify specific microbes. This restricted our ability to identify only a small subset of organisms for which established culture conditions had been described and which accounted for 5%-15% of the intestinal bacteria we know to constitute the microbiome today.183, 184 As a result, locations with limited diversity were often considered sterile given the inability to culture their resident bacteria. Today, however, nearly all locations in the body have been described to have characteristic resident microbes185-187 as a result of culture-independent sequence-based identification methodologies. Sequencing-based data have also improved our ability to culture bacteria previously considered to be unculturable. We are now able to culture a significant proportion of an individual’s fecal microbiota, using various culturing conditions,188, 189 which has allowed us to determine the relevance of microbial compositional changes and the interactions and impact of individual or groups of bacteria on host phenotypes using models such as germ-free mice.  Microscopy Early methods included scanning and transmission electron microscopy of intestinal tissue, which provided estimates of diversity based on morphology and high-resolution images of individual bacteria but did not allow bacterial identification.190, 191 The use of general stains such as the Gram stain provides resolution beyond morphology, but also is insufficient for identification. Fluorescence microscopy provides the opportunity to identify bacteria by fluorescence in situ hybridization to microbe specific 16s rRNA.192 The increased availability of sequencing data has allowed development of more precise fluorescence in situ hybridization probes and carries the advantage of not requiring culture. The fixation methods are compatible with preserving mucus and the use of multiple probes simultaneously allows detection of several bacteria within a sample.193, 194 In addition, it is 1 of the primary tools to define the biogeography of microbes within the intestine and the interaction of bacteria with the host at the mucosal surface. The advances in fluorophores, imaging, and computational tools have significantly improved our ability to visualize microbes both in vivo and in vitro. Conventional fluorescent probes require oxygen limiting their utility in vivo, but new tools using “click” chemistry allow tagging of bacteria with oxygen-independent fluorescent tags for in vivo tracking.195  Next-Generation Sequencing The early culture-independent compositional tools used denaturing gradient gel electrophoresis to separate different-sized bands that represented distinct taxonomic groups.7 However, with the advent of next-generation sequencing technologies (e.g., Illumina, 454, Ion Torrent, SOLiD, etc.), marker-based (16S rRNA gene) and shotgun sequencing of all genes within a community have superseded denaturing gradient gel electrophoresis, especially given the declining cost of sequencing. The marker-based approach takes advantage of the conservation of DNA sequence in the gene encoding the 16S rRNA subunit that is found in all microbes. Interceding variable regions are targeted for amplification by polymerase chain reaction, allowing simultaneous identification of different taxa within a sample. However, marker-based sequencing is limited in its ability to identify taxa beyond the genus level given the small amplicon sizes. Third-generation sequencing technologies, such as single-molecule real-time sequencing have emerged, which will likely supersede the current methodologies, given their potential to generate read lengths (continuous sequence from a single piece of DNA) of 10 kilobases.183  MICROBIAL FUNCTION Compositional data are limited in the ability to provide insight into host-microbe interactions; hence it is important to move beyond detailing which microorganisms are present to determining their role, function, and effects of their metabolic products on the intestinal microbial community and the host. This is especially important given that core microbial functions appear to be conserved despite compositional heterogeneity among human populations.

Metagenomics Often referred to as whole genome sequencing, or shotgun sequencing, metagenomics allows characterization of all genes in a microbial community and provides the broad functional potential of a community. It cannot, however, provide the specific functionality under a given set of conditions.  Metatranscriptomics Transcriptomic approaches like RNAseq provide a snapshot of geneexpression profiles of microbial communities under a given condition. This data can be used to further infer differential expression of metabolic pathways using analysis tools like HUMAnN2.196  Metaproteomics and Metabolomics Metaproteomics provides comprehensive characterization of proteins, whereas metabolomics provides comprehensive characterization of small molecules and metabolites, each from microbial communities. Both approaches allow characterization of the overall metabolic state of complex communities resulting from differential gene expression among communities or the same community under different conditions. For proteomics, proteins can either be directly separated based on hydrophobicity, charge, or both, using liquid chromatography (LC) or digested to peptides via proteases such as trypsin prior to chromatographic separation followed by mass spectrometry (MS) for the parent peptide and tandem MS-MS for fragmentation information. The biggest challenge currently is the downstream bioinformatics processing because a predicted protein database needs to be constructed from metagenomic information to assign the obtained peptide sequence information to the proteins. Alternatively, the vast diversity of small molecules, and differences in properties and concentrations, require that multiple methods be used to cover the vast array of metabolites; these include separation using LC, gas chromatography, high-pressure LC, ultra-pressure LC, coupled to MS, and proton nuclear magnetic resonance spectroscopy (1H-NMR).197 Metabolomics can be done in a targeted or non-targeted manner and downstream processing using statistical methods allows identification of discriminative features. One of the challenges that remains is the accurate identification of metabolites in MS spectra, though there has been significant progress with multiple spectral databases such as HMDB, METLIN, and ChemSpider, all of which are being constantly updated.  Modeling Microbes In Vitro and In Vivo Organoids Organoids are derived from tissue stem cells or pluripotent stem cells and can be maintained in culture, wherein they maintain their polarity and recapitulate the composition and organization of cells, thus representing an ideal in vitro system to study host-microbe interactions in the context of specific diseases. There are several methods used to study host-microbe dynamics including co-culture; exposing an organoid-derived monolayer to microbes/microbial products; and microinjection, which is especially relevant for studying luminal interactions as well as modeling anaerobic microbes.198  Germ-Free Mice Although humans are the ideal biological system to study microbes, animal models are needed to help deconstruct complex interactions and delineate mechanisms underlying host-microbiome interactions. Conventional mouse models provide conceptual knowledge, but they are limited in their translatability and ability to study defined colonization states. Germ-free and gnotobiotic (previously germ-free mice but now colonized with defined microbial associations) animal models allow modeling of individual microbes as well as complex communities from mice or other species (human; humanized mice) to study microbe-microbe and microbe-host interactions. Recapitulating phenotypic features of disease states following transfer of microbial communities allows for identification of microbe-driven phenotypes. They are also ideal for studying the effects of host, environment, and dietary factors on the microbiome in a controlled setting. In regard to translatability, humanized mice faithfully recapitulate the structure and function of human microbial communities199 and represent a readily translatable preclinical model.

CHAPTER 3  The Enteric Microbiota

Obesity/metabolic syndrome Diabetes IBD Non Alcoholic Fatty Liver Disease Celiac Disease

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Probiotics -Single or multispecies -Defined microbial communities -Engineered bacteria Prebiotics Synbiotics Intestinal (Fecal) microbiota transplant Bacteria-derived small molecules Diet

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Host physiology

Fig. 3.1  Characteristics of intestinal microbiota: The figure outlines the modifiable and non-modifiable host factors influencing the intestinal microbiota, the reciprocal interactions between intestinal microbiota and host physiology, the resilience of the microbiome, as well as the consequence of deleterious shifts in the microbiome and the potential mechanisms to manipulate the microbiome.

female mice. This illustrates one potential effect of sex-dependent differences in the intestinal microbiota, in which the distinctions influence hormone-dependent regulation of autoimmunity. 

Genetics The intestinal microbiota composition in monozygotic twins is more similar to one another than those of dizygotic twins, which suggests a role for host genes in selecting for certain microbial taxa.32 Some of these associations have been uncovered such as FUT2 polymorphisms,33 variants in immunity-related genes, and genes that alter bile acid levels,34 although not all taxa are influenced by host genetics; heritability appears to be a factor that drives approximately 10% of the microbial taxa,34 and, in fact, members within the Bacteroidetes phylum appear to be more influenced by environmental factors. Interestingly, one highly heritable taxon within the family Christensenellaceae, which co-occurs with other heritable taxa, is enriched in lean individuals and is associated with leanness, suggesting that heritability of certain host traits may be a result of the intergenerational transfer of key bacteria.34 

Geography and Diet Intestinal microbiota composition varies significantly with geography, which represents combined effects of cultural, dietary, and environmental factors. For example, the microbiota composition of individuals living in the United States and Europe are distinct— and less diverse than—those of individuals living in non-Western, non-urban settings, such as rural Malawi, Tanzania, Burkina Faso, or the Amazon.26, 35-37 In particular, residents of non-urban settings have a greater proportion of the genus Prevotella and a lower proportion of Bacteroides.38 The intestinal microbiome associated with Western cultures expresses more enzymes that are capable of degrading the amino acids and simple sugars, which are reflective of the high protein and simple carbohydrates Western diet, whereas the intestinal microbiome associated with traditional cultures expresses more enzymes capable of degrading starch given that these diets comprise high-starch staples such as corn and cassava.26 Diet plays an important role in shaping the intestinal microbiota composition and function within the same population39 and may in part contribute to geographical differences, but there are additional factors at play when considering

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PART I  Biology of the Gastrointestinal Tract

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can also have deleterious effects on the intestinal microbiome and increase propensity for metabolic and inflammatory disorders.45 Dietary components serve as substrates for microbial metabolic pathways and hence can influence the generation of specific microbial metabolites, which influence host physiology. Some examples include the tryptophan derivatives indole acetic acid and indole propionic acid, which are implicated in inflammation; SCFAs from dietary carbohydrates, which can influence the intestinal serotonergic pathway, thereby altering GI motility; and dietary fat-related free fatty acids and lipopolysaccharide, which are associated with enteric neurodegeneration, altered GI motility, and systemic effects contributing to obesity. In addition to direct transformation of dietary components, bacterial urease can convert host-derived urea to ammonia, contributing to hyperammonemia-associated encephalopathy in patients with liver disease46 and can also result in the altered microbiota composition associated with Crohn disease.47 

Exercise Fig. 3.2  Photomicrograph (20×) showing bacteria distributed across the mucosa in a specimen of proximal colon from a C57BL/6J mouse. Tissue was fixed in Carnoy solution (60% ethanol, 30% chloroform, 10% glacial acetic acid), which preserves mucus, and stained with Alcian Blue, which highlights mucus. The layer immediately above the colonic mucus is the mucosa-associated microbiota—a relatively stable community that likely forms a biofilm matrix that confers community stability, even after colonic lavage. There is faint stratification of the microbiota, suggesting that the organization of this community is not random. The transition zone above the mucosa-associated microbiota zone is a mixture of intestinal microbes and food particles. (Image courtesy Dr. Lev Lichtenstein, Ashdod, Israel).

differences across different geographical regions. The significant differences in the metabolome of vegans in the United States and individuals in other agrarian cultures suggest there are likely geography-specific factors that shape microbiota composition and function in addition to diet.40 The effect of diet is not limited to microbiota composition as functional differences may be seen even in the absence of compositional changes,40 which highlights the importance of multi-omic profiling to assess both microbial composition and function when evaluating the effect of diet. The intestinal microbiome is shaped in part by long-term dietary habits, but short-term dietary changes can also cause rapid but reversible shifts in the intestinal microbiome.41 This may help explain intermittent worsening of symptoms seen in GI diseases associated with alterations in the intestinal microbiome. Among dietary components, microbiota-accessible carbohydrates (MACs) found in fiber are one of the key sources of nutrients for intestinal microbes. In fermenting MACs, microbes produce short-chain fatty acids (SCFAs), which can help attenuate inflammation, serve as an energy source for epithelial cells, and improve GI transit.42 The Western diet is low in MACs42 and has been associated with the risk of inflammatory and metabolic-related diseases.42 The long-term impact of a low MAC diet is difficult to evaluate in humans as it would require study over multiple generations. Experiments in the mouse model show that deleterious changes in the intestinal microbiota induced by a low-MAC diet are largely reversible early on with a high-MAC diet,43 although feeding mice a low-MAC diet over the span of multiple generations results in a progressive loss of microbial diversity; disappearance of microbial taxa, which cannot be rescued by diet, requires transplantation of the missing bacteria.43 Low dietary fiber results in an increased reliance of intestinal microbes on the host epithelium and mucus, resulting in disruption of the epithelial barrier and an increased susceptibility to inflammation. A similar effect is also seen with a high-protein diet, which results in increased microbial density as well as an increased potential of the microbiome to cause colitis.44 In addition to dietary macronutrients, additives such as emulsifiers and substitutes such as artificial sweeteners

To date, little research has been conducted on the direct effect of exercise on the intestinal microbiota in humans, because it is difficult to isolate the effects of exercise from diet. As an example, athletes were found to have a more diverse intestinal microbiota and lower levels of inflammatory markers than non-athletic controls matched for size, age, and gender,48 however the athletes’ diets also contained more protein, fruit, and vegetables than those of the controls, complicating interpretation of the results. The effects of exercise can be separated in animal models and exerciserelated changes in intestinal microbiota composition were found to reduce susceptibility to inflammation49 and weight gain.50 Exercise-related changes in the intestinal microbiota can be similar in magnitude but compositionally different from those seen with dietary change;51 this raises the possibility that although exercise is commonly used to combat obesity, it may not attenuate all of the ill effects of a high-fat, Western diet. 

Medications Antibiotics significantly reduce microbial diversity52 and appear to have their most profound effects during early life by affecting maturation of the intestinal microbiome; even sub-therapeutic levels of antibiotics in early life were found to increase adiposity later in life.53 Similarly, in a swine model, early-life antibiotic exposure changed the intestinal microbiome, altering glucose regulation and ultimately resulting in long-lasting changes to SCFA signaling and pancreatic development.54 The intestinal microbiota composition of young children who have received multiple courses of antibiotics is less diverse than that of untreated children,55 and early antibiotic use is associated with delayed maturation of the microbiome and long-lasting changes in both microbiota composition and functionality.56 Also, peripartum use of antibiotics can result in persistent shifts in the intestinal microbiota and increased susceptibility to inflammation in the offspring;15, 16 these observations also support the observed association of early antibiotic use and increased risk for Crohn disease.57 A diverse array of other types of drugs, including PPIs, laxatives, metformin, statins, hormones, benzodiazepines, antidepressants, NSAIDs, and antihistamines among others, are associated with changes in the composition of the intestinal microbiota.4, 58, 59 Metformin, which is commonly used to treat type 2 diabetes and NAFLD, is associated with significant changes in the intestinal microbiota, and these changes are in part responsible for the metformin-related improvement in glucose metabolism.60 PPIs, which are among the 10 most widely used drugs in the world,61 are associated with decreased levels of bacterial richness, an increased abundance of oral microbes, and the presence of potential pathogens in the intestine.61 

CHAPTER 3  The Enteric Microbiota

Other Lifestyle Factors Habits such as smoking or alcohol consumption, as well as psychological stress,62 have been associated with changes in the intestinal microbiota, although it is premature to conclude that these changes contribute to the deleterious effects of stress or alcohol. The adverse effects of smoking on microbial diversity can be indirectly inferred from the increase in diversity observed after smoking cessation.4, 63 Household contacts also can have an effect on the microbiota composition. Individuals in the same household share skin microbiota and, interestingly, household pets significantly increase sharing of skin microbiota among household contacts.64 It is important to recognize that none of the individual factors mentioned above exist in isolation and, in fact, the selection pressure on microbial structure may be driven by inter-relationships between many of them; this is demonstrated by 2 studies in mice with either diverse genetic backgrounds or with a single mutation in the FUT2 gene, in which the genetic influence on the intestinal microbiome was overcome by diet.33, 65 

Microbe-Microbe Signaling There are several mechanisms that determine microbial selfselection and contribute to community dynamics and stability using quorum-sensing molecules such as auto-inducers (homoserine lactone), bacteriocins, and competence- and sporulation-stimulating factor.66, 67 These quorum-sensing molecules, especially bacteriocins, can be exploited to provide protection against infections.68-70 

THE EFFECT OF HOST–INTESTINAL MICROBIOME INTERACTIONS ON HOST PHYSIOLOGY Interactions between humans and their intestinal microbes are bidirectional: reciprocal signaling occurs between the intestinal microbiota and the immune system, the GI tract, and even the nervous system. As a result, it would be unwise to think in terms of cause and effect alone as changes in the intestinal microbiome associated with a disease state may further perpetuate the disease state. The mechanisms by which microbial mediators influence host physiology is an active area of study. The metabolism of tryptophan by the intestinal microbiota yields several bioactive molecules such as indole acetic acid and indole propionic acid that act as ligands for aryl hydrocarbon receptor (AhR) and tryptamine, which is a ligand of serotonin receptor 4. Microbiota-derived AhR ligands have been found to be protective against inflammation, both in the periphery and in the CNS, which suggests a role for them in diseases like IBD, multiple sclerosis, and neuropsychiatric disorders.71 Intestinal microbes also produce N-acyl amides similar to human N-acyl amides that interact with G protein-coupled receptors (GPCRs) to regulate GI physiology.72 GPCRs that interact with human N-acyl amides have been implicated in diseases such as diabetes, obesity, cancer, and IBD. Whether this type of molecular mimicry is common is unknown at present, but the field is evolving rapidly. Here we briefly describe what is known about the bidirectional interactions present between the intestinal microbiome and various host compartments.

Interactions Between the Intestinal Microbiome and Immune System The intestinal microbiome shapes the maturation of the immune system, and the immune system, in turn, can modulate the composition of the microbiota and its pro-inflammatory potential. Epithelial and dendritic cells represent the first line of contact with the intestinal microbiota. Host cells use pattern recognition receptors, such as Toll-like receptors (TLRs), NOD-like receptors, and C-type lectins, to recognize microorganism-associated molecular patterns on the surface of both commensal microbes

29

and pathogens. Intestinal microbes generate immune tolerance to survive in the intestine. As an example, Bacteroides fragilis produces “a symbiosis factor” (polysaccharide A) that signals through TLRs directly on regulatory T-cells to promote niche-specific mucosal immune tolerance.73 Microbes also produce a rich array of other immunomodulatory molecules, including CpG (cytosine phosphodiesterase guanine) DNA, which acts on TLR9 receptors; ATP, which acts on specific sensors (P2X and P2Y) to promote the generation of intestinal Th17 cells74, 75; and SCFAs, which act on GPCRs to down-regulate inflammatory responses.76 The host immune system, in turn, helps contain and shape the composition of the intestinal microbiota. Epithelial cells produce anti-bacterial proteins, such as α-defensins, which limit contact between bacteria and the epithelial cells.10 Disturbances of hostmicrobe signaling have been linked with aberrant expansion of some components of the microbiota that may adversely influence the inflammatory response and risk of disease.77 Defects at various levels, including specific TLRs and transcription factors involved in innate immunity, can result in the emergence of a “colitogenic” microbiota.78, 79 Epithelial cells respond to pathogen invasion by mobilizing the NLRP6 (NOD-like receptor family pyrin domain containing 6) inflammasome and a molecular cascade that culminates in release of IL-18, which simulates γ-interferon and a bactericidal immune response.80, 81 

Interactions Between the Intestinal Microbiome and Gastrointestinal Tract The key functions of the GI tract that facilitate digestion and absorption of nutrients include motility, secretion, and sensation. GI transit time varies within and between populations worldwide.82 However, variation in transit time can be associated with diverse disease states, including infections, inflammatory conditions, and functional disorders such as IBS with constipation or diarrhea.83 GI transit is an example of the bidirectional interactions between the intestinal microbiome and the GI tract. Thus transplanting a complex fecal microbial community from a healthy human into a germ-free (GF) mouse stimulates production of the neurotransmitter serotonin and significantly shortens GI transit time, suggesting a role for intestinal microbes in modulating GI transit. Alternatively, increasing or decreasing GI transit time using medications such as polyethylene glycol or loperamide in humanized mice (ex-GF mice colonized with human bacteria) significantly changes the intestinal microbial community,83 and similar alterations in intestinal microbiota composition and function have been reported in patients with diarrhea and constipation.84, 85 Some examples of microbial mediators that affect GI transit time include LPS, which can influence enteric neuronal survival, and SCFAs, which can stimulate intestinal synthesis of serotonin, which, in turn, plays an important role in GI motility, secretion, and sensation.86 It is not surprising that the magnitude of impact on GI transit depends considerably on the diet the humanized mouse is fed,83 given that diet can affect downstream mediators such as SCFAs. In addition to transit, the intestinal microbiome can also influence sensation in the GI tract as evidenced by the development of visceral hypersensitivity following the transfer of microbiota from patients with IBS to GF rats. In addition to disruption of the intestinal microbiota in early life,87 a correlation has been described between visceral hypersensitivity and expansion of Escherichia coli. The intestinal microbiome plays an important role in maintaining the epithelial barrier as well as fluid and electrolyte transport. Specific members of the intestinal microbiota can alter expression of tight junction proteins in the epithelium and microbial metabolites like butyrate play an important role in maintaining the epithelial barrier. Microbial deconjugation and metabolism of bile acids can alter the pool of bile acids such as chenodeoxycholic acid and deoxycholic acid, which act as secretagogues in the colon. 

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PART I  Biology of the Gastrointestinal Tract

The Microbiome-Gut-Brain Axis The influence of our intestinal microbes extends far beyond the GI tract. Information can travel in a “top-down” fashion, as our experiences—filtered through the brain—help shape our intestinal microbiome. For example, exposing mice to various forms of stress alters the composition of their microbiota.88, 89 Conversely, there are many avenues by which intestinal microbes can influence the nervous system in a “bottom-up” fashion. First, they can alter function of the enteric nervous system,90 which, in turn, is linked to the CNS through the vagus nerve; intestinal microbes have been shown to activate stress circuits in the brain by activating vagal pathways.89 Second, microbial metabolites can target areas of the CNS that are not protected by the blood-brain barrier such as the hypothalamic-pituitary-adrenal axis.91 Animal models suggest that certain intestinal microbes can help program the hypothalamic-pituitary-adrenal axis early in life, influencing stress reactivity across the life course.89 Finally, microbiotaderived small molecules such as SCFAs could diffuse across the blood-brain barrier.91 The intestinal microbiome has an impact on the development of the nervous system, affecting everything from the formation of the blood-brain barrier to myelination to neurogenesis.92 The microbiome has also been shown to influence behavior in mice.92, 93 These findings have spurred interest in the relationship between the intestinal microbiome and mental health in humans, including links with autism spectrum disorders, anxiety disorders, depression, pain sensitivity, learning, and memory.93, 94 

THE ROLE OF THE INTESTINAL MICROBIOME IN HUMAN DISEASE Metabolic Function Obesity (see Chapter 7): A number of lines of evidence point to a link between the intestinal microbiome and obesity. There is an abundance of observational data showing changes in microbiota composition at multiple taxonomic levels and decreased microbial diversity in obesity. The experimental data in support of the link between the microbiome and obesity include the lack of diet-induced obesity in GF mice and the greater weight gain following colonization of GF mice with intestinal microbiota from an obese human twin than from the lean twin.95 Several putative mechanisms supporting a role for the intestinal microbiome in obesity and diabetes have been proposed such as increased energy harvest by microbial glycoside hydrolases, decreased muscle fatty acid oxidation mediated by a decrease in activated protein kinase, increased hepatic lipogenesis, alteration of satiety hormones, and induction of chronic low-grade inflammation. The small intestinal microbiome plays an important role in lipid digestion and absorption and may contribute to obesity.96 Diurnal oscillation in biological processes (the circadian rhythm) is a key regulator of metabolic processes and exhibits bidirectional communication with the intestinal microbiota. The intestinal microbiota exhibit diurnal fluctuations in composition as well as function (e.g., butyrate production) and signal to the molecular clock, resulting in changes in gene expression that can be seen in distant organs, such as the liver and brain. The circadian rhythm, in turn, can alter intestinal microbiota composition. The circadian clock responds to changes in diet and is likely an important mediator of microbiota-associated effects in diet-induced obesity.97-100 Type 2 Diabetes (T2D): Similar to obesity, there are observational and experimental data supporting a role for the intestinal microbiome in T2D. In a pilot human study, IMTs (FMTs) from lean donors improved insulin sensitivity and increased microbial diversity and butyrate-producing bacteria in obese recipients.101,102 The intestinal microbiome is also an important determinant of glycemic responses to different dietary nutrients,103 which

further supports its role both as a determinant as well as therapeutic target in T2D. Cardiovascular disease: In addition to its effect on obesity and metabolic syndrome, microbial metabolism of dietary ingredients can also influence cardiovascular disease. Metabolism of substrates such as choline, phosphatidylcholine, and L-carnitine (found in red meat) by various members of the intestinal microbiota (Anaerococcus hydrogenalis, Clostridium asparagiforme, C. hathewayi, C. sporogenes, Escherichia fergusonii, Proteus penneri, Providencia rettgeri, and Edwardsiella tarda) to trimethylamine (TMA) with subsequent conversion to trimethylamine oxide (TMAO) by host flavin mono-oxygenase3 (FMO3) was found to be a major driver of atherosclerotic plaques in mice.104 Plasma L-carnitine levels with concurrently high TMAO levels were found to predict an increased risk for cardiovascular disease in human subjects,104 validating the findings from the animal model.105 The small molecule, 3,3-dimethyl-1-butanol, which decreases TMAO levels by inhibiting a wide range of TMA lyases (including those derived from human feces) across a wide array of substrates that can be converted to TMA, prevents choline diet-induced atherosclerosis in susceptible mice.106 This provides an important paradigm for treating microbiota-related diseases by manipulating host-microbial co-metabolism. NAFLD (see Chapter 87): NAFLD is a manifestation of metabolic syndrome in the liver and, similar to other metabolic disorders, is associated with shift in microbiota composition and metabolic functions. Animal studies show that NAFLD can be induced by manipulating the intestinal microbiome.107 Although the specific mechanisms underlying liver dysfunction in NAFLD remain unclear, a role for LPS and for production of ethanol by intestinal bacteria has been proposed in addition to those described above for obesity and T2D. 

INFLAMMATORY DISEASES IBD (see Chapters 115 and 116): The role of the intestinal microbiome in IBD has been extensively studied. Genetic studies link IBD with host polymorphisms in genes that function as bacterial sensors, such as nucleotide-binding oligomerization domaincontaining protein 2 (NOD2) and TLR4,53 suggesting an etiologic role for the intestinal microbiome. This relationship is further supported by improvement in subsets of IBD patients after antibiotic treatment.108 The absence of inflammation in susceptible GF animals suggests that the intestinal microbiome is an important component of IBD pathogenesis. There is significant heterogeneity among the described intestinal microbiota changes in patients with IBD, which is expected, given that IBD is a multifactorial disease and several contributing factors such as genetics, early life exposure, and diet are also known to influence the intestinal microbiota composition. A reduction in alpha diversity is seen as a consistent trend, but relative increase in the abundance of Enterobacteriaceae, including E. coli and Fusobacterium, have also been described in patients with IBD. There has been a significant effort to characterize the mucosa-associated microbiota, which is presumed to play a more significant role in pathogenesis. A greater density of mucosa-associated bacteria109 has been described in IBD110 and the mucosa-associated bacteria can vary over time with change in severity of disease.111 Ileal and rectal biopsies from newly diagnosed, treatment-naïve children with Crohn disease were found to have an increased relative abundance of Enterobacteriaceae, Pasteurellaceae, Veillonellaceae, and Fusobacteriaceae and decreased relative abundance of Bacteroidales and Clostridia.112 Together, these findings support a potential role for mucosa-associated microbiota in IBD, although it is difficult to establish causation. A recent meta-analysis found nonspecific changes in intestinal microbiota composition, which are associated with multiple disease states, making it difficult to rely on microbiota composition alone.113

CHAPTER 3  The Enteric Microbiota

Animal studies provide evidence for potential mechanisms underlying the role of the intestinal microbiome in IBD. Mice deficient in antimicrobial defense genes are predisposed to develop both dysbiosis and colitis, either spontaneously or in response to intestinal damage, reinforcing the importance of host-microbe interactions in IBD.110 Although transplanting the intestinal microbiota from IBD patients into GF mice does not cause spontaneous colitis, it does increase susceptibility to colitis with chemical induction or in genetically predisposed mice.110 The increase in microbial density in response to high levels of dietary protein exacerbates colitis, whereas increased fiber increases microbial diversity, improves intestinal barrier function, and alleviates colitis.44 Celiac disease (see Chapter 107): Celiac disease is an immunemediated condition triggered by gluten in genetically susceptible individuals.114 Attention has increasingly focused on the intestinal microbiome and its potential role in celiac disease, based on observed intestinal microbiota compositional and functional changes. Similar to IBD, there is significant heterogeneity among studies, although a significant decrease in microbial alpha diversity and expansion of Proteobacteria appears to be most consistent in recent studies using NGS.115 There is likely a role for early life exposures, as infants genetically predisposed to celiac disease have higher abundance of the phylum Firmicutes and lack of bacteria within the order Bacteroidales compared with infants without such genetic predisposition. An abnormal maturation of the microbiota was also observed: unlike nonpredisposed infants, the microbiota does not resemble that of adults even at 2 years of age. Genetically susceptible infants exposed to gluten early developed celiac disease autoimmunity more frequently than if gluten exposure were delayed until 12 months of age, suggesting an immature microbiome may further accelerate the immunologic process.116 It is difficult to establish causation in human studies, but GF mice genetically predisposed to develop celiac disease experience more severe gluten-induced pathology than identical mice that have been colonized by commensal intestine microbes, suggesting a healthy microbiome is likely protective.114 Alternately, GF rats colonized with intestinal bacteria from celiac disease patients exhibit decreased intestinal permeability when exposed to gliadin, which is a hallmark of celiac disease, and suggests a role for an unhealthy microbiome in celiac disease pathogenesis.117 The mechanisms underlying the role of the intestinal microbiome in celiac disease are still being investigated. 

CANCER Colorectal cancer (CRC; see Chapter 127): The intestinal microbiome may trigger carcinogenesis, either directly (by producing carcinogenic molecules) or indirectly (by creating a pro-inflammatory microenvironment).118 In support of this hypothesis, mouse studies show that depleting the microbiota, either in the GF state or by the use of antibiotics, reduces the risk of developing colon cancer.119 Individuals with CRC have been found to harbor Fusobacterium nucleatum119 in the tumor; interestingly, Fusobacterium, as well as the rest of the associated CRC microbiota, is also found in metastases. Elimination of Fusobacterium with a narrow-spectrum antibiotic was found to reduce cancer cell proliferation and tumor growth in mice with CRC xenografts.120 Recently, a collaboration between 2 microbes that form a biofilm in the intestine, namely enterotoxigenic B. fragilis and an E. coli strain, which produces colibactin, has been found to trigger the DNA damage leading to CRC. An association between H. pylori infection and CRC was identified in a meta-analysis of published studies, although the incidence of colon cancer does not mirror that of gastric cancer, suggesting either additional mechanisms or a complex interplay underlying this association.121 Streptococcus gallolyticus (previously known as

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S. bovis) bacteremia has also been associated with CRC though it remains unclear if it is a consequence or a driver of CRC.121 

FUNCTIONAL GASTROINTESTINAL DISORDERS (SEE CHAPTER 122) A role for intestinal bacteria in functional GI disorders, such as IBS, has been proposed based on compositional changes in the microbiota and their role in modulating host physiology, including GI transit, epithelial barrier function, intestinal secretion, visceral sensation, and modulation of the gut-brain axis. There is no consistent “IBS-microbiota” pattern, but there appears to be a decrease in microbial diversity and alterations at different taxonomic levels.122,122a Several microbial metabolites such as SCFAs, hydrogen sulfide, methane, tryptamine, and bile acids have demonstrated effects on host physiology.122 Microbiota-targeted therapies are widely used in functional GI disorders. The available data suggest improvement in global symptoms such as bloating and flatulence when considering all probiotics123 but do not provide support for a therapeutic action of any specific probiotic, prebiotic, or synbiotic (see Chapter 130). IMT (FMT) has also been used to treat patients with IBS-D, albeit with varied results.122b As with other diseases, more rigorous trials need to be performed before the role of IMT (FMT) for IBS, if any, can be determined. 

THE ROLE OF THE INTESTINAL MICROBIOME IN MODULATION OF DRUG RESPONSE The intestinal microbiome is an important factor in the observed inter-individual differences in therapeutic responses and adverse events to medications. Intestinal microbiota-encoded genes not only enhance the metabolic capabilities of the host124 but also play a role in the biotransformation of luminal compounds including medications.125 The plasticity of the microbiome makes it an even more relevant factor because, in contrast to genes, the microbiome is modifiable. The microbiome has been identified as having a role in determining response to medications, mediating the effect of medications, and metabolism of certain medications, thereby affecting their efficacy or adverse effects.126 Although several such interactions have been identified, some are described in animal models and hence need to be confirmed in humans and validated across different cohorts. Secondary bile acids and coprostanol, which are a result of microbial metabolism, may be predictive of response to statins;127 certain Bacteroides species are associated with the success of CTLA-4 antibodies used in cancer immunotherapy;128 and administration of Bifidobacterium may augment response to programmed cell death protein 1 ligand 1 (PD-L1)—antibody used in melanoma.129 The intestinal microbiome may also be responsible in part for the anti-diabetic effects of metformin.130 Eggerthella lenta carries the cardiac glycoside reductase (cgr) operon and can inactivate digoxin which has a narrow therapeutic window.131 The intestinal microbiome may also explain the inter-individual differences in response to the common analgesic acetaminophen,132 given that p-cresol produced by certain bacteria (e.g., Clostridium) can compete with acetaminophen as a substrate for Sulfotransferase Family 1A Member 1, a human liver enzyme (SULT1A1),132 and lead to a buildup of N-acetyl-p-benzoquinone imine, which, in turn, leads to hepatotoxicity. The chemotherapeutic agent irinotecan (CPT-11) used in treatment of colon and pancreatic cancer is inactivated in the liver, but the inactive metabolites can be transformed into active drug by bacterial β-glucuronidases, which in turn results in diarrhea, a significant side effect that may necessitate discontinuation of the drug in some patients.133 A targeted inhibition of such bacterial enzymes can significantly improve compliance with chemotherapeutic regimens without affecting efficacy. These examples represent just the tip of the iceberg and given the immense metabolic potential of the intestinal microbiota,134 it likely plays

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PART I  Biology of the Gastrointestinal Tract

an important role in the biotransformation and response of most therapeutic agents. 

THERAPEUTIC MODULATION OF THE INTESTINAL MICROBIOME The intestinal microbiome is an important area of study as it represents a modifiable factor in pathophysiology of disease and response to medications. There are several approaches currently used to modulate the microbiome (see Fig. 3.1) ranging from an ecosystem approach as in IMT, use of selected bacterial strains alone or in combination with probiotics, stimulation of specific bacterial community functions through prebiotics, and combination approaches as with synbiotics and diet. IMT has had the most significant impact in the management of Clostridioides difficile infection (CDI), which is now the most common health care–associated infection in the US.135, 136 There are several mechanisms that contribute to the effectiveness of IMT in CDI including an increase in secondary bile acid production; restoration of microbial diversity and filling of open nutritional niches; and changes in microbial community structure with an increase in butyrate producers. Overall, the response rate of IMT in RCDI ranges from 80% to 95%137 and in a meta-analysis (observational studies), the primary cure rate was 91.2% and the overall recurrence rate was 5.5%.138 Pilot studies in patients colonized with vancomycin-resistant enterococcus (VRE) show IMT may be beneficial in decontamination of VRE.139, 140 Stool substitutes are currently being studied and may replace IMT in the near future. A similar approach using IMT is also being tested in multiple chronic conditions ranging from GI diseases like IBD and IBS to metabolic diseases such as obesity and T2D. Early data from autologous IMT post-bone marrow transplant appear promising in reducing diarrheal disease in the post-transplant period and a few studies also show benefit of allogenic IMT in graft vs. host disease.141 An alternative to the ecosystem approach is a single bacterium or combination of bacteria as in probiotics to improve disease states. Although there are trends that support benefits for certain probiotic strains or formulations in diarrheal states, necrotizing enterocolitis, IBD, and IBS,142, 143 there are major shortcomings in relation to clinical studies of probiotics, making it difficult to derive a clinically useful message (see Chapter 130). The microbial consortia approach appears to be more promising with studies showing that defined consortia of commensal bacteria containing the Clostridium cluster XIVa species, Blautia producta and Clostridium bolteae can restore colonization resistance against VRE144; consortia of commensal bacteria within the Clostridiales order can confer resistance to Listeria monocytogenes145; and consortia containing Clostridium scindens can restore colonization resistance against C. difficile.146 The identification of specific microbial mediators and improved understanding of the mechanism underlying the effects of intestinal bacteria will help develop the next generation of more targeted probiotics, including genetically engineered commensal/probiotic organisms to deliver vaccines or therapeutic molecules.147, 148 Prebiotics were initially designed to boost certain beneficial bacteria such as Lactobacilli and Bifidobacteria, however, this approach has since evolved to focus on the overall functionality of the microbial community and its effect on host function; as a result this group is no longer restricted to specific oligosaccharides but includes a wide array of dietary ingredients. A synbiotic refers to the combination of a prebiotic with a probiotic, which in theory should amplify the benefits of the probiotic and this has in fact been seen in a large study of infants for the prevention of sepsis.149 The safety record of microbiota-targeted therapies has been good,150, 151 however, the data lack the rigor that one associates with drug safety monitoring.152 The intestinal microbiota is also a rich source of a relatively new class of therapeutics often referred to as pharmabiotics, which includes the exopolysaccharide coat153, 154 and pili155 of

certain Bifidobacteria; anti-bacterial molecules, known as bacteriocins; anti-bacterial phages; and even bacterial DNA, which has been demonstrated to exert anti-inflammatory activity.69, 156-160 

NONBACTERIAL MEMBERS OF THE INTESTINAL MICROBIOME The collection of fungi referred to as the mycobiome is currently believed to represent a minor component of the intestinal microbiota, but this may be a result of underestimation given the lack of fully annotated genomic databases, such as those available for bacteria.161 The diversity of the mycobiome, similar to that of bacteria, is estimated using sequencing of marker gene 18S and its internal transcribed spacer.162 Fungi are ubiquitous and Candida represents the most prevalent genus, containing approximately 160 species,163, 164 with C. albicans, C. tropicalis, C. glabrata, and C. parapsilosis predominantly found in humans.161 The mycobiome is influenced by the environment165 and diet. The presence of Candida is associated with immunodeficiency states and diets that are high in carbohydrates, but not with animal-based diets high in amino acids, protein, and fatty acids.166 The competitive relationship of bacteria and fungi is evident from the overgrowth of fungi following the use of antibiotics.165, 167 The biological effects of fungal overgrowth are still under investigation, but the mycobiome has been implicated in immune responses both within the GI tract such as in IBD, as well as outside the GI tract such as in allergic airway responses. Certain components of the innate immune system such as TLRs 2 and 4, dectin-1 (a C-type lectin receptor), CD5, CD 36, and SCARF1 (members of the scavenger receptor family), and components of the complement system can be activated by fungal glycoprotein cell wall components, β-glucans, chitin, and mannans, resulting in immune signaling via molecules such as interleukin 17 (IL17), IL22, and NF-κB.161 Anti-Saccharomyces cerevisiae antibodies (ASCA) directed against a fungal cell wall epitope with significant cross-reactivity to C. albicans is considered a biomarker of Crohn disease.168-170 ASCA may also represent an early immune marker predictive of developing Crohn disease (see Chapter 115).171 The virome represents one of the most diverse biological systems and primarily comprises bacteriophages which are viruses that infect bacterial cells; eukaryotic viruses account for only a minor fraction of the virome. Bacteriophages have a virulent (lytic) cycle and a temperate (lysogenic) cycle. In the lysogenic phase they can integrate their genetic material into bacterial genomes or reside as extra-chromosomal plasmids, a mechanism underlying transfer of antibiotic resistance or virulence factors among bacteria. Bacteriophages outnumber bacteria and can shape the composition of intestinal bacterial communities.172 Similar to bacteria, the virome varies among individuals, but is relatively stable within individuals and responds to dietary changes.39, 173, 174 Bacteriophages can directly affect the immune system by stimulating macrophage production of interleukin-1b (IL-1b) and tumor necrosis factor-α,175 stimulating interferon production,176 and enhancing DNA vaccine potency.177 A role has also been proposed for bacteriophages in adhering to GI mucus and providing a form of nonhost–derived innate immunity. It was found that phage enrichment in mucus results from binding of phage capsid proteins with mucin glycoproteins,178 and this may provide a defense against bacterial infection of mucosal surfaces. The effects of bacteriophage on bacteria can be exploited therapeutically and may represent a novel and important mode of treatment, especially now with the increase in multidrug-resistant bacteria. Eukaryotic viruses can also influence the immune system, such as norovirus, which has been shown to shape mucosal immunity in mice. Commensal microbiota can play an important role in determining the outcome of viral infections. Mouse mammary tumor virus (MMTV) bound to bacterial lipopolysaccharide interacts with the microbiota to induce an immune evasion pathway, triggering TLR4 and inducing production of IL-10.179

CHAPTER 3  The Enteric Microbiota

Viruses in turn can influence the host by affecting other members of the microbiota, but much work is needed to identify such transkingdom interactions, including better annotated databases of viral DNA sequences and techniques to deeply characterize viruses. 

FUTURE DIRECTIONS As we expand our understanding of microbial pathways and the interaction of resultant microbial metabolites with host physiology, we will be able to develop more precise interventions using an integrated systems biology approach, potentially tailored to an individual’s microbiome. There is a need for better understanding of microbial assembly and the potentially deleterious effects of perinatal and early life exposures, given their potential to have

33

lasting effects on the microbiome and our health. Also, we are just starting to appreciate the contribution of microorganisms other than bacteria such as fungi, bacteriophages, and parasites and the inter-kingdom signaling among the microorganisms and the host, which will prove to be crucial for effective manipulation of the microbiome. In addition to the promise of the microbiome, we also face significant challenges in the form of heterogeneity in collection, sequencing, and analysis of samples, differences in species and strains of bacteria used in interventions, reliance on association of specific microbes with disease states, and lack of recognition of the microbiome as an important biological variable in clinical studies and drug trials. Full references for this chapter can be found on www.expertconsult.com

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Gut Sensory Transduction Diego V. Bohórquez, Rodger A. Liddle

CHAPTER OUTLINE HORMONES AND NEUROTRANSMITTERS����������������������������34 Defining Hormones and Neurotransmitters ����������������������� 34 Modes of Transmitter Release 35 TRANSDUCING SIGNALS FROM THE GI LUMEN 37 Recognizing Signals Through Cell Surface Receptors 38 G Protein–Coupled Receptors ������������������������������������������� 38 Enzyme-Coupled Receptors 38 Ion Channel–Coupled Receptors��������������������������������������� 39 NUTRIENT CHEMOSENSING 39 Lipids������������������������������������������������������������������������������� 39 Proteins and Amino Acids ������������������������������������������������� 39 Tastants ��������������������������������������������������������������������������� 39 Sensing the Microbiome��������������������������������������������������� 40 Other Factors Stimulating Transmitter Release 40 THE TRANSMITTERS����������������������������������������������������������� 41 Gut Neuropeptides 41 Gastrin ����������������������������������������������������������������������������� 41 Cholecystokinin 41 Secretin ��������������������������������������������������������������������������� 42 Vasoactive Intestinal Polypeptide 42 Glucagon 42 Glucose-Dependent Insulinotropic Polypeptide ����������������� 43 Pancreatic Polypeptide Family 43 Substance P and the Tachykinins 44 Somatostatin 44 Motilin 44 Leptin������������������������������������������������������������������������������� 44 �������������������������������������������

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Ghrelin ����������������������������������������������������������������������������� NEUROTRANSMITTERS������������������������������������������������������� Acetylcholine Catecholamines ��������������������������������������������������������������� Dopamine Serotonin ������������������������������������������������������������������������� Histamine������������������������������������������������������������������������� Nitric oxide����������������������������������������������������������������������� CANNABINOIDS AND OTHER CHEMICAL TRANSMITTERS Cannabinoids ������������������������������������������������������������������� Adenosine Cytokines ������������������������������������������������������������������������� THE IMPORTANCE OF HORMONES AND NEUROTRANSMITTERS������������������������������������������������������� Growth and Abnormal Growth of the Gut��������������������������� Growth Factor Receptors Epidermal Growth Factor Transforming Growth Factor-������������������������������������������� Transforming Growth Factor-������������������������������������������� Insulin-Like Growth Factors Fibroblast Growth Factor and Platelet-Derived Growth Factor��������������������������������������������������������������� Trefoil Factors DIABETES AND THE GUT����������������������������������������������������� GASTROINTESTINAL REGULATION OF APPETITE ���������������������������������������������������������������������

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45 45 45 45 45 46 47 47 47 47 48 48 48 48 48 49 49 49 49 49 49 49 50

The gastrointestinal (GI) tract relies on hormones and neurotransmitters to integrate signals arising in the lumen with whole-body homeostasis. For instance, satiety in the brain is, to a great extent, induced by the presence of food in the gut. This process begins with ingestion of nutrients that stimulate sensory cells in the intestinal epithelium that modulate food intake via the release of specific chemical messengers. GI hormones and neurotransmitters are intimately involved with every aspect of the digestive process including ingestion and absorption of nutrients. It is not surprising therefore that these transmitters are essential for life.1,2 In this chapter, the critical role of the regulatory transmitters in GI function is analyzed by covering the following aspects: their synthesis and secretion from sensory epithelial cells, how food or other GI luminal factors trigger their release, the most representative members, and their importance in the context of disease.

or neurotransmitters. Enteroendocrine cells reside in the intestinal mucosa as single cells that are scattered among more numerous enterocytes—the absorptive cells of the gut. Most enteroendocrine cells are oriented with their apical surface open to the lumen where they are exposed to food and other contents within the gut lumen. Upon stimulation, enteroendocrine cells release from their basolateral surface hormones, which enter the paracellular space where they are taken up into the blood. In contrast to enteroendocrine cells, enteric neurons are found below the mucosal epithelium, and even though villi and crypts are richly innervated, enteric neurons are not believed to be directly exposed to food in the gut. Unlike other endocrine organs where endocrine cells are concentrated in a single organ, the function of scattered hormonecontaining cells of the GI tract has been questioned, and it becomes important to distinguish hormonal versus neuronal actions.

HORMONES AND NEUROTRANSMITTERS

Defining Hormones and Neurotransmitters

The sensory cells of the GI epithelium, enteroendocrine cells, as well as neurons of the enteric nervous system are the main producers of chemical messengers, which are released in the form of hormones

Criteria exist for determining if a candidate transmitter is a true hormone or a neurotransmitter. The first hormone to be discovered was secretin, when it was shown that injection of intestinal

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CHAPTER 4  Gut Sensory Transduction

extracts into the blood stimulated pancreatic secretion.3. Since then, the following criteria have been established to prove that a substance functions as a hormone. First, the stimulation of one organ must cause distant response by acting through the blood. Second, the response must be independent of neural stimulation. Third, no response should occur in the absence of the secretory organ. And fourth, the response should be reproducible by applying pure amounts of the candidate hormone onto the target tissue. There are more than 30 GI hormones that met these criteria, and their singularities are discussed in “The Transmitters” section of this chapter. Demonstrating that a chemical is a neurotransmitter is perhaps more challenging, but the following criteria are agreed to define a neurotransmitter. First, the candidate molecule must be present within a presynaptic neuron. Second, the transmitter must be released in response to presynaptic depolarization. And, third, specific candidate-receptors must be present on the postsynaptic cell. Hormones are commonly thought to reside exclusively in the endocrine system and neurotransmitters in the nervous system. However, these concepts were proposed when no technologies existed to visualize a single cell communicating with its surroundings. Today, it is becoming clearer that both systems are closely and synergistically related. Indeed, some cells exert both endocrine and neural actions. For example, peripheral sensory cells such as taste cells of the tongue and solitary chemosensory olfactory cells of the nose are known as paraneurons and can release both hormones in the bloodstream and neurotransmitters at synaptic connections.4 There is growing evidence that enteroendocrine cells have similar dual function.5,6 These observations extend the continuum between the endocrine and nervous systems. Moreover, one transmitter can act both as a hormone or neurotransmitter depending on its location. For instance, upon the ingestion of food, cholecystokinin (CCK) is typically released from enteroendocrine cells into the bloodstream to act as a hormone. However, CCK is also abundant in nerves of the GI tract and brain, where it is released at synaptic terminals to act as a

neurotransmitter. This conservation of transmitters allows the same messenger to have different physiologic actions at different locations, and is made possible by the manner in which the transmitter is delivered to its target tissues. 

Modes of Transmitter Release Enteroendocrine transmitters can be released onto their targets in the following manners: endocrine, paracrine, autocrine, or through synaptic neurotransmission (Fig. 4.1). Endocrine. This type of communication occurs when transmitters are secreted into the bloodstream. The most common endocrine transmitters are peptides, lipids, and mono amines, and are collectively known as hormones. In the GI tract the most predominant type of hormone is in the peptide form (e.g., peptide YY, gastrin, secretin). Hormones bind to specific receptors on the surface of target cells at remote sites and regulate metabolic processes.7 Paracrine. In contrast to endocrine mechanisms used to reach distant targets through the blood, signaling cells of the GI tract can also produce transmitters that act on neighboring cells. This process is known as paracrine signaling and is typical of enteroendocrine cells that produce somatostatin.8 Paracrine transmitters are secreted locally and cannot diffuse far. They bind to receptors on nearby cells to exert their biological actions. Once released, the transmitter is rapidly taken up by the target cell, catabolized by extracellular enzymes, or becomes adherent to extracellular matrix, thus limiting the transmitter’s ability to act at distant sites. Because paracrine signals act locally, their onset of action is generally rapid and can be terminated abruptly. By comparison, endocrine signaling takes much longer, and termination of signaling requires clearance of hormone from the circulation. Paracrine transmitters can be peptides (e.g., somatostatin) or monoamines (e.g., histamine). Autocrine. Some cells possess cell surface receptors for their own messengers. In this way, when a messenger is released, it can act on the same secreting cell. This mode of transmission is known as autocrine and has been demonstrated for several growth

Fig. 4.1 Modes of transmitter release. Transmitters can be secreted from chemosensory cells and neurons through endocrine via the blood, paracrine locally in the paracellular space, autocrine to act on the same releasing cell, or synaptic to allow neurotransmission.  

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PART I  Biology of the Gastrointestinal Tract

factors. Autocrine signaling has been implicated in the growth of certain cancers, including colorectal cancer (see Chapter 1).9. Neurotransmission. A fourth form of signaling in the GI tract is neurotransmission. This form of signaling is primarily used by the enteric nervous system. The enteric nervous system Serosa Circular muscle

Longitudinal muscle

Submucosa

Myenteric plexus

Submucosal plexus

Muscularis mucosa Mucosal nerves Mucosa Fig. 4.2  Organization of the enteric nervous system. The enteric nervous system is composed of two major plexuses, one submucosal and one located between the circular and longitudinal smooth muscle layers. These neurons receive and coordinate neural transmission from the GI tract and central nervous system.

is a complex network of nerve cells that must communicate efficiently to regulate numerous GI functions (Fig. 4.2). When neurons of the GI tract are activated, signals in the form of neurotransmitters are released at nerve-to-nerve junctions known as synapses. These structures help neurons deliver neurotransmitters at specific locations on the target cell, and influence the function of other neurons, muscle cells, epithelial and secretory cells, and other specialized cells of the GI tract such as enteric glia. Neurotransmitters are critical for the processes of digestion including the coordination of gut motility and secretion. Although the GI tract secretes a variety of neurotransmitters, the most common are peptides such as vasoactive intestinal polypeptide (VIP), or small molecules, such as acetylcholine and norepinephrine. Other molecules, such as nitric oxide (NO), can simply diffuse across the synaptic cleft to exert an effect on the postsynaptic cell. Some nerves actually release peptides or neurotransmitters directly into the blood. This process is called neurocrine signaling and may be used to cause systemic effects depending on the transmitter released. The major hormones and neurotransmitters of the GI tract are listed in Box 4.1. Their actions depend on specific receptors located on target tissues. For instance, the specificity of neurotransmitter action is dependent on the precise location at which the nerve synapses with the target cell. Adjusting their synthesis, catabolism, or secretion regulates the transmitter concentration within the releasing cell. Once secreted, the concentration of a transmitter can be quickly modulated by catabolism or, in the case of neurotransmitters, reuptake into the secretory neuron. Many peptide transmitters have very short half-lives that are generally within the 2 to 5 minute range. This allows for rapid initiation and termination of signaling. 

BOX 4.1 Hormones and Transmitters of the GI Tract PEPTIDES THAT FUNCTION MAINLY AS HORMONES Gastrin Glucose-dependent insulinotropic peptide (GIP) Glucagon and related gene products (GLP-1, GLP-2, glicentin, oxyntomodulin) Insulin Motilin Pancreatic polypeptide Peptide tyrosine tyrosine (PYY) Secretin  PEPTIDES THAT MAY FUNCTION AS HORMONES, NEUROPEPTIDES, OR PARACRINE AGENTS Cholecystokinin (CCK) Corticotropin-releasing factor (CRF) Endothelin Neurotensin Somatostatin  PEPTIDES THAT ACT PRINCIPALLY AS NEUROPEPTIDES Calcitonin gene-related peptide (CGRP) Dynorphin and related gene products Enkephalin and related gene products Galanin Gastrin-releasing peptide (GRP) Neuromedin U Neuropeptide Y Peptide histidine isoleucine (PHI) or peptide histidine methionine (PHM) Pituitary adenylate cyclase–activating peptide (PACAP) Substance P and other tachykinins (neurokinin A, neurokinin B) Thyrotropin-releasing hormone (TRH) Vasoactive intestinal peptide (VIP) Peptides That Act as Growth Factors

Epidermal growth factor Fibroblast growth factor Insulin-like factors Nerve growth factor Platelet-derived growth factor Transforming growth factor-β Vascular endothelial growth factor  PEPTIDES THAT ACT AS INFLAMMATORY MEDIATORS Interferons Interleukins Lymphokines Monokines Tumor necrosis factor-α  PEPTIDES THAT ACT ON NEURONS Cholecystokinin Gastrin Motilin Nonpeptide Transmitters Produced in the Gut Acetylcholine Adenosine triphosphate (ATP) Dopamine γ-Aminobutyric acid (GABA) Histamine 5-Hydroxytryptamine (5-HT, serotonin) Nitric oxide Norepinephrine Prostaglandins and other eicosanoids Newly Recognized Hormones or Neuropeptides Amylin Ghrelin Guanylin and uroguanylin Leptin

CHAPTER 4  Gut Sensory Transduction

TRANSDUCING SIGNALS FROM THE GI LUMEN The process of nutrient sensing involves the activation of cellsurface receptors that trigger the release of transmitters. The transmitters then either enter the bloodstream or activate sensory afferent nerves. Although the cells releasing the transmitters, enteroendocrine cells, are thought to interact with nerves indirectly through paracrine or endocrine signals, a new concept is emerging, in which enteroendocrine cells and nerves actually communicate through synaptic connections.5,6 With the use of transgenic and advanced optical tools, enteroendocrine cells have been described to have several anatomical

features observed in neurons, including dendritic-like spines, axon-like processes. These axon-like cytoplasmic processes vary in length from crypt to villus and from proximal to distal small intestine (Fig. 4.3). Moreover, enteroendocrine cells have the molecular components, genes, and proteins of synapses, and connect to sensory neurons through synaptic-like connections (Fig. 4.4). These connections may have broad applications in the biology of gastrointestinal function, including the transmission of sensory signals from nutrients and the GI microbiota. Some key components involved in the transduction of signals from the lumen of the gut to the rest of the body are described as follows.

Fig. 4.3  Axon-like processes in enteroendocrine cells. Enteroendocrine cells have cytoplasmic extensions that resemble neuronal axons. Some of these serve to act as paracrine modulators, like those in somatostatinsecreting cells; however, in other cells these axon-like basal processes serve to connect to neurons innervating the gut.

Fig. 4.4 Enteroendocrine cells as paraneurons. Enteroendocrine cells connect to afferent and efferent neurons and appear to be capable of sending and receiving neuronal signals.  

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PART I  Biology of the Gastrointestinal Tract

Recognizing Signals Through Cell Surface Receptors GI epithelial cells recognize molecules in the lumen using membrane bound receptors. When activated, receptors transduce signals from the outside of the cell into the cytoplasm. Although the process is rather complex, there are key checkpoints at which the signaling cascade can be regulated. Some of these checkpoints occur at the moment of receptor activation, desensitization, internalization, and/or resensitization. Because of their regulatory potential, these are attractive targets for therapeutic intervention. Receptors are grouped into major families depending on their structures and signaling mechanisms. The major families of cell surface receptors include G protein-coupled receptors (GPCRs), enzyme-coupled receptors, and ion channels. The following are some of the main aspects of each receptor family. 

G Protein–Coupled Receptors GPCRs are typified by their seven transmembrane domains. They are the most common family of protein receptors and have broad physiological applications, ranging from sensing light in the retina to allow vision to sensing nutrients in the gastrointestinal tract to regulate food intake. When stimulated by a specific ligand, GPCRs undergo conformational changes leading to their association with a G protein—hence their name. These G proteins are bound to the intracellular surface of the cell membrane10,11 and are composed of three distinct subunits—α, β, and γ. It is the Gα subunit that confers the name of the G protein (Table 4.1). For instance, G proteins that stimulate an effector (e.g., adenylate cyclase) are classified as Gs (for stimulatory), whereas those that inhibit an effector are called Gi (for inhibitory).12-14 When the G protein acts on the effector, this causes a rapid increase in the intracellular concentrations of a second messenger (e.g., cyclic AMP or calcium). The second messenger then changes the activity of one or more protein kinases to catalyze the phosphorylation of an existing protein and ultimately modify the physiological activity. In general, the GCPR signaling mechanism involves the following events. When the ligand or first messenger binds to the receptor, the receptor changes its conformation and binds to the G protein complex. In the resting state, the G protein complex does not interact with the receptor. However, once bound, there is a molecular substitution in the Gα subunit—a guanosine diphosphate (GDP) is replaced by a guanosine triphosphate (GTP). This replacement causes the activation of the Gα subunit. The active Gα subunit then separates from the β and γ subunits, and moves laterally in the membrane to activate an effector. Working through different Gα subunits, the activity of an effector can be up- or downregulated. When the interaction is completed, the GTP bound to the Gα subunit is hydrolyzed back to GDP and dissociated from Gα. In this way, Gα moves back to reunite with the other two subunits. The effector then induces an increase in the intracellular concentration of a second messenger. The two most common second messengers TABLE 4.1  Classification of G Protein α Subunits and Their Signaling Pathways Class

Signaling

Gαs

Adenylate cyclase, calcium channels

Gαi and Gαo

Adenylate cyclase, cyclic guanosine monophosphate, phosphodiesterase, c-Src, STAT 3

Gαq

Phospholipase C-β

Gα12 and Gα13

Sodium-hydrogen exchange

are cyclic adenosine monophosphate (cAMP) and calcium. The mechanisms involving each second messenger are briefly outlined as follows. Signaling through cyclic adenosine monophosphate (cAMP). This second messenger is a classic downstream effector of β adrenergic receptors, a family of GPCRs that have been well characterized. These receptors are coupled to Gαs and activate adenylyl cyclase, which catalyzes the conversion of ATP to cAMP. High concentrations of cAMP then modify the activity of protein kinase A (PKA) that ultimately modulates rate-limiting enzymes involved in important physiological functions. For instance, modulation of glycogen phosphorylase increases the conversion of glycogen to glucose-1 phosphate, leading to a rise in blood glucose levels. Signaling through calcium (Ca2+). GPCRs associated with Gαq subunits use Ca2+ as a second messenger. An increase in intracellular concentrations of Ca2+ can result from the activation of voltage-gated Ca2+ channels, ligand gated Ca2+ channels, or the release of cytosolic Ca2+ activated by membrane phospholipids. The latter is triggered by activation of GPCRs associated with Gαq. When active, Gαq moves along the cell membrane to activate the enzyme phospholipase Cβ. Phospholipase Cβ then cleaves the membrane phospholipid phosphatidyl inositol bisphosphate into diacylglycerol and inositol 1,4,5-trisphosphate (IP3), generating two potential signaling molecules. Diacylglycerol in the presence of Ca2+ activates protein kinase C. In addition, a rise in Ca2+ levels from internal stores can also activate Ca2+—calmodulin kinase. In this way, two different kinases are activated: Ca-calmodulin kinase by increasing cytosolic Ca2+ and protein kinase C by the action of diacylglycerol and Ca2+. These kinases then catalyze the phosphorylation of target proteins within the cell. Following receptor activation, IP3 moves from the plasma membrane into the cytoplasm to bind IP3 receptors located on the endoplasmic reticulum and mitochondria. IP3 receptor binding causes release of Ca2+ from intracellular organelles to further increase cytoplasmic Ca2+ concentrations. Ultimately, Ca2+ cytoplasmic concentrations are restored to normal by active transport out of the cell or by reuptake into intracellular Ca+2 stores. If the cell is overstimulated, a process of adaptation occurs to prevent the cell from overresponding. Attenuation of signaling occurs through either ligand-induced receptor desensitization or receptor internalization. The receptor is desensitized by means of phosphorylation. Phosphorylation can also further label the receptor for internalization, which is accomplished by activation of specific receptor kinases and the recruitment of arrestinlike molecules that uncouple the receptor from the G protein.15 Uncoupling and subsequent receptor internalization ends signaling and eventually restores cell responsiveness. 

Enzyme-Coupled Receptors The most representative of the enzyme-coupled receptors are the tyrosine kinase receptor family. These receptors are primarily targets of growth factors, such as epidermal growth factor. These receptors are unique in that they are both a receptor and a tyrosine kinase. When activated, the receptors catalyze the transfer of phosphate from ATP to the target proteins. Enzyme-coupled receptors are composed of three domains: a ligand-binding extracellular domain, a transmembrane domain, and a cytoplasmic domain. The cytoplasmic domain contains a protein tyrosine kinase region and substrate region for agonist-activated receptor phosphorylation. In this way, phosphorylation from other kinases or autophosphorylation can occur to modulate the activity of the tyrosine kinase receptor.16 In general, receptor tyrosine kinases exist in the cell membrane as monomers. However, with ligand binding, these receptors dimerize, autophosphorylate, and initiate other intracellular signal transduction pathways that ultimately modulate physiological function.17 Receptor tyrosine

CHAPTER 4  Gut Sensory Transduction

kinases are further discussed in Chapter 1 in relation to cellular growth and neoplasia.18 There are several other types of enzyme-coupled receptors, including receptor guanylate cyclases, nonreceptor tyrosine kinases, receptor tyrosine phosphatases, and receptor serine/ threonine kinases. Although these receptors act through different enzymes, the signaling principles remain similar to those of tyrosine kinase receptors. 

Ion Channel–Coupled Receptors Ion channel–coupled receptors are involved in rapid signaling between cells. This type of receptors is important in tissues where electrical impulses drive signaling, like nerve cells and muscle. For instance, in nerve cells, ion channels open or close in response to a relatively small number of neurotransmitters and allow the flow of particular ions across the plasma membrane. The kinetics of the flow depend on the concentration inside and outside the cell. This flow of ions regulates the excitability of the target cell to ultimately trigger processes such as neurotransmission, muscle contraction, electrolyte and fluid secretion, or hormone release. An example of this type of receptor is the transient receptor potential cation channel M5, or better known as TRPM5. This ion-channel receptor is activated by elevated intracellular Ca2+ concentrations and is a key component in the transduction of the taste signals bitter, sweet, and umami.19 Moreover, it has been recently shown to mediate the release of opioids and hormones like CCK from enteroendocrine cells.20 Thus ion channel-coupled receptors can be attractive targets to modulate the function of sensory cells in the epithelium of the GI tract. 

NUTRIENT CHEMOSENSING Lipids Lipids in the intestinal lumen are potent inducers of satiety and modulators of whole-body metabolism. Although the mechanisms are not completely understood, it has been recently demonstrated that specific lipids are recognized by cell surface receptors, which activate the release of several hormones, including CCK, peptide YY, and glucagon-like peptide 1. The lipids can be in the form of triglycerides or free fatty acids of various chain lengths. Different lipids are recognized by different receptors. For instance, the Gq coupled GPCRs 40 (i.e., FFAR1) and 120 respond to medium- and long-chain fatty acids; whereas the Gαi coupled GPR41 (i.e., FFAR3) and GPR43 (i.e., FFAR2) bind to short-chain fatty acids of 2 to 5 carbons.21 It is possible that some GPCRs respond to lipids in the lumen of the gut. Other non-GPCRs are also involved in lipid sensing, such as the immunoglobulin-like domain containing receptor (ILDR). ILDR is expressed in CCK cells and is activated by the combination of fatty acids and lipoproteins suggesting that fatty acids must be absorbed to stimulate CCK secretion. Although the specific location of most nutrient receptors has yet to be determined, it may be that at least some lipids need to be digested and absorbed prior to activating hormone release. This hypothesis is supported by studies, in which the infusion of lipid in the intestine triggers hormone secretion but only if chylomicrons, lipoprotein particles formed from absorbed lipids, are allowed to form.22 Some lipid-generated sensory signals appear to travel through afferent fibers of the vagus nerve. For instance, infusion lipids into the duodenum increases brown fat temperature, and this effect is abolished if lipids are infused along with tetracaine— an potent local anesthetic used to block vagal afferents activation.23 Signals traveling through afferent nerves or the bloodstream ultimately induce homeostatic changes (e.g., satiety, body temperature, GI motility) in response to the presence of nutrients in the GI lumen. 

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Proteins and Amino Acids Proteins can also be potent stimulants of GI hormone secretion. Most proteins stimulate hormone secretion only when digested to peptones and amino acids (AAs). Recently, enteroendocrine cells have been found to express several classes of amino acid receptors that mediate hormone secretion. For instance, the calcium sensing receptor (CaSR), which was originally identified for its ability to detect and respond to extracellular Ca2+ and regulation of calcium homeostasis in the kidney and parathyroid gland,24 also recognizes L-amino acids and di- and tri-peptides.25 A clear role for CaSR has been established in the regulation of L-amino acid-stimulated gastrin and gastric acid secretion.26,27 The aromatic AAs phenylalanine and tryptophan are the most potent AAs for stimulating CaSR and are also the most potent for stimulating CCK secretion. The discovery of CaSR in CCK cells and its link to secretion support its physiological importance as a nutrient sensor in the GI tract. Besides CCK, CaSR appears to also mediate the secretion of GIP, GLP-1, and PYY28-30. Another amino acid sensing receptor closely related to CaSR is the G protein-coupled receptor, GPRC6A. GPRC6A responds to basic AAs and is expressed in taste cells and enteroendocrine cells of the distal small intestine where mediates the secretion of GLP-1.31 Genetic deletion of GPRC6A leads to diet-induced obesity, implying that this receptor is important for metabolic regulation.32 Finally, the taste receptors, T1R1/T1R3, also recognize acidic AAs and do not appear to be restricted to taste cells of the tongue but instead are distributed in chemosensory cells throughout the body. Together, CaSR, GPFC6A, and T1R1/ T1R3 respond to all of the 20 L-AAs and represent a comprehensive mechanism to sense amino acid nutrient stimuli. Partially digested protein in the form of peptones can also stimulate hormone secretion. The G protein–coupled receptor GPR93 is not only a lysophosphatidic acid receptor but is also activated by peptone.33 GPR93 is expressed in enterocytes and enteroendocrine cells, where its activation has been coupled to CCK secretion.34 Thus GPR93 may be the mechanism by which peptone stimulates CCK release following a meal. Some intact proteins stimulate hormone secretion indirectly through a class of endogenous luminally active hormone releasing factors, including luminal cholecystokinin releasing factor (LCRF)35 and diazepam binding inhibitor (DBI).36. The most potent proteins are those that compete for trypsin binding and allow the endogenous releasing factor to escape proteolytic digestion within the gut lumen. 

Tastants Sensing tastants in various foods is important to regulate pleasure, reward, food intake, and other important metabolic functions. The GI tract detects chemicals and toxins through specific receptors expressed by specialized chemosensory cells. These cells are best characterized in the tongue, where they are concentrated in taste buds. Taste receptor cells can detect chemicals that give rise to the five different flavors: sweet, salty, sour, bitter, and umami—the savory taste of soy sauce. Although this is an active area of research, only the sensing mechanisms for sweet, bitter, and umami flavors are well understood. These three flavors are mediated by the activation of two families of GPCRs: taste-1 receptors (T1Rs) and taste-2 receptors (T2Rs). In humans, there are 30 T2R proteins and three T1Rs, named T1R1, T1R2, and T1R3.37-39 Sweet and umami flavors are recognized by T1Rs. In the tongue, T1R1 and T1R2 are expressed in separate taste receptor cells, but always along with T1R3. In this way, the receptors form heterodimers that allow the detection of sweet ligands in the case of T1R2 + T1R3, and umami in the case of T1R1 + T1R3.40 T1Rs are also expressed in enteroendocrine cells.41 Here, the

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PART I  Biology of the Gastrointestinal Tract

binding of glucose to T1R2 + T1R3 receptors in enteroendocrine cells in the gut lumen leads to secretion of incretin hormones, like glucagon-like peptide-1 (GLP-1). GLP-1 ultimately modulates a wide variety of functions, including insulin secretion, nutrient absorption, and gut motility.42 Consequently, gut-expressed taste signaling has become an active area of research to develop therapies for diet-related disorders like type II diabetes.43 Bitter perception functions as a warning signal against the ingestion of toxic substances through direct taste aversion, induction of the pharyngeal gag reflex, and nausea. The wide array of T2Rs present in the tongue as well as in the gut are set to recognize bitter compounds, such as toxic alkaloids in plants.44 It is believed that bitter compounds that bypass T2Rs in the tongue are recognized by T2Rs in the gut, serving as a backup mechanism for inducing a protective response such as vomiting.45 Activation of T2Rs and their associated Gα-gustducin protein result in a rapid increase in cytosolic Ca2+, which stimulates membrane depolarization and hormone release. In the gut, bitter chemicals can stimulate the release of CCK from enteroendocrine cells to slow gastric emptying and decrease appetite, thus reducing the likelihood of toxin absorption. 42,45,46 

Sensing the Microbiome Enteroendocrine cells typically have a small narrow opening to the luminal surface. Although it has been long been assumed that nutrients stimulate enteroendocrine cells at their apical portion, there are some reports that absorbed and not luminal nutrients stimulate gut hormone release.22 Thus it is possible that the apical portion of enteroendocrine cells open to the gut lumen may serve to sense bacterial inputs. Evidence supporting this hypothesis comes from the fact that some bacterial toll-like receptors (e.g., TLRs 4, 5, and 9) are exclusively expressed in enteroendocrine cells.47 When these specific TLRs are stimulated with bacterial ligands (e.g., LPS or flagellin), CCK and several chemokines are secreted. Remarkably, cytokines and defensins are secreted from an enteroendocrine cell line (i.e., STC-1) only in

response to bacterial ligands and not to fatty acids. Moreover, silencing MyD88, a central mediator of TLR signaling, reduces CCK secretion stimulated by bacterial ligands but not by fatty acids.48 This evidence suggests that there may be two different sensing pathways in enteroendocrine cells—one for bacteria and another for nutrients. It has long been assumed that chemosensory receptors on enteroendocrine cells reside on the apical surface, which is open to the gut lumen. However, this has not yet been demonstrated, and recent evidence suggests that some nutrients stimulate enteroendocrine cells when exposed to the basal lateral surface. Because gut microbiota reside in the lumen of the GI tract, it is likely that toll-like receptors are located on microvilli. In the future, elucidating the location of receptors on enteroendocrine cells may facilitate the design of drugs to target specific receptors and modulate the secretion of hormones involved in appetite regulation and insulin secretion. 

Other Factors Stimulating Transmitter Release There is evidence that GI hormones can be released by certain non-nutrient factors present in the lumen of the gut (Fig. 4.5). CCK was the first hormone shown to be regulated by an intraluminal releasing factor.49,50 Luminal CCK-releasing factor was purified from intestinal washings and shown to stimulate CCK release when instilled into the lumen of animals. Other luminal factors causing the release of CCK are the diazepam-binding inhibitor and the pancreatic monitor peptide.51,52 It has been proposed that a secretin-releasing factor regulates secretin secretion in an acid-sensitive way.53 The pancreatic secretory trypsin inhibitor, better known as monitor peptide, is an endogenous trypsin inhibitor produced by pancreatic acinar cells.54 When secreted into the duodenum, monitor peptide directly stimulates CCK secretion from I cells. These proteins act directly on enteroendocrine cells, most likely through cell surface receptors. The existence of these releasing factors highlights the existence of underappreciated bioactive molecules within the lumen of the gut. 

Fig. 4.5 Regulation of cholecystokinin (CCK) secretion by intraluminal releasing factors. Intestinal epithelial cells secrete factors, which are known as CCK-releasing factors because of their ability to stimulate CCK release from enteroendocrine cells (green). CCK is released into the bloodstream to stimulate pancreatic secretion of monitor peptide and trypsin. Monitor peptide further stimulates the release of CCK and constitutes a feed forward mechanism. In turn, trypsin in the intestine digests food and inhibits the actions of monitor peptide and CCK releasing factor. Trypsin acts therefore as a feedback regulator.  

CHAPTER 4  Gut Sensory Transduction

THE TRANSMITTERS The same factors that stimulate transmitter release simultaneously modulate the expression of specific transmitter genes through specific gene regulatory elements. Gut hormone gene expression is generally linked to peptide production, and regulated according to the physiologic needs of the organism. For example, once a biological response is elicited, signals may then be sent back to the endocrine cell to “turn off” hormone secretion. This negative feedback mechanism is common to many physiologic systems and avoids excess production and secretion of hormones. All GI peptides are synthesized via transcription of DNA into messenger RNA, which is subsequently translated into precursor proteins also known as preprohormones. The newly translated protein contains a signal sequence that directs to the endoplasmic reticulum to prepare the peptide precursor for structural modifications.55 These precursors are transported to the Golgi apparatus, where further structure modifications occur before the peptide is packaged in secretory granules. Secretory granules may be targeted for immediate release or stored in close proximity to the plasma membrane ready to be releases. Although many hormones are produced from a single gene, there can be multiple molecular forms in tissues and blood. The different molecular forms result from differences in pretranslational or posttranslational processing. A common pretranslational processing mechanism is the alternative splicing of mRNA, which generates unique peptides from the same gene. Posttranslational modifications can occur by cleavage of precursor molecules, where enzymatic cleavage of the signal peptide produces a prohormone. Other posttranslational features that result in mature GI peptides include peptide cleavage to smaller forms (e.g., somatostatin), amidation of the carboxyl terminus (e.g., gastrin), and sulfation of tyrosine residues (e.g., CCK). These processing steps are critical for biological activity of the hormone. For example, sulfated CCK is 100-fold more potent than its unsulfated form. The vast biochemical complexity of gastroenteropancreatic hormones is evident in the different tissues that secrete these peptides. As GI peptides are secreted from endocrine as well as nervous tissue, the distinct tissue involved often determines the processing steps for production of the peptide. Many hormone genes are capable of manufacturing alternatively spliced mRNAs or proteins that undergo different posttranslational processing and ultimately produce hormones of different sizes. These modifications are important for receptor binding, signal transduction, and consequent cellular responses.56 As follows, we outline the major characteristics of GI transmitters, including neuropeptides, neurotransmitters, and other transmitters.

Gut Neuropeptides It was previously believed that a single enteroendocrine cell (EEC) produced only one hormone. However, with transcriptomic profiling of purified EECs, it is now known that EECs produce multiple types of peptide hormones and neurotransmitters.57-59 Therefore categorization of EECs by the hormones they produce is not as straightforward as the traditional single letter nomenclature implied. It is also evident that stimulation of a single EEC can cause the release of multiple transmitters and thereby exert a variety of physiological responses. We summarize the major biological actions of the major transmitters from the gut as follows. 

Gastrin As discussed in more detail in Chapter 51, gastrin is the major hormone that stimulates gastric acid secretion. Subsequently, gastrin was found to have growth-promoting effects on the

41

gastric mucosa and possibly some cancers.60 Human gastrin is the product of a single gene located on chromosome 17. The active hormone is generated from a precursor peptide called preprogastrin. Human preprogastrin contains 101 AAs, but is processed by sequential enzymatic cleavage to the two major forms of gastrin: G34 and G17 and some small forms. The common feature of all gastrins is an amidated tetrapeptide (Try-Met-Asp-Phe-NH2) carboxyl terminus, which imparts full biological activity. A nonamidated form of gastrin known as glycine-extended gastrin is produced by colonic mucosa. Glycine-extended gastrin has been shown in animal models to stimulate proliferation of normal colonic mucosa and enhance the development of colorectal cancer. It is not known whether local production of this form of gastrin contributes to human colon carcinogenesis, and the receptor for glycine-extended gastrin has not been identified.61 Most gastrin is produced in endocrine cells of the gastric antrum.62 Much smaller amounts of gastrin are produced in other regions of the GI tract, including the proximal stomach, duodenum, jejunum, ileum, colon, and pancreas. Gastrin has also been found outside the GI tract, including in the brain, adrenal gland, respiratory tract, and reproductive organs, although its biological role in these sites is unknown. The receptors for gastrin and CCK are related and constitute the so-called gastrin-CCK receptor family. The CCK-1 and CCK-2 (previously known as CCK-A and -B) receptor complementary DNAs were cloned from the pancreas and brain, respectively, after which it was recognized that the CCK-2 receptor is identical to the gastrin receptor of the stomach.63 The CCK-1 receptor is present in the gallbladder and, in most species, in the pancreas. The CCK-1 receptor has a 1000-fold higher affinity for CCK than for gastrin. The CCK-1 and CCK-2 gastrin receptors have greater than 50% sequence homology and respond differently to various receptor antagonists and to gastrin. Gastrin is released from specialized endocrine cells (G cells) into the circulation in response to a meal. The specific components of a meal that stimulate gastrin release include protein, peptides, and AAs. Gastrin release is profoundly influenced by the pH of the stomach. Fasting and increased gastric acidity inhibit gastrin release, whereas a high gastric pH is a strong stimulus for its secretion. Hypergastrinemia occurs in pathologic states associated with decreased acid production, such as atrophic gastritis. Serum gastrin levels can also become elevated in patients on prolonged acid-suppressive medications, such as histamine receptor antagonists and proton pump inhibitors. Hypergastrinemia in these conditions is caused by stimulation of gastrin production by the alkaline pH environment. Another important but far less common cause of hypergastrinemia is a gastrin-producing tumor, also known as Zollinger-Ellison syndrome (see Chapter 34). 

Cholecystokinin CCK is a peptide transmitter produced primarily by enteroendocrine cells of the proximal small intestine and is secreted into the blood following ingestion of a meal. Circulating CCK binds to specific CCK-1 receptors on the gallbladder, pancreas, smooth muscle of the stomach, and peripheral nerves to stimulate gallbladder contraction and pancreatic secretion, regulate gastric emptying and bowel motility, and induce satiety.64 These effects serve to coordinate the ingestion, digestion, and absorption of dietary nutrients. Ingested fat and protein are the major food components that stimulate CCK release. CCK was originally identified as a 33–amino acid peptide. However, since its discovery, larger and smaller forms of CCK have been isolated from blood, intestine, and brain. All forms of CCK are produced from a single gene by posttranslational processing of a preprohormone. Forms of CCK ranging in size from CCK-58 to CCK-8 have similar biological activities.65

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CCK is the major hormonal regulator of gallbladder contraction. It also plays an important role in regulating meal-stimulated pancreatic secretion (see Chapter 56). In many species, this latter effect is mediated directly through receptors on pancreatic acinar cells, but in humans, in whom pancreatic CCK-1 receptors are less abundant, CCK appears to stimulate pancreatic secretion indirectly through enteropancreatic neurons that possess CCK-1 receptors. In some species, CCK has trophic effects on the pancreas, although its potential role in human pancreatic neoplasia is speculative. CCK also has been shown to delay gastric emptying.66 This action may be important in coordinating the delivery of food from the stomach to the intestine. CCK has been proposed as a major mediator of satiety and food intake, an effect that is particularly noticeable when food is in the stomach or intestine. CCK inhibits gastric acid secretion by binding to CCK-1 receptors on somatostatin (D) cells in the antrum and oxyntic mucosa. Somatostatin acts locally to inhibit gastrin release from adjacent G cells and directly inhibits acid secretion from parietal cells.67 Clinically, CCK has been used together with secretin to stimulate pancreatic secretion for pancreatic function testing. It is also used radiographically or scintigraphically to evaluate gallbladder contractility. There are no known diseases of CCK excess. Low CCK levels have been reported in individuals with celiac disease who have reduced intestinal mucosal surface area and in those with bulimia nervosa.68,69 Elevated levels of CCK have been reported in some patients with chronic pancreatitis (see Chapter 59), presumably because of reduced pancreatic enzyme secretion and interruption of negative feedback regulation of CCK release.70 

Secretin The first hormone, secretin, was discovered when it was observed that intestinal extracts, when injected intravenously into dogs, caused pancreatic secretion.71 Secretin is released by acid in the duodenum and stimulates pancreatic fluid and bicarbonate secretion, leading to neutralization of acidic chyme in the intestine (see Chapter 56). Secretin also inhibits gastric acid secretion (see Chapter 51) and intestinal motility. Human secretin is a 27–amino acid peptide and, similar to many other GI peptides, is amidated at the carboxyl terminus. It is the founding member of the secretin-glucagon-VIP family of structurally related GI hormones. Secretin is most abundant in enteroendocrine cells of the small intestine but appears to be expressed in nearly all EECs.72 The secretin receptor is a member of a large family of G protein–coupled receptors (GPCRs) that is structurally similar to receptors for glucagon, calcitonin, parathyroid hormone, pituitary adenylate cyclase–activating peptide (PACAP), and VIP. One of the major physiological actions of secretin is stimulation of pancreatic fluid and bicarbonate secretion (see Chapter 56). Pancreatic bicarbonate, on reaching the duodenum, neutralizes gastric acid and raises the duodenal pH, thereby “turning off” secretin release (negative feedback). It has been suggested that acid-stimulated secretin release is regulated by an endogenous intestinal secretin-releasing factor.73 This peptide stimulates secretin release until the flow of pancreatic proteases is sufficient to degrade the releasing factor and terminate secretin release. Although the primary action of secretin is to produce pancreatic fluid and bicarbonate secretion, it is also an enterogastrone, a substance that is released when fat is present in the GI lumen and that inhibits gastric acid secretion. In physiologic concentrations, secretin inhibits gastrin release, gastric acid secretion, and gastric motility.74 The most common clinical application of secretin is in the diagnosis of gastrin-secreting tumors,75 as discussed in Chapter 34. 

Vasoactive Intestinal Polypeptide VIP is a neuromodulator that has broad significance in intestinal physiology. VIP is a potent vasodilator that increases blood flow in the GI tract and causes smooth muscle relaxation and epithelial cell secretion.76,77 As a chemical messenger, VIP is released from nerve terminals and acts locally on cells bearing VIP receptors. VIP belongs to a family of GI peptides, including secretin and glucagon, that are structurally related. The VIP receptor is a G protein–­ coupled receptor that stimulates intracellular cAMP generation. Like other GI peptides, VIP is synthesized as a precursor molecule that is cleaved to an active peptide of 28 AAs. VIP is expressed primarily in neurons of the peripheral-enteric and central nervous systems and is released along with other peptides, including primarily PHI and/or PHM (see Box 4.1).78 VIP is an important neurotransmitter throughout the central and peripheral nervous systems.79 Because of its wide distribution, VIP has effects on many organ systems; most notably, in the GI tract, VIP stimulates fluid and electrolyte secretion from intestinal epithelium and bile duct cholangiocytes.80,81 VIP, along with NO, is a primary component of nonadrenergic, noncholinergic nerve transmission in the gut.82 GI smooth muscle exhibits a basal tone, or sustained tension, caused by rhythmic depolarizations of the smooth muscle membrane potential. VIP serves as an inhibitory transmitter of this rhythmic activity, causing membrane hyperpolarization and subsequent relaxation of GI smooth muscle. Accordingly, VIP is an important neuromodulator of sphincters of the GI tract, including the lower esophageal sphincter and sphincter of Oddi. In certain pathologic conditions, such as achalasia and Hirschsprung disease, the lack of VIP innervation is believed to play a major role in defective esophageal relaxation and bowel dysmotility, respectively.83,84 Unlike GI endocrine cells that line the mucosa of the gut, VIP is produced and released from neurons and it is likely that most measurable VIP in serum is of neuronal origin. Normally, serum VIP levels are low and do not appreciably change with a meal. However, in pancreatic cholera, also known as Verner-Morrison syndrome and manifested by watery diarrhea, hypokalemia, and achlorhydria,85 VIP levels can be extraordinarily high.80 VIP-secreting tumors usually produce a voluminous diarrhea86 (see Chapter 34). 

Glucagon Glucagon is synthesized and released from pancreatic alpha cells and from intestinal endocrine cells of the ileum and colon. Pancreatic glucagon is a 29–amino acid peptide that regulates glucose homeostasis via gluconeogenesis, glycogenolysis, and lipolysis, and is counterregulatory to insulin. The gene for glucagon encodes not only preproglucagon but also glucagon-like peptides (GLPs). This precursor peptide consists of a signal peptide, a glucagon-related polypeptide, glucagon, and GLP-1 and GLP-2. Tissue-specific peptide processing occurs through prohormone convertases that produce glucagon in the pancreas and GLP-1 and GLP-2 in the intestine (Fig. 4.6).87,88 Glucagon and GLP-1 regulate glucose homeostasis.89 Glucagon is released from the endocrine pancreas in response to a meal and binds to G protein–coupled receptors on skeletal muscle and the liver to exert its glucoregulatory effects. GLP-1 stimulates insulin secretion and augments the insulin-releasing effects of glucose on the pancreatic beta cell (see later, “Enteroinsular Axis”). GLP-1 analogs have been developed for the treatment of type II diabetes mellitus. A long-acting human GLP-1 analog improves beta cell function and can lower body weight in patients with type II diabetes.90,91 GLP-2 is an intestinal growth factor that increases villus height, stimulates intestinal crypt proliferation, and prevents enterocyte apoptosis. Based on these actions, GLP-2 agonists are used for the treatment of short bowel ­syndrome. 

CHAPTER 4  Gut Sensory Transduction

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Fig. 4.6  Posttranslational processing of glucagon. The glucagon gene is transcribed and translated into proglucagon, a precursor peptide. Proglucagon undergoes enzymatic cleavage (yellow box). The product of the cleavage depends on the type of enzyme. For instance, PC2 expressed in the pancreas cleaves proglucagon into active glucagon; whereas, PC1/3 expressed in the intestine cleaves proglucagon into a peptide fragment that gives rise to glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2). In the intestine, GLP-1 is further processed into smaller fragments with different bioactive functions. Some of the enzymes involved in the process are dipeptidyl peptidase-4 (DPP4) and neutral endopeptidase (NEP).

Glucose-Dependent Insulinotropic Polypeptide GIP was discovered because of its ability to inhibit gastric acid secretion (enterogastrone effect) and was originally termed gastric inhibitory polypeptide. It was subsequently shown that the effects on gastric acid secretion occur only at very high concentrations that are above the physiologic range. However, GIP has potent effects on insulin release that (like GLP-1) potentiates glucose-stimulated insulin secretion.92 Based on this action, GIP was redefined as glucose-dependent insulinotropic polypeptide. GIP is a 42–amino acid peptide produced by cells in the mucosa of the small intestine. GIP is released into the blood in response to ingestion of glucose or fat. In the presence of elevated blood glucose levels, GIP binds to its receptor on pancreatic beta cells, activating adenylate cyclase and other pathways that increase intracellular calcium concentrations, leading to insulin secretion. Importantly, however, the effects on insulin secretion occur only if hyperglycemia exists; GIP does not stimulate insulin release under normoglycemic conditions. GIP receptors are also expressed on adipocytes, through which GIP augments triglyceride storage, which may contribute to fat accumulation. Based on the insulinotropic properties of GIP, coupled with its effects on adipocytes, it has been proposed that GIP may play a role in obesity and development of insulin resistance associated with type II diabetes mellitus.93 Consistent with this proposal was the experimental finding that mice lacking the GIP receptor do not gain weight when placed on a high-fat diet.94 It remains to be seen whether GIP antagonists can be used

to treat obesity. In rare circumstances, receptors for GIP may be aberrantly expressed in the adrenal cortex, resulting in fooddependent Cushing syndrome.95,96 

Pancreatic Polypeptide Family Originally isolated during the preparation of insulin, pancreatic polypeptide (PP) is the founding member of the PP family.97 The PP family of peptides includes NPY and peptide tyrosine tyrosine (PYY), which were discovered because of the presence of a C-terminal tyrosine amide.98, 99 PP is stored and secreted from specialized pancreatic endocrine cells (PP cells),100 whereas NPY is a principal neurotransmitter found in the central and peripheral nervous systems.101 PYY has been localized to enteroendocrine cells throughout the GI tract but is found in greatest concentrations in the ileum and colon, where it is produced in the same cells that synthesize GLPs.102 The PP-PYY-NPY family of peptides functions as endocrine, paracrine, and neurocrine transmitters in the regulation of a number of actions that result from binding to one of five receptor subtypes.103 PP inhibits pancreatic exocrine secretion, gallbladder contraction, and gut motility.104 PYY inhibits vagally stimulated gastric acid secretion and other motor and secretory functions.105 An abbreviated form of PYY lacking the first two AAs of the normally produced 36 amino acid peptide, PYY3-36, has been shown to reduce food intake when administered to humans, indicating that intestinally released peptide may play a role in regulating meal size.106 Many PYY cells possess neuropods that run along the basal surface of adjacent enterocytes, which possess Y1 and

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Y2 PYY receptor subtypes. It is likely that locally released PYY exerts a colonic antisecretory effect.107 NPY is one of the most abundant peptides in the central nervous system and, in contrast to PYY3-36, is a potent stimulant of food intake.108 Peripherally, NPY affects vascular and GI smooth muscle function.109 

Substance P and the Tachykinins Substance P belongs to the tachykinin family of peptides, which includes neurokinin A and neurokinin B. The tachykinins are found throughout the peripheral and central nervous systems and are important mediators of neuropathic inflammation.110 Tachykinins, as a group, are encoded by two genes that produce preprotachykinin A and preprotachykinin B. Common to both is a well-conserved C-terminal pentapeptide. Transcriptional and translational processing produce substance P, neurokinin A, and/ or neurokinin B, which are regulated in large part by alternative splicing. These peptides function primarily as neuropeptides. Substance P is a neurotransmitter of primary sensory afferent neurons and binds to specific receptors in lamina I of the spinal cord.111 Three receptors for this family of peptides have been identified—NK-1, NK-2, and NK-3.112 Substance P is the primary ligand for the NK-1 receptor, neurokinin A for the NK-2 receptor, and neurokinin B for the NK-3 receptor. However, all these peptides can bind and signal through all three receptor subtypes. Substance P has been implicated as a primary mediator of neurogenic inflammation. In the intestine, Clostridium difficile– initiated experimental colitis results from toxin-induced release of substance P and consequent activation of the NK-1 receptor.113 These inflammatory sequelae can be blocked by substance P receptor antagonists. Substance P receptors are more abundant in the intestine of patients with ulcerative colitis and Crohn disease.114 

Somatostatin This is a 14–amino acid cyclic peptide that was initially identified as an inhibitor of growth hormone secretion. Since its discovery, it has been found in almost every organ in the body and throughout the GI tract. In the gut, somatostatin is produced by D cells in the gastric and intestinal mucosa and islets of the pancreas, as well as enteric neurons.115 Somatostatin has a number of pharmacologic effects that are mostly inhibitory. In the stomach, somatostatin plays an important role in regulating gastric acid secretion.116 In the antrum, D cells are open to the lumen, where they are directly exposed to acid. A low gastric pH stimulates D cells that lie in close proximity to gastrin-producing cells to secrete somatostatin and inhibit gastrin release (see Chapter 51). Reduced gastrin secretion decreases the stimulus for acid production and the pH of the stomach contents rises. Thus some of the inhibitory effects of gastric acid on gastrin release (see earlier, “Gastrin”) are mediated by somatostatin. Somatostatin release is also influenced by mechanical stimulation, dietary components of a meal, including protein, fat, and glucose, and other hormones and neurotransmitters.117 Muscarinic stimulation appears to be the most important neural stimulus to somatostatin secretion. At least five somatostatin receptors have been identified that account for divergent pharmacologic properties.118 For example, receptor subtypes 2 and 3 couple to inhibitory G proteins but receptor subtype 1 does not. In addition, only somatostatin receptor subtype 3 inhibits adenylate cyclase. The inhibitory effects of somatostatin are mediated by a decrease in cAMP, Ca2+ channel inhibition, or K+ channel opening. In the gut, somatostatin has broad inhibitory actions. In addition to effects on gastric acid, somatostatin reduces pepsinogen secretion. Somatostatin profoundly inhibits pancreatic enzyme,

fluid, and bicarbonate secretion and reduces bile flow.119 The effects of somatostatin on gut motility are largely inhibitory, with the exception that it stimulates the migrating motor complex (MMC), possibly through effects on motilin. Somatostatin also reduces intestinal transport of nutrients and fluid, reduces splanchnic blood flow, and has inhibitory effects on tissue growth and proliferation.120,121 Because of its varied physiologic effects, somatostatin has several clinically important pharmacologic uses. Many endocrine cells possess somatostatin receptors and are sensitive to inhibitory regulation. Therefore somatostatin and more recently developed somatostatin analogs are used to treat conditions of hormone excess produced by endocrine tumors, such as acromegaly, carcinoid tumors, and islet cell tumors (including gastrinomas).122 Its ability to reduce splanchnic blood flow and portal venous pressure has led to somatostatin analogs being used in treating esophageal variceal bleeding (see Chapter 92).123 The inhibitory effects on secretion have been exploited by using somatostatin analogs to treat some forms of diarrhea and reduce fluid output from pancreatic fistulas. Many endocrine tumors express abundant somatostatin receptors, making it possible to use radiolabeled somatostatin analogs, such as octreotide, to localize even small tumors throughout the body. 

Motilin Motilin is a 22–amino acid peptide produced by endocrine cells of the duodenal epithelium.124 Motilin is not released by the stimulation of food but instead is secreted into the blood in a periodic and recurrent pattern that is synchronized with the MMC under fasting conditions. Elevations in blood motilin levels regulate the phase III contractions that initiate in the antroduodenal region and progress toward the distal gut. Motilin binds to specific receptors on smooth muscle cells of the esophagus, stomach, and small and large intestines through which it exerts propulsive activity.125 Agonists to the motilin receptor such as erythromycin have pronounced effects on GI motility, which occasionally produces undesired side effects of abdominal cramping and diarrhea.126 However, motilin agonists may be useful to treat conditions of impaired gastric and intestinal motility and are being investigated for the treatment of constipation-predominant irritable bowel syndrome.127 

Leptin Leptin is a 167–amino acid protein that is secreted primarily from adipocytes. Blood leptin levels reflect total body fat stores.128 Its primary action appears to be to reduce food intake. Leptin is a member of the cytokine family of signaling molecules. Five different forms of leptin receptors have been reported.129 A short form of the receptor appears to transport leptin from the blood across the blood-brain barrier, where it has access to the hypothalamus. A long form of the leptin receptor is located in hypothalamic nuclei, where leptin binds and activates the Janus kinase signal transduction and translation system (JAK STAT).130 Small amounts of leptin are produced by the chief cells of the stomach and by the placenta, and are present in breast milk. Peripheral administration of leptin reduces food intake. However, this effect is reduced as animals become obese. Interestingly, when injected into the central nervous system, obese animals respond normally to leptin and reduce food intake, suggesting that leptin “resistance” in obesity occurs at the level of the leptin receptor that transports leptin across the blood-brain barrier.131 Leptin’s ability to reduce food intake occurs within the brain by decreasing NPY (a potent stimulant of food intake) and by increasing α–melanocyte-stimulating hormone (α−MSH), an inhibitor of food intake.132 Peripherally, leptin acts synergistically with CCK to reduce meal size.133 In obese rats lacking

CHAPTER 4  Gut Sensory Transduction

the leptin receptor, the synergistic effects of leptin plus CCK to reduce meal size are lost, but could be restored with genetic reconstitution of the leptin receptor in the brain.134 One might expect loss of leptin-CCK synergy on meal size in those rare cases of human obesity caused by leptin receptor defects or even with leptin resistance. Blood levels of leptin increase as obesity develops and leptin appears to reflect total fat content.135 At the cellular level, large adipocytes produce more leptin than small adipocytes. Because of its effects on food intake, it was initially thought that exogenous leptin could be used therapeutically to treat obesity. However, only a very modest effect on weight loss has been demonstrated in clinical trials. Leptin deficiency has been reported as a cause of obesity in a few families, but this condition is extremely rare.136,137 Mutation of the leptin receptor has been described as a cause of obesity in at least one family.138 

Ghrelin Ghrelin is a 28–amino acid peptide produced by the stomach and is the natural ligand for the growth hormone secretagogue (GHS) receptor.139 When administered centrally or peripherally, ghrelin stimulates growth hormone secretion, increases food intake, and produces weight gain.140,141 Circulating ghrelin levels increase during periods of fasting or under conditions associated with negative energy balance, such as starvation or anorexia. In contrast, ghrelin levels are low after eating and in obesity. Ghrelin appears to play a central role in the neurohormonal regulation of food intake and energy homeostasis. The gastric fundus is the most abundant source of ghrelin, although lower amounts of ghrelin are found in the intestine, pancreas, pituitary, kidney, and placenta. Ghrelin is produced by distinctive endocrine cells known as P/D1 cells142,143 that are of two types, open and closed. The open type is exposed to the lumen of the stomach, where it comes into contact with gastric contents, whereas the closed type lies in close proximity to the capillary network of the lamina propria.144 Both cell types secrete hormone into the bloodstream. Based on its structure, ghrelin is a member of the motilin family of peptides and, like motilin, ghrelin stimulates gastric contraction and enhances stomach emptying. The observations that circulating ghrelin levels increase sharply before a meal and fall abruptly after a meal suggest that it serves as a signal for initiation of feeding. The effects of food on plasma ghrelin levels can be reproduced by ingestion of glucose and appear to be unrelated to the physical effects of a meal on gastric distention. Circulating ghrelin levels are low in states of positive energy balance such as obesity and are inversely correlated with body mass index.145,146 Conversely, ghrelin levels are high in fasting, cachexia, and anorexia. Importantly, weight loss increases circulating ghrelin levels.147 Ghrelin released from the stomach acts on the vagus nerve to exert its effects on feeding. However, it is also active when delivered to the central nervous system, and in this location, ghrelin activates NPY and agouti-related protein-producing neurons in the arcuate nucleus of the hypothalamus, which are involved in the regulation of feeding.141,148 Gastric bypass patients do not demonstrate the premeal increase in plasma ghrelin that is seen in normal individuals.149 This lack of ghrelin release may be one of the mechanisms contributing to the overall effectiveness of gastric bypass surgery for inducing weight loss. Prader-Willi syndrome is a congenital obesity syndrome characterized by severe hyperphagia, growth hormone deficiency, and hypogonadism. Although obesity is ordinarily associated with low ghrelin levels, patients with Prader-Willi syndrome have high circulating ghrelin levels that do not decline after a meal.150,151 The levels of ghrelin in this syndrome are similar to those that

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can stimulate appetite and increase food intake in individuals receiving infusions of exogenous ghrelin, suggesting that abnormal ghrelin secretion may be responsible for the hyperphagia in Prader-Willi syndrome.152 

NEUROTRANSMITTERS Only limited number of transmitters have been described in neurotransmission throughout the GI tract. Even though their distribution is widespread, they confer specific and time limited actions at precise sites by virtue of their local release and reuptake or inactivation.

Acetylcholine Acetylcholine is synthesized in cholinergic neurons and is the principal regulator of GI motility and pancreatic secretion. Acetylcholine is stored in nerve terminals and released by nerve depolarization. Released acetylcholine binds to postsynaptic muscarinic and/or nicotinic receptors. Nicotinic acetylcholine receptors belong to a family of ligand-gated ion channels and are homopentamers or heteropentamers composed of α, β, γ, δ, and ε subunits.153 The α subunit is believed to be the mediator of postsynaptic membrane depolarization following acetylcholine receptor binding. Muscarinic receptors belong to the heptahelical GPCR family. There are five known muscarinic cholinergic receptors (M1 to M5). Muscarinic receptors can be further classified based on receptor signal transduction, with M1, M3, and M5 stimulating adenylate cyclase and M2 and M4 inhibiting this enzyme. Acetylcholine is degraded by the enzyme acetylcholinesterase, and the products may be recycled through high-affinity transporters on the nerve terminal. 

Catecholamines The primary catecholamine neurotransmitters of the enteric nervous system include norepinephrine and dopamine. Norepinephrine is synthesized from tyrosine and released from postganglionic sympathetic nerve terminals that innervate enteric ganglia and blood vessels. Tyrosine is converted to dopa by tyrosine hydroxylase. Dopa is initially converted into dopamine by dopa decarboxylase and packaged into secretory granules. Norepinephrine is formed from dopamine by the action of dopamine β-hydroxylase in the secretory granule. After an appropriate stimulus, norepinephrine-containing secretory granules are released from nerve terminals and bind to adrenergic receptors. Adrenergic receptors are G protein–coupled, have seven typical membrane-spanning domains, and are of two basic types, α and β. α-Adrenergic receptors are further classified into α1A, α1B, α2A, α2B, α2C, and α2D. Similarly, β receptors include β1, β2, and β3. Adrenergic receptors are known to signal through various G proteins, resulting in stimulation or inhibition of adenylate cyclase and other effector systems. Norepinephrine signaling is terminated by intracellular monoamine oxidase or by rapid reuptake by an amine transporter. The actions of adrenergic receptor stimulation regulate smooth muscle contraction, intestinal blood flow, and GI secretion. 

Dopamine Dopamine is an important mediator of GI secretion, absorption, and motility and is the predominant catecholamine neurotransmitter of the central and peripheral nervous systems. In the central nervous system, dopamine regulates food intake, emotions, and endocrine responses and, peripherally, controls hormone secretion, vascular tone, and GI motility. Characterization of dopamine in the GI tract has been challenging for several reasons. First, dopamine can produce inhibitory and excitatory

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effects on GI motility.154 In general, the excitatory response, which is mediated by presynaptic receptors, occurs at a lower agonist concentration than the inhibitory effect, which is mediated by postsynaptic receptors. Second, localization of dopamine receptors has been hampered by identification of dopamine receptors in locations that appear to be species specific.155 Third, studies of dopamine in GI tract motility have often used pharmacologic amounts of this agonist. Therefore the interpretation of results has been confounded by the ability of dopamine to activate adrenergic receptors at high doses. Classically, dopamine was thought to act via two distinct receptor subtypes, type 1 and type 2. Molecular cloning has now demonstrated five dopamine receptor subtypes, each with a unique molecular structure and gene locus.155 Dopamine receptors are integral membrane GPCRs, and each receptor subtype has a specific pharmacologic profile when exposed to agonists and antagonists. After release from the nerve terminal, dopamine is cleared from the synaptic cleft by a specific dopamine transporter. 

Serotonin Serotonin has long been known to play a role in GI neurotransmission.156 The GI tract contains more than 95% of the total body serotonin, and serotonin is important in various processes, including epithelial secretion, bowel motility, nausea, and emesis.157 Serotonin is synthesized from tryptophan, an essential amino acid, and is converted to its active form in nerve terminals. Secreted serotonin is inactivated in the synaptic cleft by reuptake

via a serotonin-specific transporter. Most plasma serotonin is derived from the gut, where it is found in mucosal enterochromaffin cells and the enteric nervous system. Serotonin mediates its effects by binding to a specific receptor. There are seven different serotonin receptor subtypes found on enteric neurons, enterochromaffin cells, and GI smooth muscle (5-HT1 to 5-HT7). The actions of serotonin are complex (Fig. 4.7).158 It can cause smooth muscle contraction through stimulation of cholinergic nerves or relaxation by stimulating inhibitory NO-containing neurons.157 Serotonin released from mucosal cells stimulates sensory neurons, initiating a peristaltic reflex and secretion (via 5-HT4 receptors), and modulates sensation through activation of 5-HT3 receptors.156 The myenteric plexus contains serotoninergic interneurons that project to the submucosal plexus and ganglia extrinsic to the bowel wall. Extrinsic neurons activated by serotonin participate in bowel sensation and may be responsible for abdominal pain, nausea, and symptoms associated with irritable bowel syndrome. Intrinsic neurons activated by serotonin are primary components of the peristaltic and secretory reflexes responsible for normal GI function. Serotonin may also activate vagal afferent pathways and, in the central nervous system, modulates appetite, mood, and sexual function. Because of these diverse effects, it is not surprising that selective serotonin reuptake inhibitor drugs (SSRIs), commonly used to treat depression and anxiety, have prominent GI side effects when compared with placebo treatment. Serotonin and its receptor have been implicated in the pathogenesis of motility disorders of the GI tract.159 Characterization

Fig. 4.7 Serotonin in the enteric nervous system. About 90% of the serotonin’s body is produced by enterochromaffin cells (green) of the intestinal epithelium. Like enteroendocrine cells, enterochromaffin cells are sensory cells that release serotonin, also known as 5- hydroxytryptamine (5-HT), in response to GI luminal contents. Released 5-HT stimulates afferent fibers of the vagus nerve, which carry sensory information to the brain. The cell bodies of these vagal neurons are clustered in the nodose ganglia. In addition, 5-HT can also stimulate nerve fibers from neurons in the submucosal plexus or myenteric plexus. The information integrated at these plexus ultimately regulates the excitation or inhibition of both the circular and/or the longitudinal smooth muscle. The synchronous contraction of these two layers of smooth muscle ultimately allows churning and propelling the chyme (partly digested food).  

CHAPTER 4  Gut Sensory Transduction

of specific serotonin receptor subtypes has led to the development of selective agonists and antagonists for the treatment of irritable bowel syndrome and chronic constipation and diarrhea. For example, 5-HT3 receptor antagonists, which reduce intestinal secretion, are used to treat diarrhea-predominant irritable bowel syndrome. 5-HT4 receptor agonists elicit prokinetic effects and are used to treat constipation-predominant irritable bowel syndrome and other motility disorders.160,161 Serotonin can also be enzymatically converted to melatonin by serotonin N-acetyltransferase.162 Other than the pineal gland, the GI tract is the major source of the body’s melatonin. Melatonin is produced in enterochromaffin cells and released into the blood after ingestion of a meal. A number of actions on the GI tract have been described for melatonin, including reducing gastric acid and pepsin secretion, inducing smooth muscle relaxation, and preventing epithelial injury through an antioxidant effect.163 It has been proposed that melatonin released after a meal may contribute to postprandial somnolence.164 

Histamine In the GI tract, histamine is best known for its central role in regulating gastric acid secretion (see Chapter 51) and intestinal motility. Histamine is produced by enterochromaffin-like cells of the stomach and intestine, as well as enteric nerves. Histamine is synthesized from L-histidine by histidine decarboxylase and activates three GPCR subtypes. H1 receptors are found on smooth muscle and vascular endothelial cells, and are linked to phospholipase C (PLC) activation. As such, the H1 receptor mediates many of the allergic responses induced by histamine. H2 receptors are present on gastric parietal cells, smooth muscle, and cardiac myocytes. H2 receptor binding stimulates Gs (G proteins that stimulate adenylate cyclase) and activates adenylate cyclase. H3 receptors are present in the central nervous system and GI tract enterochromaffin cells. These receptors signal through Gi and inhibit adenylate cyclase.165 Histamine can also interact with the N-methyl-D-aspartate (NMDA) receptor and enhance activity of NMDA-bearing neurons independently of the three known histamine receptor subtypes.

Unlike other neurotransmitters, there is no known transporter responsible for termination of histamine’s action. However, histamine is metabolized to telemethylhistamine by histamine N-methyltransferase and is then degraded to telemethylimidazoleacetic acid by monoamine oxidase B and an aldehyde dehydrogenase. 

Nitric oxide NO is a unique chemical messenger produced from L-arginine by the enzyme nitric oxide synthase (NOS).166 Three types of NOS are known. Types I and III are also known as endothelial NOS and neuronal NOS, respectively, and are constitutively active. Small changes in NOS activity can occur through elevations in intracellular calcium. The inducible form of NOS (type II) is apparent only when cells become activated by specific inflammatory cytokines. This form of NOS is capable of producing large amounts of NO and is calcium independent. NOS is often colocalized with VIP and PACAP in neurons of the enteric nervous system.167 NO, being an unstable gas, has a relatively short half-life. Unlike most neurotransmitters and hormones, NO does not act via a membrane-bound receptor. Instead, NO readily diffuses into adjacent cells to activate guanylate cyclase directly (Fig. 4.8). NO activity is terminated by its oxidation to nitrate and nitrite. Many enteric nerves use NO to signal neighboring cells and induce epithelial secretion, vasodilation, or muscle relaxation. NO is also produced by macrophages and neutrophils to help kill invading organisms.168 

CANNABINOIDS AND OTHER CHEMICAL TRANSMITTERS Cannabinoids There are three categories of cannabinoids: synthetic, phytocannabinoids found in plants, and endocannabinoids. Endocannabinoids, in particular, have similar functions to neurotransmitters, in that they participate in synaptic transmission.169 In contrast to typical neurotransmitters, however, the flow of endocannabinoid signaling is retrograde to conventional neurontransmitters.170 Because of their lipophilic nature,

Fig. 4.8 Relaxing smooth muscle tone through nitric oxide (NO). NO, synthesized from arginine by nitric oxide synthase, diffuses across the plasma membrane into smooth muscle cells. NO binds to and activates guanylyl cyclase, which converts guanosine triphosphate to cGMP. cGMP causes smooth muscle relaxation. (Modified from Alberts B, Bray D, Lewis J, et al, eds. Molecular Biology of the Cell. 4th ed. New York: Garland Science; 2002, p. 831.)  

 

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endocannabinoids are membrane-bound molecules thought to be enriched in postsynaptic neurons. Thus when released, endocannabinoids move from postsynapses to act on presynaptic cannabinoid receptors and depress presynaptic function.171 In this manner, endocannabinoid signaling helps postsynaptic neurons regulate the secretion of transmitters from the sensory cell. There are several types of endocannabinoid ligands, including arachidonoylethanolamide (anandamide), 2-arachidonoyl (2-AG), 2-arachidonyl glyceryl ether (Noladin ether), N-arachidonoyl-dopamine (NADA), virodhamine (OAE), and lysophosphatidylinositol. Endocannabinoids, as well as other cannabinoids, modulate metabolism and behavior by acting on the GPCR cannabinoid receptors CB1 and CB2. Both receptors are distributed throughout the body, although CB1 is primarily found in neurons and epithelial chemosensory cells and CB2 is mainly present in cells of the immune system. In the GI tract, CB1 receptors are also involved in counteracting proinflammatory responses and preventing the development of colitis.172 In addition to activating classical cannabinoid receptors, endocannabinoids can also stimulate GPCRs such as GPR119. Importantly, GPR119 is a receptor found in enteroendocrine cells of the small intestine, and its activation by endocannabinoids triggers the release of satiety-inducing hormones like CCK and peptide YY.172 These findings have made the field of GI endocannabinoid research an active area for the development of therapeutic treatments. 

Adenosine Adenosine is an endogenous nucleoside that acts through any of four GPCR subtypes.173 Adenosine causes relaxation of intestinal smooth muscle and stimulates intestinal secretion. Adenosine can also cause peripheral vasodilation and activation of nociceptors that participate in neural pain pathways. 

Cytokines Cytokines are a group of polypeptides produced by various immunomodulatory cells and are involved in cell proliferation, immunity, and inflammation. Cytokines are induced by specific stimuli, such as toxins produced by pathogens, and often elicit a complex response involving other cellular mediators to eradicate the foreign substance. Cytokines may be categorized as interleukins (ILs), tumor necrosis factors (TNFs), lymphotoxins, interferons, colony-stimulating factors (CSFs), and others.174 Interleukins can be further subtyped into at least 35 separate substances, IL-1 to IL-35. There are two TNFs, TNF-α and TNF-β, which are also known as lymphotoxin-α. Interferons are produced during viral or bacterial infection and come in two varieties, interferon-α (also known as leukocyte-derived interferon or interferon-β) and interferon-γ. Interferon-α is produced by T lymphocytes and is used clinically for the treatment of viral hepatitis (see Chapters 79 and 80). The major CSFs are granulocyte mononuclear phagocyte CSF, mononuclear phagocyte CSF, and granulocyte CSF. These agents are used for chemotherapy-induced neutropenia and marrow support after bone marrow transplantation. Chemokines initiate and propagate inflammation and are of two groups, CXC (α chemokines) and CC (β chemokines). Other cytokines, such as transforming growth factor-β (TGF)-β and platelet-derived growth factor (PDGF), have proliferative effects. 

THE IMPORTANCE OF HORMONES AND NEUROTRANSMITTERS Growth and Abnormal Growth of the Gut Growth of GI tissues is a balance between cellular proliferation and senescence. Many factors participate in maintenance

of the GI mucosa. Nutrients and other luminal factors stimulate growth of the intestinal mucosa and are necessary to maintain normal digestive and absorptive functions. Hormones and transmitters serve as secondary messengers that are normally secreted in response to food ingestion and mediate many of the nutrient effects on the GI tract. They play a key role in cellular proliferation. Alterations in intestinal proliferation are manifested by atrophy, hyperplasia, dysplasia, or malignancy (see Chapter 1). In addition to GLP-2 (described previously), there are several growth factors that have important growth promoting effects on the GI tract, including peptides of the EGF, TGF-β, IGF, FGF, and PDGF families, hepatocyte growth factors, trefoil factors, and many cytokines (including ILs).175 The following are outlined important properties of some of these receptors. 

Growth Factor Receptors Growth factors regulate cellular proliferation by interacting with specific cell surface receptors. These receptors are membrane proteins that possess specific binding sites for the growth factor ligand. An unusual form of signaling occurs when the ligand interacts with its receptor within the same cell. For example, PDGF receptors present on the intracellular surface of fibroblast cell lines are activated by intracellular ligand. This process is known as intracrine signaling. Most peptide growth factors, however, interact with receptors on different cells to regulate proliferation. Growth factor receptors can be single polypeptide chains containing one membrane-spanning region, such as the receptor for EGF, or they may be composed of two subunit heterodimers, with one subunit containing a transmembrane domain and the other residing intracellularly but covalently bound to the transmembrane subunit. Heterodimers may also dimerize to form a receptor composed of four subunits (e.g., IGF receptor). Binding of the ligand to its receptor usually causes aggregation of two or more receptors and activation of intrinsic tyrosine kinase activity. Growth factor receptors also have the ability to autophosphorylate when bound to a ligand. In addition, receptor tyrosine kinase activity may phosphorylate other intracellular proteins important in signal transduction. Autophosphorylation attenuates the receptor’s kinase activity and often leads to downregulation and internalization of the receptor. Mutation of the receptor at its autophosphorylation site may lead to constitutive receptor activity and cellular transformation. Growth factor receptors may couple to various intracellular signaling pathways, including adenylate cyclase, phospholipase C, calcium-calmodulin protein kinases, MAP kinase, and nuclear transcription factors. Thus growth factors play important and varied roles in most cells of the GI tract. It is not surprising therefore that mutations in growth factor receptors or downstream signaling proteins can lead to unregulated cell growth and neoplasia (see Chapter 1). An important action of growth factors is their ability to modulate the expression of transacting transcription factors that can regulate expression of many other genes.176 Early response genes such as jun and fos are activated rapidly after ligand binding and control the expression of many other genes involved in cellular proliferation. Other important transcriptional factors include c-myc and nuclear factor κB (NF-κB). The latter is found in the cytoplasm in an inactive form and, following ligand binding, translocates to the nucleus, where it activates other transcription factors. NF-κB is a key target for strategies to regulate cellular proliferation and inflammation. In its phosphorylated form Rb-1, originally identified in retinoblastoma, is an inhibitor of cellular proliferation that complexes with the transcription factor p53. Dephosphorylation of Rb-1 releases p53, which activates other genes leading to cellular proliferation.

CHAPTER 4  Gut Sensory Transduction

Almost all growth factors of the GI tract exert paracrine effects. However, many growth factors also possess autocrine and even intracrine actions. It has become apparent that growth factors and other signaling molecules secreted into the lumen of the gut can have important local biological actions. Distant effects of growth factors found in the circulation may be important for growth of certain types of cancers, particularly lung and colon cancer. 

Epidermal Growth Factor EGF was the first growth factor to be discovered. It is the prototype for a family of growth factors that are structurally related and have similarly related receptors. Other members of the family include TGF-α, amphiregulin, and heparin-binding EGF. EGF is identical to urogastrone (originally isolated from urine), which was shown to inhibit gastric acid secretion and promote healing of gastric ulcers. EGF is secreted from submaxillary glands and Brunner glands of the duodenum. It is likely that EGF interacts with luminal cells of the GI tract to regulate proliferation. EGF has important trophic effects on gastric mucosa, and the wide distribution of EGF receptors suggests that EGF has mitogenic actions on various cells throughout the gut. The EGF receptor has been reported to be responsible for gastric hyperplasia in patients with Mιnιtrier disease.177 Moreover, two patients were effectively treated with a monoclonal antibody that blocks ligand binding to the EGF receptor.178 EGF receptors are considered important targets for the experimental treatment of human cancer based on the evidence that they play a critical role in the growth and survival of certain tumors. Monoclonal antibodies as well as small tyrosine kinase inhibitors have been undergoing clinical evaluation for the treatment of human tumors.179 

Transforming Growth Factor-α TGF-α is produced by most epithelial cells of the GI tract and acts through the EGF receptor. Therefore it shares trophic properties with EGF. It is believed to play a key role in gastric reconstitution after mucosal injury. Moreover, it appears to be important in intestinal neoplasia because most gastric and colon cancers produce TGF-α (see Chapters 54 and 127). 

Transforming Growth Factor-β A family of TGF-β peptides exerts various biological actions, including stimulation of proliferation, differentiation, embryonic development, and formation of extracellular matrix.180 In contrast with the TGF-α receptor, there are three distinct TGF-β receptors.181 TGF-β modulates cell growth and proliferation in nearly all cell types and can enhance its own production from cells. It is likely that TGF-β plays a critical role in inflammation and tissue repair. TGF-β augments collagen production by recruitment of fibroblasts through its chemoattractant properties. This action can have beneficial or deleterious effects, depending on its site of deposition and abundance. For example, TGF-β may play a key role in the development of adhesions following surgery.182 

Insulin-Like Growth Factors Alternative splicing of the insulin gene produces two structurally related peptides, IGF I and IGF II.183 IGFs signal through at least three different IGF receptors. The IGF I receptor is a tyrosine kinase, and the IGF II receptor is identical to the mannose 6-phosphate receptor. Although the exact function of IGFs in the GI tract is not clearly understood, they have potent mitogenic activity in intestinal epithelium. IGF II appears to be critical for embryonic development. 

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Fibroblast Growth Factor and Platelet-Derived Growth Factor At least seven related FGFs have been identified.184 These peptides have mitogenic effects on various cell types, including mesenchymal cells, and likely play an important role in organogenesis and neovascularization.185 Although not unique to the GI tract, PDGF is one of the most thoroughly studied growth factors. It is important for fibroblast growth, and its receptor is expressed in the liver and throughout the GI tract, where it appears to promote wound healing. 

Trefoil Factors Trefoil factors (pS2, spasmolysin, and intestinal trefoil factor, also known as TTF1, 2, and 3, respectively) are a family of proteins expressed throughout the GI tract.186 They share a common structure, having six cysteine residues and three disulfide bonds, creating a cloverleaf appearance that stabilizes the peptide within the gut lumen. The pS2 peptide is produced in the gastric mucosa, spasmolysin is found in the antrum and pancreas, and intestinal trefoil factor is produced throughout the small and large intestines. These peptides are produced by mucous neck cells in the stomach or goblet cells in the intestine and are secreted onto the mucosal surface of the gut. It is likely that trefoil factors act on the apical surface of the epithelial cells, where they have growthpromoting properties on the GI mucosa. Other peptides signaling through GPCRs may also have growth-promoting effects. Three important examples include gastrin, CCK, and gastrin-releasing peptide (GRP). Gastrin stimulates the growth of enterochromaffin-like cells of the stomach and induces proliferation of the oxyntic mucosa containing parietal cells.187 Gastrin binds to CCK-2 receptors of the stomach and activates PLC and Ras pathways, which ultimately results in activation of protein kinase C and MAP kinase, respectively. MAP kinase, which can also be activated by tyrosine kinase receptors typical of growth factors, causes the phosphorylation of transcription factors that are involved in cellular proliferation. In some cells, cAMP and PKA exert synergistic effects on cellular growth through activation of nuclear transcription factors such as cAMPresponsive element binding (protein; CREB). However, in other cells, cAMP antagonizes proliferation. Therefore depending on the cell type, the effects of growth factors such as EGF, IGF, and PDGF may be enhanced by hormones that stimulate cAMP production. Certain colon cancer cells possess CCK-2 receptors and respond to the proliferative effects of gastrin. Moreover, gastrin may be produced by some colon cancers, enabling it to exert an autocrine effect to promote cancer growth.188 Whether circulating gastrin initiates colon cancer development is unknown. 

DIABETES AND THE GUT GI hormones play an important role in the regulation of insulin secretion and glucose homeostasis. These hormones control processes that facilitate the digestion and absorption of nutrients, as well as disposal of nutrients that have reached the bloodstream. In particular, gut peptides control postprandial glucose levels through three different mechanisms: (1) stimulation of insulin secretion from pancreatic beta cells; (2) inhibition of hepatic gluconeogenesis by suppression of glucagon secretion; and (3) delaying the delivery of carbohydrates to the small intestine by inhibiting gastric emptying.189 Each of these actions reduces the blood glucose excursions that normally occur after eating. Approximately 50% of the insulin released after a meal is the result of GI hormones that potentiate insulin secretion.190 This interaction is known as the enteroinsular axis and the gut peptides that stimulate insulin release are known as incretins. The major incretins are GLP-1 and GIP. GLP-1 not only stimulates

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PART I  Biology of the Gastrointestinal Tract

insulin secretion but also increases beta cell mass, inhibits glucagon secretion, and delays gastric emptying. GIP stimulates insulin secretion when glucose levels are elevated and decreases glucagon-stimulated hepatic glucose production.191 Thus on ingestion of a meal, glucose, as it is absorbed, stimulates GLP-1 and GIP secretion. Circulating glucose then stimulates beta cell production of insulin, and this effect is substantially augmented by incretins acting in conjunction with glucose to increase insulin levels. Postprandial hyperglycemia may also be controlled by delaying the delivery of food from the stomach to the small intestine, allowing the rise in insulin to keep pace with the rate of glucose absorption. Several gut hormones that delay gastric emptying have been shown to reduce postprandial glucose levels (Box 4.2).189 Amylin (islet amyloid polypeptide) is a 37–amino acid peptide synthesized primarily in the beta cells of the pancreatic islets together with insulin. Although it was originally recognized for its ability to form amyloid deposits in association with beta cell loss, it has more recently been found to suppress glucagon secretion, delay gastric emptying, and induce satiety.192 Insulin resistance in obese patients is associated with increased levels of both insulin and amylin. Type 2 diabetes mellitus is characterized by high circulating insulin levels and insulin resistance. In addition, insulin levels do not increase appropriately after a meal and significant hyperglycemia occurs, which is consistent with an impaired incretin effect. GIP secretion is preserved in type II diabetes; however, the insulinotropic effect of GIP is reduced.193 Although the precise cause is unknown, the defect in GIP-stimulated insulin release is most pronounced in the late phase of insulin secretion. In contrast to GIP, GLP-1 secretion is reduced in insulin-resistant type II diabetics. The lower GLP-1 levels are caused by impaired secretion rather than increased degradation of the hormone.194 Unlike GIP, the insulin response to infusion of GLP-1 is preserved, indicating that the beta cell can respond normally to this incretin hormone. These observations suggest that GLP-1 administration could be a viable treatment for the hyperglycemia associated with diabetes.195 The growing evidence that beta cell failure may develop in type II diabetes supports the use of incretin hormones, such as GLP-1, or agents that delay GLP-1 degradation by the enzyme dipeptidyl peptidase-4 (DPP-4) to enhance beta cell function.196,197 Several incretin analogs are now used clinically for the treatment of diabetes.198 

BOX 4.2 GI Peptides That Regulate Postprandial Blood Glucose Levels STIMULATE INSULIN RELEASE Glucagon-like peptide-1 Glucose-dependent insulinotropic peptide Gastrin releasing peptide Cholecystokinin (potentiates amino acid–stimulated insulin release) Gastrin (in presence of amino acids) Vasoactive intestinal peptide (potentiates glucose-stimulated insulin release) Pituitary adenylate cyclase–activating peptide (potentiates glucosestimulated insulin release) Motilin  DELAY GASTRIC EMPTYING Cholecystokinin Amylin Secretin  INHIBIT GLUCAGON RELEASE Amylin

GASTROINTESTINAL REGULATION OF APPETITE During a meal, ingested nutrients interact with cells of the mouth and GI tract. Endocrine cells of the stomach and small intestine possess receptors that are linked to the secretion of GI hormones. GI peptides (see Chapters 7 and 9) are then released into the surrounding space, where they exert paracrine actions or are taken up into the circulation, where they function as hormones.199 Each of these transmitters facilitates the ingestion, digestion, absorption, or distribution of nutrients that are essential for the organism. Some GI hormones control the size of an ingested meal and are known as satiety signals. Satiety hormones share several qualities.200 First, they decrease meal size. Second, blocking their endogenous activity leads to increased meal size. Third, reduction of food intake is not the result of an aversion to food. Fourth, secretion of the hormone is caused by ingestion of food that normally causes cessation of eating (Table 4.2). Most satiety signals interact with specific receptors on nerves leading from the GI tract to the hindbrain. The discovery that enteroendocrine cells synapse to nerves raises the possibility that satiety signals are initially regulated by neurotransmission signals and subsequently reinforced by hormonal signals.57,201 Other sensory systems, such as taste, integrate both mechanisms to accomplish short- and long-term sensory signaling. CCK is one of the most extensively studied satiety hormones. In a time- and dose-dependent manner, CCK reduces food intake in animals and humans,202 an effect that is mediated by CCK-1 receptors residing on vagus nerve endings.203 The effect of CCK on food intake is a proven physiologic action because administration of a CCK receptor antagonist induces hunger and results in larger meal sizes. CCK also delays the rate at which food empties from the stomach, which may explain why the satiety actions of CCK are most apparent when the stomach is distended. Together these findings indicate that CCK provides a signal for terminating a meal. GLP-1 is produced by enteroendocrine cells in the ileum and colon and is released in response to food in the intestine. Although the primary action of GLP-1 is to stimulate insulin secretion, it also delays gastric emptying. Moreover, infusion of GLP-1 increases satiety and produces feelings of fullness, thereby reducing food intake without causing aversion.204 GLP-1 receptors are found in the periventricular nucleus, dorsal medial hypothalamus, and arcuate nucleus of the hypothalamus, which are important areas in the regulation of hunger. Like CCK, central administration of GLP-1 suppresses food intake. PYY is also produced by enteroendocrine cells of the ileum and colon. Two forms of PYY are released into the circulation, PYY1-36 and PYY3-36. PYY1-36 binds to all subtypes of the neuropeptide Y family of receptors, whereas PYY3-36 has strong affinity for the Y2 receptor. When administered to animals, PYY3-36 causes a reduction in food intake, and mice lacking the Y2 receptor are resistant to the anorexigenic effects of PYY3-36, indicating that PYY3-36 signals satiety through this receptor.205 PYY3-36 has been shown in humans to decrease hunger scores and caloric TABLE 4.2  GI Peptides That Regulate Satiety and Food Intake Reduce Food Intake

Increase Food Intake

Cholecystokinin (CCK)

Ghrelin

Glucagon-like peptide-1 Peptide tyrosine tyrosine (PYY3-36) Gastrin-releasing peptide Amylin Apolipoprotein A-IV Somatostatin

CHAPTER 4  Gut Sensory Transduction

intake.206 Interestingly, most of the GI peptide receptors involved in satiety are also found in the brain, where they mediate similar satiety effects. This may represent conservation of peptide signals that serve similar purposes. Leptin is referred to as an adiposity signal because it is released into the blood in proportion to the amount of body fat and is considered a long-term regulator of energy balance. Together with CCK, leptin reduces food intake and produces a greater reduction in body weight than either agent alone.133 Therefore it appears that long-term regulators of energy balance can affect short-term regulators through a decrease in meal size, which may promote weight reduction. Hunger and initiation of a meal are intimately related. Ghrelin is intriguing because it is the only known circulating GI hormone that has orexigenic effects.149 Produced by the stomach, ghrelin levels increase abruptly before the onset of a meal and decrease

51

rapidly after eating, suggesting that it signals initiation of a meal. Consistent with this role are studies demonstrating that administration of antighrelin antibodies or a ghrelin receptor antagonist suppresses food intake.207 It is not known if ghrelin is responsible for the hunger pains and audible bowel sounds that occur in people who are hungry. Bariatric surgery, in particular Roux-en-Y gastric bypass, is the most effective procedure for long-term weight loss in morbid obesity. Although it had been assumed that weight loss accompanying this procedure was the result of reduced gastric capacity and calorie malabsorption, recent evidence of reduced ghrelin release and exaggerated PYY release after a meal has suggested that hormonal factors may contribute to reduced calorie intake.208 Full references for this chapter can be found on www.expertconsult.com

.

4

PART II

5

Nutrition in Gastroenterology

Nutritional Principles and Assessment of the Gastroenterology Patient Joel B. Mason

CHAPTER OUTLINE BASIC NUTRITIONAL CONCEPTS����������������������������������������52 Energy Stores�������������������������������������������������������������������52 Energy Metabolism����������������������������������������������������������52 Proteins 55 Carbohydrates 56 Lipids 56 Major Minerals 57 MICRONUTRIENTS��������������������������������������������������������������57 Vitamins 57 Trace Minerals�����������������������������������������������������������������57 Physiologic and Pathophysiologic Factors Affecting ­Micronutrient Requirements 62 STARVATION�����������������������������������������������������������������������63 MALNUTRITION�������������������������������������������������������������������64 Protein-Energy Malnutrition (PEM) 65 Physiologic Impairments Caused by Protein-Energy ­Malnutrition 67 NUTRITIONAL ASSESSMENT TECHNIQUES�������������������������68 History 68 Physical Examination�������������������������������������������������������69 Anthropometry 69 Functional Measures of Protein-Calorie Status�����������������70 Biochemical Measures of Protein-Calorie Status 71 Rapid Screening Tools for Assessment of Targeted ­Populations������������������������������������������������������������������72 AGGRESSIVE NUTRITIONAL SUPPORT IN THE HOSPITALIZED PATIENT������������������������������������������������������73 Malnourished Patients Undergoing Major Surgery 73 Patients Hospitalized with Decompensated Alcohol-­ Associated Liver Disease 73 Patients Undergoing Radiation Therapy 73 ����������������������������������������������������������������������������

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Diligent attention to patients’ nutritional needs can have a major positive impact on medical outcomes. This is particularly true in GI and liver disease because many of these conditions, in addition to altering nutrient metabolism and requirements, are prone to interfere with ingestion and assimilation of nutrients. Nutritional management, however, often continues to be an inadequately or incorrectly addressed component of patient care. Inadequate or misdirected attention to nutritional issues is due, in part, to failure to distinguish patients who stand to benefit from nutritional care from those whose outcomes will not respond to nutritional

52

intervention. The fact that many clinical trials have failed to demonstrate a benefit of nutritional support in hospitalized patients is often because such a distinction has not been made. The major aim of this chapter is to provide the scientific principles and practical tools necessary to recognize patients who will benefit from focused attention to their nutritional needs, and to provide the guidance necessary to develop a suitable nutritional plan for these individuals. Over- or under-feeding a patient can be detrimental to clinical outcomes, so developing a nutritional plan most appropriately begins by determining the patient’s estimated caloric and protein needs.

BASIC NUTRITIONAL CONCEPTS Energy Stores Endogenous energy stores are oxidized continuously for fuel. Triglyceride (TG) present in adipose tissue is the body’s major fuel reserve and is critical for survival during periods of starvation (Table 5.1). The high energy density and hydrophobic nature of TGs make them a five-fold better fuel per unit mass than glycogen. TGs liberate 9.3 kcal/g when oxidized and are stored compactly as oil inside the fat cell. In comparison, glycogen produces only 4.1 kcal/g on oxidation and is stored intracellularly as a gel, containing approximately 2 g of water per gram of glycogen. Adipose tissue cannot provide fuel for certain tissues like bone marrow, erythrocytes, leukocytes, renal medulla, eye tissues, and peripheral nerves, which cannot oxidize lipids and require glucose for their energy supply. During endurance exercise, glycogen and TGs in muscle tissue provide an important source of fuel for working muscles. 

Energy Metabolism Energy is required continuously for normal organ function, maintenance of metabolic homeostasis, heat production, and performance of mechanical work. Daily total energy expenditure (TEE) has three components: resting energy expenditure (REE) (≈70% of TEE); the energy expenditure of physical activity (≈20% of TEE); and the thermic effect of feeding (≈10% of TEE), which is the temporary increase in energy expenditure that accompanies enteral ingestion or parenteral administration of nutrients. Although the latter two components of TEE should be considered when estimating caloric needs for ambulatory individuals, in acutely ill, hospitalized patients, the energy expended in physical activity is typically ignored and the energy expended in the thermic effect of feeding is built into the predictive equations that follow.

Resting Energy Expenditure REE represents energy expenditure while a person lies quietly awake in an interprandial state; under these conditions, about 1 kcal/kg body

CHAPTER 5  Nutritional Principles and Assessment of the Gastroenterology Patient

weight is consumed per hour in healthy adults. Energy requirements of specific tissues differ dramatically (Table 5.2). The liver, intestine, brain, kidneys, and heart constitute roughly 10% of total body weight but account for about 75% of REE. In contrast, skeletal muscle at rest consumes some 20% of REE, but represents approximately 40% of body weight. Adipose tissue consumes less than 5% of REE but usually accounts for greater than 20% of body weight. An accurate assessment of REE is best obtained by indirect calorimetry, in which in vivo energy expenditure is estimated by measuring carbon dioxide production and oxygen consumption while the subject is at rest. Although indirect calorimetry is considered a gold standard for determining REE, obtaining such a measurement is not always practical and, in most instances, is unnecessary. Instead, one of several empiric equations can be used to estimate resting energy requirements (Table 5.3).1-4 The Harris-Benedict and Mifflin equations are designed for use in adults, whereas the WHO formulas includes equations for both children and adults. These equations are generally accurate in healthy subjects but are inaccurate, for example, in persons who are at extremes in weight because of anomalous body composition, and it is in these settings where determination by indirect calorimetry is useful.5 In the setting of acute illness, the predictive equations are usually adequate although it is necessary to insert correction factors of one type or another since inflammation and metabolic stress greatly influence energy expenditure. Proteinenergy malnutrition (PEM) and hypocaloric feeding without superimposed illness each decrease REE to values 10% to 15% below those expected for actual body size, whereas acute illness or trauma predictably increases energy expenditure (see later). 

The effect of physical activity on energy expenditure depends on the intensity and duration of daily activities. Highly trained athletes can increase their TEE 10- to 20-fold during athletic events. The activity factors shown in Table 5.4, each expressed as a TABLE 5.1  Endogenous Fuel Stores in a 70-kg Man Mass Fuel source

multiple of REE, can be used to estimate TEE in active patients. The energy expended during a particular physical activity is equal to (REE per hour) × (activity factor) × (duration of activity in hours). TEE represents the summation of energy expended during all daily activities, including rest periods. 

Thermic Effect of Feeding Eating or infusing nutrients increases metabolic rate. Dietary protein causes the greatest stimulation of metabolic rate, followed by carbohydrate and then fat. A meal containing all these nutrients usually increases metabolic rate by 5% to 10% of ingested or infused calories. 

Recommended Energy Intake in Hospitalized Patients In arriving at a nutritional plan for hospitalized patients, it is usually not necessary to obtain actual measurements of energy expenditure with a bedside indirect calorimeter. A number of simple formulas can be used instead and make up in practical value what they lack in accuracy. A few examples follow. Methods Incorporating Metabolic Stress Factors Metabolic stress (i.e., any injury or illness that incites some degree of systemic inflammation) will increase the metabolic rate through a variety of mechanisms (see later). The increase in energy expenditure is roughly proportional to the magnitude of the stress.6 Thus, the total daily energy requirement of an acutely ill patient can be estimated by multiplying the predicted REE (as determined by the Harris-Benedict or WHO equations) by a stress factor: TEE  =  REE  ×  Stress factor

Energy Expenditure of Physical Activity

Tissue

Grams

Kilocalories

Adipose

Triglyceride

13,000

121,000

Liver

Protein Glycogen Triglyceride

300 100 50

1,200 400 450

Muscle

Protein Glycogen Triglyceride

6,000 400 250

24,000 1,600 2,250

Blood

Glucose Triglyceride Free fatty acids

3 4 0.5

12 37 5

Table 5.5 delineates metabolic stress factors that accompany some common conditions and clinical scenarios in inpatients. Because the Mifflin equation was not designed to be used to estimate TEE with stress factors, it is not recommended in this context. In acutely ill hospitalized patients, it is not usually necessary to include an activity factor. An alternative and simple formula for adult inpatients, although accompanied by some further loss in accuracy, is:   

• 2  0 to 25 kcal/kg of actual body weight (ABW)/day for unstressed or mildly stressed patients • 25 to 30 kcal/ABW/day for moderately stressed patients • 30 to 35 kcal/ABW/day for severely stressed patients   

In using this formula, adjustments are necessary when the ABW is a misleading reflection of lean body mass. An adjusted ideal body weight (IBW) should be substituted for ABW in obese individuals who are more than 30% heavier than their IBW (desirable body weights appear in Table 5.6). Using an adjusted IBW helps prevent an overestimation of energy requirements6 and is calculated as: Adjusted IBW  =  IBW  +  0.5  (ABW − IBW)

TABLE 5.2  Resting Energy Requirements of Various Tissues in a 70-kg Man Tissue Mass

Energy Consumed

Tissue

Grams

Percentage Body Weight

Kcal/Day

Kcal/g Tissue/Day

Percentage REE

Liver

1,550

2.2

445

0.28

19

GI tract

2,000

3.0

300

0.15

13

Brain

1,400

2.0

420

0.30

18

Kidneys

300

0.4

360

1.27

15

Heart

300

0.4

235

0.80

10

Skeletal muscle

28,000

40.0

400

0.014

18

Adipose

15,000

21.0

80

0.005

4

  

REE, Resting energy expenditure.   

53

5

54

PART II  Nutrition in Gastroenterology

TABLE 5.3  Commonly Used Formulas for Calculating Resting Energy Expenditure

TABLE 5.5  Metabolic Stress Factors for Estimating Total Energy Expenditure in Hospitalized Patients

Harris-Benedict Equation Men

Injury or Illness

Relative Stress Factor*

66 + (13.7 × W) + (5 × H) − (6.8 × A)

1.6-2.0

Women

665 + (9.6 × W) + (1.8 × H) − (4.7 × A)

Second- or third-degree burns, >40% BSA

Mifflin Equation Men

Multiple trauma

1.5-1.7

(10 × W) + (6.25 × H) − (5 × A) + 5

1.4-1.5

Women

(10 × W) + (6.25 × H) − (5 × A) − 161

Second- or third-degree burns, 20%-40% BSA Severe infections

1.3-1.4

Female

Acute pancreatitis

1.1-1.2

Second- or third-degree burns, 10%-20% BSA

1.2-1.4

Long bone fracture

1.2

Peritonitis

1.2

Uncomplicated postoperative state

1.1

World Health Organization Formula Age (yr) Male 0-3

(60.9 × W) − 54

(60.1 × W) − 51

3-10

(22.7 × W) − 495

(22.5 × W) + 499

10-18

(17.5 × W) + 651

(12.2 × W) + 746

18-30

(15.3 × W) + 679

(14.7 × W) + 996

30-60

(11.2 × W) + 879

(8.7 × W) + 829

>60

(13.5 × W) + 987

(10.5 × W) + 596

  

Calculated as kilocalories per day. A, Age in years; H, height in centimeters; W, weight in kilograms.

  

*A stress factor of 1.0 is assumed for healthy controls. BSA, Body surface area. From Psota T, Chen KY. Measuring energy expenditure in clinical populations: rewards and challenges. Eur J Clin Nutr 2013; 67:436–42.   

  

TABLE 5.4  Relative Thermic Effect of Various Levels of Physical Activity Activity Level

Examples

Resting

Activity Factor 1.0

Very light

Standing, driving, typing

1.1-2.0

Light

Walking 2-3 miles/hr, shopping, light housekeeping

2.1-4.0

Moderate

Walking 3-4 miles/hr, biking, gardening, scrubbing floors

4.1-6.0

Heavy

Running, swimming, climbing, basketball

6.1-10.0

  

Adapted from Alpers DA, Stenson WF, Bier DM. Manual of nutritional therapeutics. Boston: Little, Brown; 1995.   

In patients with large artifactual increases in weight due to extracellular fluid retention (e.g., ascites), the IBW should be used to estimate energy requirements rather than the ABW.  Method Without a Stress Factor The most accurate and extensively validated equation for predicting daily energy expenditure in ill patients is one that does not incorporate a stress factor; it does, however, require knowledge of the minute ventilation, so its use is restricted to patients on mechanical ventilation.4 This formula (often referred to as the “Penn State Equation”) is: TEE = (REE calculated by Mifflin equation × 0.96) + (Tmax × 167) + (Ve × 31) − 6212 Tmax is the maximum temperature in Celsius over the past 24 hours; Ve is expired minute ventilation in liters. Table 5.7 describes a simple alternative method for estimating total daily energy requirements in hospitalized patients; it is based on BMI.7 It lacks the extensive validation of the prior algorithm as well as some of its accuracy, but it does not require knowledge of minute ventilation, is straightforward, and consequently has some genuine utilitarian value. Common sense has to be applied when using an inexact means such as this to estimate energy expenditure in hospitalized individuals, because illness commonly interjects artifacts into these calculations (e.g., ascites, anasarca).  Caloric Delivery and Avoidance of Hyperglycemia Over the past 2 decades, the trend has generally been toward a more conservative approach to caloric delivery in acutely ill

patients. One reason for this conservatism is that acute illness and its management often exacerbate preexisting diabetes or produce de novo glucose intolerance. As a result, hyperglycemia is a frequent consequence of enteral, and especially parenteral, nutrition. The issue seems to be particularly germane for ICU patients, in whom even modest hyperglycemia results in worse clinical outcomes, usually of an infectious nature. High-quality clinical trials in surgical ICU (SICU)8 and medical ICU (MICU)9 patients have found that morbidity is substantially and significantly reduced in those randomized to intensive insulin therapy who maintained serum glucose levels below 111 mg/dL, compared with those whose glucose values were maintained below 215 mg/dL. Mortality was also significantly lower among SICU patients randomized to receive tight glucose control, although in the MICU study, such reductions in mortality caused by tight glucose control were only realized in those who resided in the MICU greater than 3 days. Similarly, in a clinical trial of pediatric ICU patients, secondary infections, length of PICU stay, and mortality were all reduced by intensive age-specific glucose control.10 These observations are almost certainly the clinical expression of the numerous mechanistic impairments that acute hyperglycemia produces in the innate immune system.11 The clinical benefits of tight glucose control in the ICU, however, have not always been reproducible12 and come at the cost of more frequent hypoglycemic episodes,8-10, 12 so the issue of how tight glucose control should be remains controversial. Extremely tight control, with a target range of 81 to 108 mg/dL, produced a 13-fold greater risk of hypoglycemia and a significantly greater mortality in a large multicenter trial of ICU patients,13 and is, therefore, excessive. A panel of experts recently recommended instituting protocols to keep blood sugar levels at 150 mg/dL or lower in ICU patients, preferably by use of a continuous infusion of insulin, with monitoring every 1 to 2 hours so that appropriate adjustments can be made and blood sugar values less than 70 mg/ dL are avoided.14 The results of a meta-analysis of 29 trials in critically ill patients recapitulate the previously observed discrepancies between SICU and MICU patients.15 Overall, the relative risk of septicemia was reduced approximately 25% in those randomized to tight glucose control, although this salutary effect was largely attributable to the SICU patients, in whom reduction in septicemia was almost 50%; no benefit was observed in MICU patients, nor were differences in overall mortality evident in any of the categories of critically ill patients. The question of appropriate caloric delivery to critically ill overweight and obese patients who account for a burgeoning

CHAPTER 5  Nutritional Principles and Assessment of the Gastroenterology Patient

55

TABLE 5.6  Desirable Weight in Relation to Height for Men and Women 25 Years or Older Men, Medium Frame

Women, Medium Frame

Weight (lb)

Weight (lb)

Height (ft/inches)

Range

Midpoint

Range

Midpoint

5′1″

113-124

118.5

4′8″

Height (ft/inches)

93-104

98.5

5′2″

116-128

122

4′9″

95-107

101

5′3″

119-131

125

4′10″

98-110

104

5′4″

122-134

128

4′11″

101-113

107

5′5″

125-138

131.5

5′0″

104-116

110

5′6″

129-142

135.5

5′1″

107-119

113

5′7″

133-147

140

5′2″

110-123

116.5

5′8″

137-151

144

5′3″

113-127

120

5′9″

141-155

148

5′4″

117-132

124.5

5′10″

145-160

153

5′5″

121-136

128.5

5′11″

149-165

157

5′6″

125-140

132.5

6′0″

153-170

161.5

5′7″

129-144

136.5

6′1″

157-175

166

5′8″

133-148

140.5

6′2″

162-180

171

5′9″

137-152

144.5

6′3″

167-185

176

5′10″

141-156

148.5

  

Corrected to nude weights and heights by assuming 1-inch heel for men, 2-inch heel for women, and indoor clothing weight of 5 and 3 lbs for men and women, respectively. Data from Metropolitan Life Insurance Company. New height standards for men and women. Statistical Bulletin 1959; 40:1-4.   

TABLE 5.7  Estimated Energy Requirements for Hospitalized Patients Based on Body Mass Index Body Mass Index

(kg/m2)

Energy Requirements (kcal/kg/ day)*

loss) represents anabolism and a net increase in total body protein, whereas a negative N balance represents net protein catabolism. For example, a negative N balance of 1 g/day represents a 6.25 g/day loss of body protein, which is equivalent to a 30 g/day loss of hydrated lean tissue. In practice, N balance studies tend to be artificially positive because of overestimation of dietary N intake and underestimation of losses due to incomplete urine collections and unmeasured outputs. It is best to wait at least 4 days after a substantial change in protein delivery before N balance is determined, because a labile N pool exists and this tends to dampen and retard changes that otherwise would be observed as a result of altered protein intake. 

Carbohydrates Complete digestion of the principal dietary digestible carbohydrates—starch, sucrose, and lactose—generate monosaccharides (glucose, fructose, and galactose). In addition, 5 to 20 g of indigestible carbohydrates (soluble and insoluble fibers) are typically consumed daily. All cells can generate energy (adenosine triphosphate [ATP]) by metabolizing glucose to 3-carbon compounds via glycolysis, or to carbon dioxide and water via glycolysis and the tricarboxylic acid (TCA) cycle. There is no absolute dietary requirement for carbohydrate; glucose can be synthesized endogenously from either AAs or glycerol. Regardless, carbohydrate is an important fuel because of the interactions between carbohydrate and protein metabolism. Carbohydrate intake stimulates insulin secretion, which inhibits muscle protein breakdown, stimulates muscle protein synthesis, and decreases endogenous glucose production from AAs. In addition, glucose is the required or preferred fuel for red and white blood cells, the renal medulla, eye tissues, peripheral nerves, and the brain. However, once glucose requirements for these tissues are met (≈150 g/day), the protein-sparing effects of carbohydrate and fat are similar.21 

Lipids Lipids consist of TGs, sterols, and phospholipids. These compounds serve as sources of energy; precursors for steroid hormone, prostaglandin, thromboxane, and leukotriene synthesis; structural components of cell membranes; and carriers of essential nutrients. Dietary lipids are composed mainly of TGs, which contain saturated and unsaturated long-chain fatty acids (FAs) of 16 to 18 carbons. Use of fat as a fuel requires hydrolysis of endogenous or exogenous TGs and cellular uptake of released FAs (see Chapter 102). Long-chain FAs are delivered across the outer and inner mitochondrial membranes by a carnitine-dependent transport system. Once inside the mitochondria, FAs are degraded by beta oxidation to acetyl coenzyme A (CoA), which then enters the TCA cycle. Therefore, the ability to use fat as a fuel depends on normally functioning mitochondria. A decrease in the abundance or function of mitochondria associated with aging22 or deconditioning favors the use of carbohydrate as fuel.23

CHAPTER 5  Nutritional Principles and Assessment of the Gastroenterology Patient

Essential Fatty Acids Humans lack the desaturase enzyme needed to produce the n-3 (double bond between carbons 3 and 4) and n-6 (double bond between carbons 6 and 7) FA series. Linoleic acid (C18:2, n-6) and linolenic acid (C18:3, n-3) are essential FAs and, therefore, should constitute at least 2% and 0.5%, respectively, of the daily caloric intake to prevent a deficiency state. Before the advent of parenteral nutrition, essential fatty acid deficiency (EFAD) was only recognized in infants and manifested as a scaly rash with a specific alteration in the plasma FA profile (see later). Adults were thought not to be susceptible to EFAD because of sufficient essential FA stores in adipose tissue. However, an abnormal FA profile in conjunction with a clinical syndrome of EFAD is now known to sometimes occur in adults with severe short bowel syndrome who are on long-term TPN that lacks parenteral lipids.24 Adults who have moderate-to-severe fat malabsorption (fractional fat excretion >20%) from other causes and who are not TPN-dependent also frequently display a biochemical profile of EFAD,25 although whether such a biochemical state carries adverse clinical consequences is unclear. Moreover, TPN lacking any source of fat may lead to EFAD in adults if no exogenous source of EFAs is available. The plasma pattern of EFAD may be observed as early as 10 days after glucose-based TPN is started and before the onset of any clinical features. In this situation, EFAD is probably due to the increase in plasma insulin concentrations caused by TPN, because insulin inhibits lipolysis and, therefore, the release of endogenous essential FAs. The biochemical diagnosis of EFAD is defined as an absolute and relative deficiency in the 2 EFAs in the plasma FA profile. The full clinical EFAD syndrome includes alopecia, scaly dermatitis, capillary fragility, poor wound healing, increased susceptibility to infection, fatty liver, and growth retardation in infants and children. 

57

or prosthetic groups, others as biochemical substrates or hormones; in some cases, their functions are not well defined. The average daily dietary intake for each micronutrient required to sustain normal physiologic operations is measured in milligrams or smaller quantities. In this way, micronutrients are distinguished from macronutrients (carbohydrates, fats, and proteins) and macrominerals (calcium, magnesium, and phosphorus). An individual’s dietary requirement for any given micronutrient is determined by many factors, including its bioavailability, the amount needed to sustain its normal physiologic functions, a person’s sex and age, any diseases or drugs that affect the nutrient’s metabolism, and certain lifestyle habits like smoking and alcohol use. The U.S. National Academy of Sciences Food and Nutrition Board regularly updates dietary guidelines that define the quantity of each micronutrient that is “adequate to meet the known nutrient needs of practically all healthy persons.” These RDAs underwent revision between 1998 and 2001, and the values for adults appear in Tables 5.10 and 5.11. Formulating an RDA takes into account the biologic variability in the population, so RDAs are set two SDs above the mean requirement; this allows the requirements of 97% of the population to be met. Thus, ingestion of quantities that are somewhat less than the RDA are often sufficient to meet the needs of a particular individual. A “tolerable upper limit (TUL),” which is “the maximal daily level of oral intake that is likely to pose no adverse health risks,” has been established for most micronutrients (see Tables 5.10 and 5.11). Present recommendations for how much of each micronutrient is needed in individuals on TPN are based on far less data than were available for development of the RDAs. Nevertheless, it is important to have guidelines, and Table 5.12 provides such recommendations.

Vitamins

Major minerals are inorganic nutrients that are required in large (>100 mg/day) quantities and are important for ionic equilibrium, water balance, and normal cell function. Malnutrition and nutritional repletion can have dramatic effects on major mineral balance. Evaluation of macromineral deficiency and the RDA of minerals for healthy adults are shown in Table 5.9. 

Vitamins are categorized as fat soluble (A, D, E, K) or water soluble (all others) (see Table 5.10). This categorization remains physiologically meaningful; none of the fat-soluble vitamins appear to serve as coenzymes, whereas almost all of the watersoluble vitamins appear to function in that role. Also, the absorption of fat-soluble vitamins is primarily through a micellar route, whereas the water-soluble vitamins are not absorbed in a lipophilic phase in the intestine (see Chapter 103). 

MICRONUTRIENTS

Trace Minerals

Micronutrients (vitamins and trace minerals) are a diverse array of dietary components that are necessary to sustain health. The physiologic roles of micronutrients are as varied as their composition. Some are used in enzymes as coenzymes

Compelling evidence exists for the essential nature of 10 trace elements in humans: iron, zinc, copper, chromium, selenium, iodine, fluorine, manganese, molybdenum, and cobalt (see Table 5.11). The biochemical functions of trace elements have not been

Major Minerals

TABLE 5.9  Major Mineral Requirements and Assessment of Deficiency Laboratory Evaluation

Mineral

Enteral

Parenteral (mmol)

Test

Comment

Calcium

1000-1200 mg

5-15

Metabolic bone disease, tetany, arrhythmias

24-hr urinary calcium Dual energy radiation absorptiometry

Reflects recent intake Reflects bone calcium content

Magnesium

300-400 mg

5-15

Weakness, twitching, tetany, arrhythmias, hypocalcemia

Serum magnesium Urinary magnesium

May not reflect body stores May not reflect body stores

Phosphorus

800-1200 mg

20-60

Weakness, fatigue, leukocyte and platelet Plasma phosphorus dysfunction, hemolytic anemia, cardiac failure, decreased oxygenation

May not reflect body stores

Potassium

2-5 g

60-100

Weakness, paresthesias, arrhythmias

Serum potassium

May not reflect body stores

Sodium

0.5-5 g

60-150

Hypovolemia, weakness

Urinary sodium

May not reflect body stores; clinical evaluation is best

Symptoms or Signs of Deficiency

5

58

PART II  Nutrition in Gastroenterology

TABLE 5.10  Salient Features of Vitamins Vitamin

Deficiency (RDA)*

Toxicity (TUL)†

Assessment of Status

A

Follicular hyperkeratosis and night blindness are early indicators. Conjunctival xerosis, degeneration of the cornea (keratomalacia), and dedifferentiation of rapidly proliferating epithelia are later indications of deficiency. Bitot spots (focal areas of the conjunctiva or cornea with foamy appearance) are an indication of xerosis. Blindness caused by corneal destruction and retinal dysfunction may ensue. Increased susceptibility to infection is also a consequence (1 μg of retinol is equivalent to 3.33 IU of vitamin A; F, 700 μg; M, 900 μg).

In adults, >150,000 μg may cause acute toxicity: fatal intracranial hypertension, skin exfoliation, and hepatocellular injury. Chronic toxicity may occur with habitual daily intake of >10,000 μg: alopecia, ataxia, bone and muscle pain, dermatitis, cheilitis, conjunctivitis, pseudotumor cerebri, hepatic fibrosis, hyperlipidemia, and hyperostosis are common. Single large doses of vitamin A (30,000 μg) or habitual intake of >4500 μg/ day during early pregnancy can be teratogenic. Excessive intake of carotenoids causes a benign condition characterized by yellowish discoloration of the skin (3000 μg).

Retinol concentration in the plasma, as well as vitamin A concentrations in milk and tears, are reasonably accurate measures of status. Toxicity is best assessed by elevated levels of retinyl esters in plasma. A quantitative measure of dark adaptation for night vision and electroretinography are useful functional tests.

D

Deficiency results in decreased mineralization of Excess amounts result in abnormally Serum concentration of the newly formed bone, a condition called rickets in high concentrations of calcium and major circulating metabolite, childhood and osteomalacia in adults. Deficiency phosphate in the serum; metastatic 25-hydroxyvitamin D, is an also contributes to osteoporosis in later life and calcifications, renal damage, and excellent indicator of systemic is common following gastric bypass procedures. altered mentation may occur (100 μg status except in advanced kidney Expansion of epiphyseal growth plates and for ages >9). disease (stages 4-5), in which replacement of normal bone with unmineralized impairment of renal 1-hydroxylation bone matrix are the cardinal features of rickets; results in dissociation of the the latter feature also characterizes osteomalacia. mono- and dihydroxy vitamin Deformity of bone and pathologic fractures result. concentrations; measuring Decreased serum concentrations of calcium and the serum concentration of phosphate may occur (1 μg is equivalent to 40 IU; 1,25-dihydroxyvitamin D is then 15 μg, ages 19-70; 20 μg, ages > 70). necessary.

E

Deficiency caused by dietary inadequacy is rare in developed countries. Usually seen in premature infants, individuals with fat malabsorption, and individuals with abetalipoproteinemia. RBC fragility occurs and can produce hemolytic anemia. Neuronal degeneration produces peripheral neuropathies, ophthalmoplegia, and destruction of the posterior columns of the spinal cord. Neurologic disease is frequently irreversible if deficiency is not corrected early enough. May contribute to hemolytic anemia and retrolental fibroplasia in premature infants. Has been reported to suppress cell-mediated immunity (15 mg).

Depressed levels of vitamin K-dependent procoagulants, potentiation of oral anticoagulants, and impaired leukocyte function have been reported. Doses of 800 mg/day have been reported to increase slightly the incidence of hemorrhagic stroke (1000 mg).

Plasma or serum concentration of alpha-tocopherol is used most commonly. Additional accuracy is obtained by expressing this value per mg of total plasma lipid. The RBC peroxide hemolysis test is not entirely specific but is a useful measure of the susceptibility of cell membranes to oxidation.

K

Deficiency syndrome is uncommon except in breast-fed newborns (in whom it may cause “hemorrhagic disease of the newborn”), adults who have fat malabsorption or are taking drugs that interfere with vitamin K metabolism (e.g., warfarin, phenytoin, broad-spectrum antibiotics), and individuals taking large doses of vitamin E and anticoagulant drugs. Excessive hemorrhage is the usual manifestation (F, 90 μg; M, 120 μg).

Rapid IV infusion of vitamin K1 has been associated with dyspnea, flushing, and cardiovascular collapse; this is likely related to the dispersing agents in the dissolution solvent. Supplementation may interfere with warfarin-based anticoagulation. Pregnant women taking large amounts of the provitamin menadione may deliver infants with hemolytic anemia, hyperbilirubinemia, and kernicterus (TUL not established).

Prothrombin time is typically used as a measure of functional vitamin K status; it is neither sensitive nor specific for vitamin K deficiency. Determination of fasting plasma vitamin K is an accurate indicator. Undercarboxylated plasma prothrombin is also an accurate metric, but only for detecting the deficient state, and is less widely available.

59

CHAPTER 5  Nutritional Principles and Assessment of the Gastroenterology Patient

TABLE 5.10  Salient Features of Vitamins—cont’d Toxicity (TUL)†

5

Vitamin

Deficiency (RDA)*

Assessment of Status

Thiamine (vitamin B1)

Classic deficiency syndrome (beriberi) remains Excess intake is largely excreted in the endemic in Asian populations consuming polished urine, although parenteral doses of rice diet. Globally, alcoholism, chronic renal >400 mg/day are reported to cause dialysis, and persistent nausea and vomiting after lethargy, ataxia, and reduced tone of bariatric surgery are common precipitants. High the GI tract (TUL not established). carbohydrate intake increases the need for B1. Mild deficiency commonly produces irritability, fatigue, and headaches. More pronounced deficiency can produce peripheral neuropathy, cardiovascular and cerebral dysfunction. Cardiovascular involvement (wet beriberi) includes heart failure and low peripheral vascular resistance. Cerebral disease includes nystagmus, ophthalmoplegia, and ataxia (Wernicke encephalopathy), as well as hallucinations, impaired short-term memory, and confabulation (Korsakoff psychosis). Deficiency syndrome responds within 24 hr to parenteral thiamine but is partially or wholly irreversible after a certain stage (F, 1.1 mg; M, 1.2 mg).

The most effective measure of vitamin B1 status is the RBC transketolase activity coefficient, which measures enzyme activity before and after addition of exogenous TPP; RBCs from a deficient individual express a substantial increase in enzyme activity with addition of TPP. Thiamine concentrations in the blood or urine are also measured.

Riboflavin (vitamin B2)

Deficiency is usually seen in conjunction with Toxicity has not been reported in deficiencies of other B vitamins. Isolated humans (TUL not established). deficiency of riboflavin produces hyperemia and edema of nasopharyngeal mucosa, cheilosis, angular stomatitis, glossitis, seborrheic dermatitis, and normochromic, normocytic anemia (F, 1.1 mg; M, 1.3 mg).

Most common method of assessment is determining the activity coefficient of glutathione reductase in RBCs (the test is invalid for individuals with glucose6-phosphate dehydrogenase deficiency). Measurements of blood and urine concentrations are less desirable methods.

Niacin (vitamin B3)

Pellagra is the classic deficiency syndrome and is Human toxicity is known largely through Assessment of status is problematic; often seen in populations in which corn is the major studies examining hypolipidemic blood levels of the vitamin are source of energy. Still endemic in parts of China, effects; includes flushing, not reliable. Measurement of Africa, and India. Diarrhea, dementia (or associated hyperglycemia, hepatocellular injury, urinary excretion of the niacin symptoms of anxiety or insomnia), and a and hyperuricemia (35 mg). metabolites N-methylnicotinamide pigmented dermatitis that develops in sun-exposed and 2-pyridone are thought to areas are typical features. Glossitis, stomatitis, be the most effective means of vaginitis, vertigo, and burning dysesthesias are assessment. early signs. Occasionally occurs in carcinoid syndrome, because tryptophan is diverted to other synthetic pathways (F, 14 mg; M, 16 mg).

Pantothenic acid (vitamin B5)

Deficiency is rare; reported only as a result of feeding semisynthetic diets or consumption of an antagonist such as calcium homopantothenate, which has been used to treat Alzheimer disease. Experimental isolated deficiency in humans produces fatigue, abdominal pain and vomiting, insomnia, and paresthesias of the extremities (5 mg).

Diarrhea is reported to occur with doses exceeding 10 g/day (TUL not established).

Whole blood and urine concentrations of pantothenic acid are indicators of status; serum levels are not thought to be accurate.

Pyridoxine (vitamin B6)

Deficiency is usually seen in conjunction with other water-soluble vitamin deficiencies. Stomatitis, angular cheilosis, glossitis, irritability, depression, and confusion occur in moderate to severe depletion; normochromic, normocytic anemia has been reported in severe deficiency. Abnormal EEGs and, in infants, convulsions also have been reported. Isoniazid, cycloserine, penicillamine, ethanol, and theophylline are drugs that can inhibit B6 metabolism (ages 19-50, 1.3 mg; >50 yr, 1.5 mg for women, 1.7 mg for men).

Chronic use with doses exceeding 200 mg/day (in adults) may cause peripheral neuropathies and photosensitivity (100 mg).

Many useful laboratory methods of assessment exist. Plasma or erythrocyte PLP levels are most common. Urinary excretion of xanthurenic acid after an oral tryptophan load or activity indices of RBC aminotransferases (ALT and AST) all are functional measures of B6-dependent enzyme activity.

Biotin (vitamin B7)

Isolated deficiency is rare. Deficiency in humans Toxicity has not been reported in has been produced experimentally by dietary humans, with doses as high as inadequacy, prolonged administration of TPN that 60 mg/day in children (TUL not lacks the vitamin, and ingestion of large quantities established). of raw egg white, which contains avidin, a protein that binds biotin with such high affinity that it renders it bio-unavailable. Alterations in mental status, myalgias, hyperesthesias, and anorexia occur. Later, seborrheic dermatitis and alopecia develop. Biotin deficiency is usually accompanied by lactic acidosis and organic aciduria (30 μg).

Plasma and urine concentrations of biotin are diminished in the deficient state. Elevated urine concentrations of methyl citrate, 3-methylcrotonylglycine, and 3-hydroxyisovalerate are also observed in deficiency.

Continued

60

PART II  Nutrition in Gastroenterology

TABLE 5.10  Salient Features of Vitamins—cont’d Toxicity (TUL)†

Vitamin

Deficiency (RDA)*

Folate (Vitamin B9)

Women of childbearing age are the most likely Daily dosage >1000 μg may partially to develop deficiency. The classic deficiency correct the anemia of B12 syndrome is a megaloblastic anemia. deficiency and therefore mask Hematopoietic cells in the bone marrow become (and perhaps exacerbate) the enlarged and have immature nuclei, reflecting associated neuropathy. Large ineffective DNA synthesis. The peripheral blood doses are reported to lower seizure smear demonstrates macro-ovalocytes and threshold in individuals prone to polymorphonuclear leukocytes with an average seizures. Parenteral administration of more than 3.5 nuclear lobes. Megaloblastic is rarely reported to cause allergic changes in other rapidly proliferating epithelia phenomena from dispersion agents (e.g., oral mucosa, GI tract) produce glossitis (1000 μg). and diarrhea, respectively. Sulfasalazine and diphenytoin inhibit absorption, predisposing to deficiency. Habitually low intake may increase the risk of colorectal cancer. (400 μg of dietary folate equivalent [DFE]; 1 μg folic acid = 1 μg DFE; 1 μg food folate = 0.6 μg DFE).

Serum folate levels reflect short-term folate balance, whereas RBC folate is a better reflection of tissue status. Serum homocysteine levels rise early in deficiency but are nonspecific because B12 or B6 deficiency, renal insufficiency, and older age may also cause elevations.

Cobalamin (vitamin B12)

Dietary inadequacy is a rare cause of deficiency, A few allergic reactions have been except in strict vegetarians. The vast majority of reported from crystalline B12 cases of deficiency arise from loss of intestinal preparations and are probably due absorption—a result of pernicious anemia, to impurities, not the vitamin (TUL pancreatic insufficiency, atrophic gastritis, SIBO, not established). or ileal disease. Megaloblastic anemia and megaloblastic changes in other epithelia (see “Folate”) are the result of sustained depletion. Demyelination of peripheral nerves, the posterior and lateral columns of the spinal cord, and nerves within the brain may occur. Altered mentation, depression, and psychoses occur. Hematologic and neurologic complications may occur independently. Folate supplementation in doses exceeding 1000 μg/day may partly correct the anemia, thereby masking (or perhaps exacerbating) the neuropathic complications (2.4 μg).

Serum or plasma concentrations are generally accurate. Subtle deficiency with neurologic complications is increasingly recognized among those ≥ 60 yr of age, and can best be established by concurrently measuring the concentration of plasma B12 and (1) serum methylmalonic acid (MMA) or (2) holotranscobalamin II (holoTCII) because the latter are sensitive indicators of cellular deficiency. A low-normal plasma B12 of 200-350 pg/mL (=148-258 pmol/L) with an elevated MMA or decreased holoTCII should be considered a state of deficiency.

Ascorbic and Overt deficiency is uncommonly observed in dehydroascorbic developed countries. The classic deficiency acid (vitamin C) syndrome is scurvy, characterized by fatigue, depression, and widespread abnormalities in connective tissues (e.g., inflamed gingivae, petechiae, perifollicular hemorrhages, impaired wound healing, coiled hairs, hyperkeratosis, and bleeding into body cavities). In infants, defects in ossification and bone growth may occur. Tobacco smoking lowers plasma and leukocyte vitamin C levels (F, 75 mg; M, 90 mg; the requirement for cigarette smokers is increased by 35 mg/day).

Assessment of Status

Quantities exceeding 500 mg/day (in Plasma ascorbic acid concentration adults) sometimes cause nausea and reflects recent dietary intake, diarrhea. Acidification of the urine whereas leukocyte levels more with vitamin C supplementation, closely reflect tissue stores. and the potential for enhanced Plasma levels in women are ≈20% oxalate synthesis, have raised higher than in men for any given concerns regarding nephrolithiasis, dietary intake. but this has yet to be demonstrated. Supplementation with vitamin C may interfere with laboratory tests based on redox potential (e.g., fecal occult blood testing, serum cholesterol, serum glucose). Withdrawal from chronic ingestion of high doses of vitamin C supplements should occur gradually over 1 month because accommodation does seem to occur, raising a concern for rebound scurvy (2000 mg).

  

*RDA, Recommended daily allowance; established for female (F) and male (M) adults by the U.S. Food and Nutrition Board, 1999-2001 (updated in 2010 for vitamin D and calcium). In some cases, data are insufficient to establish an RDA, in which case the adequate intake (AI) established by the board is listed. †TUL, Tolerable upper level; established for adults by the U.S. Food and Nutrition Board, 1999-2001. EEG, Electroencephalogram; PLP, pyridoxyl 5-phosphate; RBC, red blood cell; TPP, thiamine pyrophosphate. Adapted from Goldman L, Ausiello D, Arend W, et al, editors. Cecil textbook of medicine. 23rd ed. Philadelphia: WB Saunders; 2014. With permission.   

61

CHAPTER 5  Nutritional Principles and Assessment of the Gastroenterology Patient

TABLE 5.11  Salient Features of Trace Minerals Toxicity (TUL)†

5

Mineral

Deficiency (RDA)*

Chromium

Deficiency in humans is only described for patients Toxicity after oral ingestion is uncommon on long-term TPN containing inadequate and seems confined to gastric irritation. chromium. Hyperglycemia or impaired Airborne exposure may cause contact glucose tolerance is uniformly observed. dermatitis, eczema, skin ulcers, and Elevated plasma free fatty acid concentrations, bronchogenic carcinoma (No TUL neuropathy, encephalopathy, and abnormalities established). in nitrogen metabolism are also reported. Whether supplemental chromium may improve glucose tolerance in mildly glucose intolerant but otherwise healthy individuals remains controversial (F, 25 μg; M, 35 μg).

Copper

Dietary deficiency is rare; it has been observed Acute copper toxicity has been described Practical methods for detecting marginal in premature and low-birth-weight infants after excessive oral intake and with deficiency are not available. Marked exclusively fed a cow’s milk diet and in absorption of copper salts applied to deficiency is reliably detected by individuals on long-term TPN without copper. burned skin. Milder manifestations diminished serum copper and Clinical manifestations include depigmentation include nausea, vomiting, epigastric pain, ceruloplasmin concentrations, as of skin and hair, neurologic disturbances, and diarrhea; coma and hepatocellular well as low erythrocyte superoxide leukopenia and hypochromic, microcytic injury may ensue in severe cases. dismutase activity. anemia, skeletal abnormalities, and poor wound Toxicity may be seen with doses as healing. The anemia arises from impaired low as 70 μg/kg/day. Chronic toxicity uptake of iron and is, therefore, a secondary is also described. Wilson disease is a form of iron deficiency anemia. The deficiency rare inherited disease associated with syndrome, except the anemia and leukopenia, abnormally low ceruloplasmin levels and is also observed in Menkes disease, a rare accumulation of copper particularly in inherited condition associated with impaired the liver and brain, eventually leading to copper uptake (900 μg). damage of these 2 organs (10 mg).

Fluoride

Intake of 2 mg/day in adults) relying primarily on food from soils with low may induce hypothyroidism by iodine content have endemic iodine deficiency. blocking thyroid hormone synthesis. Maternal iodine deficiency leads to fetal Supplementation with >100 μg/day to deficiency, which produces spontaneous an individual who was formerly deficient abortions, stillbirths, hypothyroidism, cretinism, occasionally induces hyperthyroidism and dwarfism. Rapid brain development (1.1 mg). continues through the second year, and permanent cognitive deficits may be induced by iodine deficiency during that period. In adults, compensatory hypertrophy of the thyroid (goiter) occurs, along with varying degrees of hypothyroidism (150 μg).

Iron

Most common micronutrient deficiency in the world. Women of childbearing age constitute the highest risk group because of menstrual blood losses, pregnancy, and lactation. Hookworm infection is the most common cause worldwide. The classic deficiency syndrome is hypochromic microcytic anemia. Glossitis and koilonychia (spoon nails) are also observed. Easy fatigability often develops as an early symptom before appearance of anemia. In children, mild deficiency of insufficient severity to cause anemia is associated with behavioral disturbances and poor school performance (postmenopausal F, 8 mg; M, 8 mg; premenopausal F, 18 mg).

Iron overload typically occurs when habitual Negative iron balance initially leads to dietary intake is extremely high, intestinal depletion of iron stores in the bone absorption is excessive, repeated marrow; bone marrow biopsy and parenteral administration of iron occurs, the concentration of serum ferritin or a combination of these factors exists. are accurate and early indicators Excessive iron stores usually accumulate of such depletion. As deficiency in reticuloendothelial tissues and becomes more severe, serum iron cause little damage (hemosiderosis). If (SI) decreases and total iron binding overload continues, iron will eventually capacity (TIBC) increases; an iron begin to accumulate in tissues such saturation (= SI/TIBC) of 60% raises suspicion trait. Excessive intestinal absorption of of iron overload, although systemic iron is observed in homozygotes (45 mg). inflammation elevates serum ferritin level regardless of iron status.

Manganese

Manganese deficiency has not been conclusively demonstrated in humans. It is said to cause hypocholesterolemia, weight loss, hair and nail changes, dermatitis, and impaired synthesis of vitamin K–dependent proteins (F, 1.8 mg; M, 2.3 mg).

Toxicity by oral ingestion is unknown in humans. Toxic inhalation causes hallucinations, other alterations in mentation, and extrapyramidal movement disorders (11 mg).

Acute ingestion of >30 mg/kg body weight of fluoride is likely to cause death. Excessive chronic intake (0.1 mg/kg/ day) leads to mottling of the teeth (dental fluorosis), calcification of tendons and ligaments, and exostoses, and may increase brittleness of bones (10 mg).

Assessment of Status Plasma or serum concentration of chromium is a crude indicator of chromium status; it appears to be meaningful when the value is markedly above or below the normal range.

Estimates of intake or clinical assessment are used because no reliable laboratory test exists.

Urinary excretion of iodine is an effective laboratory means of assessment. The thyroid-stimulating hormone (TSH) level in the blood is an indirect, not entirely specific means of assessment. Iodine status of a population can be estimated by the prevalence of goiter.

Until the deficiency syndrome is better defined, an appropriate measure of status will be difficult to develop.

Continued

62

PART II  Nutrition in Gastroenterology

TABLE 5.11  Salient Features of Trace Minerals—cont’d Toxicity (TUL)†

Mineral

Deficiency (RDA)*

Molybdenum

Cases of human deficiency are extremely rare; Molybdenum has low toxicity; occupational caused by TPN lacking the element or by exposures and high dietary intake are parenteral administration of sulfite. Reported to linked to hyperuricemia and gout in result in hyperoxypurinemia, hypouricemia, low epidemiologic studies (2 mg). urinary sulfate excretion, and CNS disturbances (45 μg).

Assessment of Status

Selenium

Deficiency is rare in North America but has been Toxicity is associated with nausea, diarrhea, Erythrocyte glutathione peroxidase observed in individuals on long-term TPN alterations in mental status, peripheral activity and plasma, or whole blood, lacking selenium. Such individuals have myalgias neuropathy, and loss of hair and nails; selenium concentrations are the and/or cardiomyopathy. Populations in some such symptoms were observed in adults most commonly used methods of regions of the world, most notably some parts who inadvertently consumed between 27 assessment. They are moderately of China, have marginal intake of selenium. and 2400 mg (400 μg). accurate indicators of status. It is in these regions of China that Keshan disease is endemic, a condition characterized by cardiomyopathy. Keshan disease can be prevented (but not treated) by selenium supplementation (55 μg).

Zinc

Deficiency of zinc has its most profound effect Acute zinc toxicity can usually be induced by There are no accurate indicators of zinc on rapidly proliferating tissues. Mild deficiency ingestion of >200 mg of zinc in a single day status available for routine clinical causes growth retardation in children. More (in adults). It is manifested by epigastric use. Plasma, erythrocyte, and hair severe deficiency is associated with growth pain, nausea, vomiting, and diarrhea. zinc concentrations are frequently arrest, teratogenicity, hypogonadism and infertility, Hyperpnea, diaphoresis, and weakness misleading. Acute illness, in particular, dysgeusia, poor wound healing, diarrhea, may follow inhalation of zinc fumes. is known to diminish plasma zinc dermatitis on the extremities and around orifices, Copper and zinc compete for intestinal levels, in part by inducing a shift of glossitis, alopecia, corneal clouding, loss of dark absorption: chronic ingestion of >25 mg zinc out of the plasma compartment adaptation, and behavioral changes. Impaired zinc/day may lead to copper deficiency. and into the liver. Functional tests cellular immunity also is observed. Excessive loss Chronic ingestion of >150 mg/day has that determine dark adaptation, taste of GI secretions (e.g., through chronic diarrhea or been reported to cause gastric erosions, acuity, and rate of wound healing lack fistulas) may precipitate deficiency. Acrodermatitis low high-density lipoprotein cholesterol specificity. enteropathica is a rare recessively inherited levels, and impaired cellular immunity (40 disease in which intestinal absorption of zinc is mg). impaired (F, 8 mg; M, 11 mg).

No effective clinically available assessment exists. Rare cases of deficiency are associated with hypouricemia, hypermethionemia, and low levels of urinary sulfate with elevated excretion of sulfite, xanthine, and hypoxanthine.

  

*Recommended Daily Allowance (RDA) established for female (F) and male (M) adults by the U.S. Food and Nutrition Board, 1999-2001. In some cases, insufficient data exist to establish an RDA, in which case the adequate intake (AI) established by the Board is listed. †Tolerable upper level (TUL) established for adults by the U.S. Food and Nutrition Board, 1999-2001. Adapted from Goldman L, Ausiello D, Arend W, et al, editors. Cecil textbook of medicine. 22nd ed. Philadelphia: WB Saunders; 2004. With permission.   

as well characterized as those of the vitamins, but most of their functions appear to be as components of prosthetic groups or as cofactors for enzymes. Aside from iron, the trace mineral depletion clinicians are most likely to encounter is zinc deficiency. Zinc depletion is a particularly germane issue to the gastroenterologist, because the GI tract is a major site for zinc excretion. Chronically excessive losses of GI secretions, such as chronic diarrhea in IBD, is a known precipitant for zinc deficiency, and, in this setting, zinc requirements often increase several-fold.26 Nevertheless, a biochemical diagnosis of zinc deficiency is problematic (as is true for many of the other essential trace minerals) because accurate laboratory assessment of zinc status is complicated by the very low concentrations of zinc in bodily fluids and tissues, a lack of correlation between serum and red blood cell levels of zinc with levels in the target tissues, and the reality that suitable functional tests have yet to be devised. Furthermore, it is well recognized that in acute illness a shift in zinc occurs from the serum compartment into the liver, further obscuring the diagnostic value of serum zinc levels.27 Alkaline phosphatase is a zinc-dependent protein, and therefore serum activity of the enzyme has sometimes been proposed as a functional measure of zinc status. However, its predictive value is quite low and therefore is inadequate for assessing individuals in a clinical setting. It is often best to simply proceed with empiric zinc supplementation in patients whose clinical scenario puts them at high risk of zinc deficiency.

Some reports have indicated that TPN solutions that deliver several-fold more manganese than what is recommended in Table 5.12 may lead to deposition of the mineral in the basal ganglia, with resulting extrapyramidal symptoms, seizures, or both.28 Because the content of manganese varies widely in the different trace element mixtures available for TPN compounding, health professionals need to be mindful of this issue as protocols for TPN mixtures are developed. 

Physiologic and Pathophysiologic Factors Affecting Micronutrient Requirements Age An evolution of physiology continues throughout the life cycle, with an impact on the requirements of certain micronutrients with aging; specific RDAs for older adults have now been developed. The mean vitamin B12 status of most populations, for example, declines significantly with older age, in large part because of the high prevalence of atrophic gastritis and its resultant impairment of protein-bound vitamin B12 absorption.29 Some 10% to 15% of the older ambulatory population is thought to have significant vitamin B12 depletion because of this phenomenon, and neuropathic degeneration may occur in older individuals whose plasma vitamin B12 levels are in the low-normal range (150 to 300 pg/mL), even in the absence of

CHAPTER 5  Nutritional Principles and Assessment of the Gastroenterology Patient

TABLE 5.12  Guidelines for Daily Administration of Parenteral Micronutrients in Adults and Children Micronutrient

Adults

Fat-Soluble Vitamins A 1000 μg (= 3300 IU)

Children 700 μg

D

5 μg (= 200 IU)

10 μg

E

10 mg (= 10 IU)

7 mg

K

1 mg

200 μg

Water-Soluble Vitamins C

100 mg

80 mg

B6

4 mg

1 mg

B12

5 μg

1 μg

Biotin

60 μg

20 μg

Folate

400 μg

140 μg

Niacin

40 mg

17 mg

Pantothenic acid

15 mg

5 mg

Riboflavin

3.6 mg

1.4 mg

Thiamine

3 mg

1.2 mg

Trace Elements Chromium

10-15 μg

0.2 μg/kg/day

Copper

0.5-1.5 mg

20 μg/kg/day

Iodine*

—

—

Iron

1-2 mg

1 mg/day

Manganese

0.1 mg

1 μg/kg/day

Molybdenum

15 μg

0.25 μg/kg/day

Selenium

100 μg

2 μg/kg/day

Zinc

2.5-4.0 mg

50 μg/kg/day

  

*Naturally occurring contamination of parenteral nutrition formulas appears to provide sufficient quantities of iodine. Adult vitamin guidelines adapted from American Society of Parenteral and Enteral Nutrition (ASPEN). Board of Directors and the Clinical Guidelines Task Force. Guidelines for the use of parenteral and enteral nutrition in adult and pediatric patients. J Parenter Enteral Nutr 2002; 26:144. Children’s values adapted from Greene HL, Hambidge KM, Schanler R, Tsang RC. Guidelines for the use of vitamins, trace elements, calcium, magnesium, and phosphorus in infants and children receiving total parenteral nutrition: report of the Subcommittee on Pediatric Parenteral Nutrient Requirements from the Committee on Clinical Practice Issues of the American Society for Clinical Nutrition. Am J Clin Nutr 1988; 48:1324; Am J Clin Nutr 1989; 49:1332; and Am J Clin Nutr 1989; 50:560.   

hematologic manifestations. For this reason, the use of sensitive indicators of cellular depletion of vitamin B12 (e.g., serum methylmalonic acid levels in conjunction with serum levels of vitamin B12) are now recommended for diagnosis.30 Some experts also suggest that older adults should consume a portion of their vitamin B12 requirement in the crystalline form (i.e., as a supplement) rather than relying only on the naturally occurring protein-bound forms found in food. Compared with younger adults, elders require greater quantities of vitamins B6 and D and calcium to maintain health, and these requirements are reflected in the new RDAs (see Tables 5.10 and 5.11). 

Malabsorption and Maldigestion Both fat- and water-soluble micronutrients are absorbed predominantly in the proximal small intestine, the only exception being vitamin B12, which is absorbed in the ileum. Diffuse mucosal diseases that affect the proximal portion of the GI tract are, therefore, likely to result in multiple deficiencies. Even in the absence of proximal small intestinal disease, however, extensive

63

ileal disease, SIBO, and chronic cholestasis may interfere with the maintenance of adequate intraluminal conjugated bile acid concentrations and thereby may impair absorption of fat-soluble vitamins. Conditions that produce fat malabsorption are frequently associated with selective deficiencies of the fat-soluble vitamins. The early stages of many vitamin deficiencies are not apparent clinically and therefore may go undetected until progression of the deficiency has resulted in significant morbidity. This can be disastrous in conditions like spinocerebellar degeneration due to vitamin E deficiency, which often is irreversible.31 Fat-soluble vitamin deficiencies are well-recognized complications of cystic fibrosis and congenital biliary atresia, in which fat malabsorption often is overt, but monitoring is also necessary in conditions associated with more subtle fat malabsorption, such as the latter stages of chronic cholestatic liver disease.31 Restitution of vitamin deficiencies can sometimes be difficult when severe fat malabsorption is present, and initial correction may require parenteral administration. In severe fat malabsorption, chemically modified forms of vitamins D and E that largely bypass the need for the lipophilic phase of intestinal absorption are commercially available for oral use and can be helpful. The polyethylene glycol succinate form of vitamin E (Nutr-E-Sol) is very effective in patients with severe fat malabsorption who cannot absorb conventional alpha-tocopherol.32 Similarly, hydroxylated forms of vitamin D (1-hydroxyvitamin D [Hectorol] and 1,25-dihydroxyvitamin D [Rocaltrol]) can be used in patients resistant to the more conventional forms of vitamin D. Monitoring of serum calcium levels is indicated in the first few weeks of therapy with hydroxylated forms of vitamin D, because they are considerably more potent than vitamin D2 or D3, and risk of vitamin D toxicity exists. In contrast, water-miscible preparations of fat-soluble vitamins, in which a conventional form of vitamin A or E is dissolved in polysorbate 80 (e.g., Aquasol-E, Aquasol-A), have not been proved to improve overall absorption. Maldigestion usually results from chronic pancreatic insufficiency, which, if untreated, frequently causes fat malabsorption and deficiencies of fat-soluble vitamins. Vitamin B12 malabsorption also can be demonstrated in this setting, but clinical vitamin B12 deficiency is rare unless other conditions known to diminish its absorption are also present (e.g., atrophic gastritis or chronic administration of PPIs).33 Whether long-term administration of PPIs alone warrants occasional checks of vitamin B12 status is a matter of debate.34 Regardless, malabsorption of vitamin B12 from atrophic gastritis or with PPIs is confined to dietary sources of vitamin B12. Small supplemental doses of crystalline vitamin B12 are absorbed readily in both cases. Histamine-2 receptor antagonists also inhibit protein-bound vitamin B12 absorption, although the effect generally is believed to be less potent than with the PPIs.35 Many medications may adversely affect micronutrient status. The manner in which drug-nutrient interaction occurs varies; some of the more common mechanisms are described in Table 5.13. A comprehensive discussion of drug-nutrient interactions is beyond the scope of this chapter, and the reader is referred to other references for a detailed discourse on this topic.36 

STARVATION During periods of energy or protein deficit or both, an array of compensatory mechanisms serves to lessen the pathophysiologic impact of these deficiencies. These responses decrease the metabolic rate, maintain glucose homeostasis, conserve body nitrogen, and increase the uptake of adipose tissue TGs to meet energy needs. To appreciate how acute illness disrupts this compensatory scheme, it is first necessary to understand how the body adapts to starvation in the absence of underlying disease.

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TABLE 5.13  Interactions of Drugs on Micronutrient Status Drug(s)

Nutrient

Mechanism(s)

Cholestyramine

Vitamin D, folate

Adsorbs nutrient, decreases absorption

Dextroamphetamine, fenfluramine, levodopa

Potentially all Induces anorexia micronutrients

Isoniazid

Pyridoxine

Impairs uptake of vitamin B6

NSAIDs

Iron

GI blood loss

Penicillamine

Zinc

Increases renal excretion

PPIs

Vitamin B12

Modest bacterial overgrowth, decreases gastric acid/ pepsin, impairs absorption

Sulfasalazine

Folate

Impairs absorption and inhibits folate-dependent enzymes

  

From Goldman L, Ausiello D, Arend W, et al, editors. Cecil textbook of medicine. 22nd ed. Philadelphia: WB Saunders; 2004. With permission.   

During the first 24 hours of fasting, the most readily available energy substrates (i.e., circulating glucose, FAs and TGs, and liver and muscle glycogen) are used as fuel sources. The sum of energy provided by these stores in a 70-kg man, however, is only about 5000 kJ (1200 kcal) and therefore is less than a full day’s requirements. Hepatic glucose production and oxidation decrease, whereas whole-body lipolysis increases, the latter providing additional FAs and ketone bodies.37 Oxidation of FAs released from adipose tissue TGs accounts for about 65% of the energy consumed during the first 24 hours of fasting. During the first several days of starvation, obligate glucoserequiring tissues like the brain and blood cells, which collectively account for about 20% of total energy consumption, can use only glycolytic pathways to obtain energy. Because FAs cannot be converted to carbohydrate by these glycolytic tissues, they must use glucose or substrates that can be converted to glucose. Glucogenic AAs derived from skeletal muscle (chiefly alanine and glutamine) are a major source of substrate for this purpose. Approximately 15% of the REE is provided by oxidation of protein.38 The relative contribution of gluconeogenesis to hepatic glucose production increases as the rate of hepatic glycogenolysis declines because the latter process becomes redundant; after 24 hours of fasting, only 15% of liver glycogen stores remain. During short-term starvation (1 to 14 days), several adaptive responses appear that lessen the loss of lean mass. A decline in levels of plasma insulin, an increase in plasma epinephrine levels, and an increase in lipolytic sensitivity to catecholamines stimulate adipose tissue lipolysis.39, 40 The increase in FA delivery to the liver, in conjunction with an increase in the ratio of plasma glucagon-to-insulin concentrations, enhances the production of ketone bodies by the liver. A maximal rate of ketogenesis is reached by 3 days of starvation, and plasma ketone body concentration is increased 75-fold by 7 days. In contrast to FAs, ketone bodies can cross the blood-brain barrier and provide most of the brain’s energy needs by 7 days of starvation.41 The use of ketone bodies by the brain greatly diminishes glucose requirements and thus spares the need for muscle protein degradation to provide glucose precursors. If early protein breakdown rates were to continue throughout starvation, a potentially lethal amount of muscle protein would be catabolized in less than 3 weeks. Similarly, the heart, kidney, and skeletal muscle change their primary fuel substrate to

FAs and ketone bodies. Other tissues like bone marrow, renal medulla, and peripheral nerves switch from full oxidation of glucose to anaerobic glycolysis, resulting in increased production of pyruvate and lactate. The latter two compounds can be converted back to glucose in the liver using energy derived from fat oxidation via the Cori cycle, and the resulting glucose is available for systemic consumption. This enables energy stored as fat to be used for glucose synthesis. Whole-body glucose production decreases by greater than 50% during the first few days of fasting because of a marked reduction in hepatic glucose output. As fasting continues, conversion of glutamine to glucose in the kidney represents almost 50% of total glucose production. Energy is conserved by a decrease in physical activity secondary to fatigue and a roughly 10% reduction in REE resulting from increased conversion of active thyroid hormone to its inactive form and suppressed sympathetic nervous system activity. During long-term starvation (14 to 60 days), maximal adaptation is reflected by a plateau in lipid, carbohydrate, and protein metabolism. The body relies almost entirely on adipose tissue for its fuel, providing greater than 90% of daily energy requirements.42 Muscle protein breakdown decreases to less than 30 g/day, causing a marked decrease in urea nitrogen production and excretion. The decrease in osmotic load diminishes urine volume to 200 mL/day, thereby reducing fluid requirements. Total glucose production decreases to approximately 75 g/day, providing fuel for glycolytic tissues (40 g/day) and the brain (35 g/day) while maintaining a constant plasma glucose concentration. Energy expenditure decreases by 20% to 25% at 30 days of fasting and remains relatively constant thereafter despite continued starvation. The metabolic response to short- and long-term starvation differs somewhat between lean and obese persons. Obesity is associated with a blunted increase in lipolysis and decrease in glucose production compared with that in lean persons.43, 44 In addition, protein breakdown and nitrogen losses are less in obese persons, thereby helping conserve muscle protein.45 Events that mark the terminal phase of starvation have been studied chiefly in laboratory animals. Body fat mass, muscle protein, and the sizes of most organs are markedly decreased. The weight and protein content of the brain, however, remain relatively stable. During the final phase of starvation, body fat stores reach a critical level, energy derived from body fat decreases, and muscle protein catabolism is accelerated. Death commonly occurs when there is a 30% to 50% loss of skeletal muscle protein.46 In humans, it has been proposed that there are certain thresholds beyond which lethality is inevitable: depletion of total body protein between 30% and 50% and of fat stores between 70% and 95%, or reduction of BMI below 13 kg/m2 for men and 11 kg/m2 for women.47, 48 

MALNUTRITION In the broadest sense, malnutrition implies a sustained imbalance between nutrient availability and nutrient requirements. This imbalance results in a pathophysiologic state in which intermediary metabolism, organ function, and body composition are variously altered. Sustained is an important element of this definition, because homeostatic mechanisms and nutrient reserves are usually adequate to compensate for any short-term imbalance. Customarily, the term malnutrition is used to describe a state of inadequacy in protein, calories, or both and is more precisely called protein-energy malnutrition or protein-calorie malnutrition. Occasionally it is used to describe a state of excessive availability, such as a sustained excess of calories (e.g., obesity) or a vitamin (e.g., vitamin toxicity).

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CHAPTER 5  Nutritional Principles and Assessment of the Gastroenterology Patient

Protein-Energy Malnutrition (PEM) There are different pathways whereby PEM may evolve. Primary PEM is caused by inadequate intake of protein, calories, or both, or, less commonly, when the protein ingested is of such poor quality that one or more essential AAs becomes a limiting factor in the maintenance of normal protein metabolism. Secondary PEM is caused by illness or injury. Acute illnesses and injuries increase bodily requirements for protein and energy substrate and impair digestion, absorption, and uptake of these nutrients in various ways. Consequently, secondary PEM usually arises from multiple factors. Illness and injury also commonly induce anorexia (see later for mechanisms), so primary and secondary factors often act in concert to create PEM in the setting of illness. Illness or injury may directly interfere with nutrient assimilation; for example, extensive ileal disease or resection may directly produce fat malabsorption and a caloric deficit. The most common causes of secondary PEM, however, are the remarkable increases in protein catabolism and energy expenditure that occur as a result of a systemic inflammatory response. REE may increase as much as 80% above basal levels in a manner roughly proportional to the magnitude of the inflammatory response, which in turn is roughly proportional to the severity and acuity of the illness. Thus, REE in patients with extensive second- and third-degree burns (the prototype for maximal physiologic stress) may approach twice normal; with sepsis, REE is about 1.5 times normal, and with a localized infection or fracture of a long bone, REE is 25% above normal.6 Such stress factors can be used to construct a formula for predicting the caloric needs of ill individuals (see Table 5.5). Protein catabolism during illness or injury also increases in proportion to the severity and acuity of the insult and therefore parallels the increase in energy consumption. The magnitude of increase in protein catabolism, however, is proportionately greater than that observed with energy consumption, such that urinary urea N losses, which reflect the degree of protein catabolism in acute illness, are about 2.5 times the basal level with maximal stress.6 This increase in catabolism results in a net loss of protein because the rate of synthesis usually does not rise in concert with the rise in catabolism.49 No known storage form of protein exists in the body, so any net loss of protein represents a loss of functionally active tissue. A healthy adult typically loses about 12 g N/day in urine, and excretion may increase to as much as 30 g/day during critical illness. Because 1 g of urinary N represents the catabolism of approximately 30 g of lean mass, it follows that severe illness may produce a daily loss of up to about 0.5 kg of lean mass as a result of excess protein catabolism. Most of this loss comes from skeletal muscle, where the efflux of AAs increases two- to six-fold in critically ill patients.50 Mobilization of AAs from skeletal muscle appears to be an adaptive response. Once liberated, these AAs, in part, are deaminated and used for gluconeogenesis; they are also taken up by the liver and other visceral organs. The proteolysis of muscle under stress thus enables the body to shift AAs from skeletal muscle (the somatic protein compartment) to the visceral organs (the visceral protein compartment), the functions of which are more critical for immediate survival during illness. Nevertheless, with sustained stress, the limitations of this adaptive response become evident, and even the visceral protein compartment sustains a contraction in mass.42

Primary Versus Secondary Protein-Energy Malnutrition: A Body Compartment Perspective The type of tissue lost as malnutrition evolves is critical in determining the pathologic ramifications of weight loss. Over 95% of energy expenditure resides in the lean body mass, which, therefore,

contains the bulk of metabolism that sustains homeostasis. It is the maintenance of this body compartment that is most critical for health. Lean body mass can be subdivided further into somatic and visceral protein compartments, blood and bone cells, and extracellular lean mass, such as plasma and bone matrix (Fig. 5.1). In totalor semi-starvation in otherwise healthy individuals, adipose tissue predominates as a primary energy source; thus, fat mass contracts to a much greater degree proportional to the loss of lean mass.42 Alterations in metabolism from injury or illness, however, produce a proportionately greater loss of muscle mass such that it matches or exceeds the loss in fat mass.51 Although the lean mass lost in illness is preferentially from the somatic protein compartment, with sustained stress there also will be a significant contraction of the visceral protein compartment (Table 5.14). The metabolic forces associated with acute illness and injury are potent, and restoration of muscle mass is unlikely with nutritional support unless the underlying inflammatory condition is corrected. There is increasing interest in attenuating or reversing net catabolism with the use of exogenous anabolic agents in conjunction with nutrition, although, to date, it remains unclear whether administration of β-hydroxymethylbutyrate, growth hormone, oxandrolone, propranolol, or other anabolic agents in acute illness, improve clinical outcomes and outweigh their potential side effects.52 Another important ramification of the potency of the catabolic state associated with acute illness is that most of the weight gained with provision of nutritional support is the result of increases in fat mass and body water; only minor increases in lean mass are observed until the inflammatory focus is resolved.53 Blood cells, bone cells, etc. 7%

Extracellular lean mass (plasma, bone mineral, etc.) 36%

Visceral mass 7%

Muscle mass 22% Fat mass 28% Fig. 5.1  Body composition analysis by weight in a healthy adult. Speckled segments and gray segment collectively represent lean body mass. Speckled segments alone represent body cell mass. (Adapted from Mason JB. Gastrointestinal cancer: nutritional support. In: Kelsen D, Daly J, Kern S, et al., editors. Principles and practice of gastrointestinal oncology. Philadelphia: Lippincott Williams & Wilkins; 2002.)

TABLE 5.14  Body Compartment Wasting and Losses in Simple Starvation Versus Metabolic Stress Parameter

Skeletal Muscle Wasting

Visceral Wasting

Loss of Fat Mass

Starvation

+

+/−*

+++

Metabolic stress

+++

++/−*

+++

  

*Relatively spared early in the process; can become pronounced with extended starvation or metabolic stress.   

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Cytokines are the most important mediators of alterations in energy and protein metabolism that accompany illness and injury. In a wide spectrum of systemic illnesses, increased secretion of interleukin (IL)-1β, tumor necrosis factor -α, IL-6, and interferon-γ has been observed to be associated with increased energy expenditure and protein catabolism, as well as the shift of AAs into the visceral compartments.54-56 Such observations concur with in vitro studies in human cells and animal models that have shown remarkably potent effects of these cytokines (Table 5.15). In the wasting syndrome associated with cancer, proteolysis-inducing factor and zinc-α-2-glycoprotein (‘lipid-mobilizing factor’) are humoral mediators that appear to be unique to cancer cachexia, contributing to protein catabolism and loss of adipose tissue, respectively.57 Promising data in animal models of cancer cachexia indicate that specific inhibitors of cancer-mediated protein catabolism can be designed that greatly reduce the morbidity and mortality associated with the cachexia produced by this disease.58 

Protein-Energy Malnutrition in Children Undernutrition in children differs from that in adults because it affects growth and development. Much of our understanding of undernutrition in children comes from observations made in

TABLE 5.15  Major Cytokines That Mediate Hypercatabolism and Hypermetabolism Associated with Metabolic Stress Cytokine Cell Sources

Metabolic Effects

IFN-γ

Lymphocytes, pulmonary macrophages

Increased monocyte respiratory burst

IL-1β

Monocytes/macrophages, Increased ACTH and cortisol neutrophils, lymphocytes, levels keratinocytes, Kupffer cells Increased acute-phase protein synthesis Increased AA release from muscles Decreased insulin secretion Fever

IL-6

Monocytes/macrophages, keratinocytes, endothelial cells, fibroblasts, T cells, epithelial cells

Increased acute-phase protein synthesis Fever Decreased appetite

TNF-α

Monocytes/macrophages, lymphocytes, Kupffer cells, glial cells, endothelial cells, natural killer cells, mast cells

Decreased FFA synthesis Increased lipolysis Increased AA release from muscles Increased hepatic AA uptake Fever

  

AA, Amino acid; FFA, free fatty acid; IFN, interferon; IL, interleukin. Adapted from Smith M, Lowry S. The hypercatabolic state. In: Shils M, Olson J, Shike M, Ross AC, editors. Modern nutrition in health and disease. Baltimore: Williams & Wilkins; 1999. p 1555.

underdeveloped nations where poverty, inadequate food supply, and unsanitary conditions lead to a high prevalence of PEM. The Waterlow classification of malnutrition (Table 5.16) takes into account a child’s weight for height (the inadequacy of which is termed “wasting”) and height for age (the inadequacy of which is termed “stunting”).59 The characteristics of the three major clinical PEM syndromes in children—kwashiorkor, marasmus, and nutritional dwarfism—are outlined in Table 5.17.60 Although these 3 syndromes are classified separately, in reality, clinical presentations in which they overlap often occur. Kwashiorkor The word kwashiorkor, from the Ga language of West Africa, means “disease of the displaced child” because it was commonly seen after weaning. The presence of peripheral edema distinguishes children with kwashiorkor from those with marasmus and nutritional dwarfism. Children with kwashiorkor also have characteristic skin and hair changes (see later). The abdomen is protuberant because of weakened abdominal muscles, intestinal distention, and hepatomegaly, but ascites is rare. The presence of ascites, therefore, should prompt the clinician to search for liver disease or peritonitis. Children with kwashiorkor are typically lethargic and apathetic, but become very irritable when held. Kwashiorkor most often occurs when a physiologic stress (e.g., infection) is superimposed on an already malnourished child. Because infection or other acute stress is usually present in kwashiorkor, the metabolic aberrations associated with secondary PEM are in play, and contractions of the visceral protein compartment are evident. A decrease in serum proteins like albumin is common, distinguishing it from pure marasmus. Kwashiorkor is characterized by leaky cell membranes that permit movement of potassium and other intracellular ions into the extracellular space, causing water movement and edema. 

TABLE 5.17  Features of Protein-Energy Malnutrition Syndromes in Children Syndrome Parameter

Kwashiorkor

Marasmus

Nutritional Dwarfism

Appetite

Poor

Good

Good

Edema

Present

Absent

Absent

Mood

Irritable when picked up, apathetic when alone

Alert

Alert

Weight for age (% expected)

60-80

70 yr Cardiovascular disease Chronic LGI bleeding/iron deficiency anemia Recurrent bleeding of variable severity

Anastomotic ulceration

Prior intestinal surgical anastomosis

Radiation enteritis or proctitis

History of abdominal radiation therapy

emesis or fresh bloody emesis that is witnessed do not require placement of an NG tube for diagnostic purposes but may need an NG tube to help clear the gastric blood for better endoscopic visualization and to minimize the risk of aspiration. 

Laboratory Studies Blood from the patient with acute GI bleeding should be sent for standard hematology, chemistry, liver biochemical, and

coagulation studies and for typing and crossmatching for packed RBCs. The hematocrit or hemoglobin values immediately after the onset of bleeding may not reflect blood loss accurately, because it takes more than 24 to 72 hours for the vascular space to equilibrate with extravascular fluid and hemodilution results from IV administration of saline.5 A mean corpuscular volume (MCV) lower than 80 fL suggests chronic GI blood loss and iron deficiency, which can be confirmed by the finding of low blood iron, high total iron-binding capacity (TIBC), and low ferritin

CHAPTER 20  Gastrointestinal Bleeding

levels. A low MCV and negative fecal occult blood test (FOBT) result raise the possibility of celiac disease. A high MCV (>100 fL) suggests chronic liver disease or folate or vitamin B12 deficiency. An elevated WBC count may occur in more than half of patients with UGI bleeding and has been associated with greater severity of bleeding.6 A low platelet count can contribute to the severity of bleeding and suggests chronic liver disease or a hematologic disorder. In patients with UGI bleeding, the blood urea nitrogen level typically increases to a greater extent than the serum creatinine level because of increased intestinal absorption of urea after the breakdown of blood proteins by intestinal bacteria.7 The prothrombin time (PT) and INR assess whether a patient has impairment of the extrinsic coagulation pathway. Values can be elevated in chronic liver disease or with warfarin. 

Clinical Determination of the Bleeding Site Presentation with hematemesis, coffee-ground emesis, or NG lavage with return of a large amount of blood or coffee-ground emesis indicates a UGI source of bleeding. A small amount of coffee-ground material or pink-tinged fluid that clears easily may represent mucosal trauma from the NG tube rather than active bleeding from a UGI source. A clear (nonbloody) NG aspirate does not necessarily indicate a more distal GI source bleeding, because at least 16% of patients with actively bleeding UGI lesions have a clear NG aspirate.8 The presence of bile in the NG aspirate makes acute UGI bleeding unlikely but can be seen with an intermittently bleeding UGI source. Melena generally indicates a UGI source but can be seen with small intestinal or proximal colonic bleeding. Hematochezia generally implies a colonic or anorectal source of bleeding unless the patient is hypotensive, which could indicate a severe, brisk UGI bleed with rapid transit of blood through the GI tract.4,9 Marooncolored stool can be seen with an actively bleeding UGI source or a small intestinal or proximal colonic source. 

Hospitalization Patients with severe GI bleeding require hospitalization, whereas those who present with only mild acute bleeding (self-limited hematochezia or infrequent melena) and who are hemodynamically stable (not suspected to be volume depleted), have normal blood test results, and can be relied on to return to the hospital if symptoms recur, may be candidates for semiurgent outpatient endoscopy rather than direct admission to the hospital.10,11 Patients should be hospitalized in an ICU if they have large amounts of red blood in the NG tube or per rectum, have unstable vital signs, or have had severe acute blood loss that may exacerbate other underlying medical conditions. Patients who have had an acute GI bleed but are hemodynamically stable can be admitted to a monitored bed (step-down unit) or standard hospital bed, depending on their clinical condition. Urgent endoscopy performed in the emergency department in patients with a suspected UGI bleed can help determine optimal hospital ­placement.12,13 

Resuscitation Resuscitation efforts should be initiated at the same time as initial assessment in the emergency department and continue during the patient’s hospitalization. At least 1 large-bore (14- or 16-gauge) catheter should be placed intravenously, and 2 should be placed when the patient has ongoing bleeding. Normal saline is infused as fast as needed to keep the patient’s systolic blood pressure higher than 100 mm Hg and pulse lower than 100/min. Patients should be transfused with packed RBCs, platelets, and fresh frozen plasma as necessary to keep the hemoglobin level greater than 7 g/dL, platelet count higher than 50,000/mm3, and PT less

279

than 15 seconds, respectively. In a large study from Barcelona, patients with severe UGI bleeding were randomized to receive transfusions either when the hemoglobin level was less than 7 g/ dL or when the hemoglobin level was less than 9 g/dL.14 The former (“restrictive”) transfusion strategy was associated with a higher survival rate and lower rebleeding rate in patients with bleeding owing to peptic ulcer and in those with Child-Pugh class A or B cirrhosis but a lower survival rate and higher rebleeding rate in those with Child-Pugh class C cirrhosis (see Chapter 92). Decisions about the timing of transfusion need to be individualized based on a patient’s clinical status and comorbidities and the rapidity of blood loss. An endoscopist should be consulted as soon as possible to expedite the patient’s assessment and determine the optimal timing of endoscopy. In hospitals with an LT program, the transplantation hepatology service should also be notified if the patient is known to have cirrhosis and is a potential transplant candidate (see Chapter 97). The patient’s vital signs should be monitored frequently, as appropriate to the level of hospitalization. Laboratory-determined hematocrit and hemoglobin values (not fingerstick hematocrit values, which are less reliable) should be obtained every 4 to 8 hours until the hematocrit and hemoglobin values are stable. In patients with active bleeding, an indwelling urinary catheter should be placed to monitor the patient’s urine output. Endotracheal intubation should be considered in patients with active ongoing hematemesis or with altered mental status to prevent aspiration pneumonia. Patients who are older than 60 years of age, have chest pain, or have a history of cardiac disease should be evaluated for myocardial infarction with electrocardiography and serial troponin measurements. A chest x-ray should also be considered. 

Initial Medical Therapy Administration of a PPI is useful for reducing rebleeding rates in patients with PUD (see later). Starting a PPI in the emergency department or ICU before endoscopy is performed in patients with severe UGI bleeding has become a common practice but is still controversial.15 Several clinical studies and meta-analyses have shown that infusion of a PPI in a high dose before endoscopy accelerates the resolution of endoscopic stigmata of recent hemorrhage (SRH) in ulcers (see later) and reduces the need for endoscopic therapy but does not result in improvement in clinical major outcomes.16-19 Patients with a strong suspicion of portal hypertension and variceal bleeding should be started empirically on IV octreotide (bolus followed by infusion [see later and Chapter 92]), which can reduce the risk of rebleeding to a rate similar to that following endoscopic therapy (Fig. 20.2; also see Fig. 20.1).20,21 

Endoscopy GI endoscopy will identify the bleeding site and permit therapeutic hemostasis in most patients with GI bleeding.22 There is a controversy about the timing of endoscopy for patients with severe UGI bleeding. The consensus is that for patients with severe comorbidities (such as American Society of Anesthesiologists Physical Status class 3 to 4) (see Chapter 42), the optimal period for performing EGD associated with the least mortality is after the patient has been hemodynamically resuscitated but within 12 to 20 hours of presentation. Emergency endoscopy before or after this interval is associated with higher mortality rates. For hemodynamically stable patients with less severe comorbidity (American Society of Anesthesiologists class 1 to 2), EGD within 24 hours is associated with lower mortality. Endoscopy should be done only when it is safe to do so and when the information obtained from the procedure will

20

280

PART III  Symptoms, Signs, and Biopsychosocial Issues

EGD

Major stigmata (active bleeding, NBVV, or clot)

Oozing

Flat pigmented spot or clean-based ulcer

Combination endoscopic hemostasis (e.g., epinephrine injection, multipolar electrocoagulation)

Hemoclip or thermal hemostasis

Oral PPI and early discharge Fig. 20.2  Algorithm for the endoscopic and medical management of severe peptic ulcer hemorrhage following hemodynamic stabilization. NBVV, nonbleeding visible vessel.

Oral PPI twice daily High-dose PPI (IV bolus plus infusion for 72 hr), followed by oral PPI

Severe hematochezia Ongoing hemodynamic resuscitation History, physical examination, NG tube Consult gastroenterologist ± surgeon Oral or NG-tube colonic purge

Anoscopy Colonoscopy (or flexible sigmoidoscopy)

Source identified (see Fig. 20.4)

No source identified

EGD or push enteroscopy

Source identified: Treat appropriately (see Figs. 20.1 and 20.2)

Source identified: Arteriographic embolization or surgery

No source identified: RBC scintigraphy Angiography

No source identified: Consider repeat endoscopic studies, capsule endoscopy, deep enteroscopy*, or surgery

influence patient care. Ideally, the patient should be hemodynamically stable, with a heart rate of less than 100/min and a systolic blood pressure higher than 100 mm Hg. Respiratory insufficiency, altered mental status, or ongoing hematemesis indicates the need for endotracheal intubation before emergency EGD to stabilize the patient and protect the airway. Proper medical resuscitation will not only allow safer endoscopy but also ensure a better diagnostic examination for lesions, such as varices, that are volume dependent, and it will allow more effective hemostasis because of the correction of coagulopathy (Figs. 20.3 and 20.4; also see Figs. 20.1 and 20.2). Patients with active hemorrhage (i.e., a high-volume bloody NG lavage or ongoing hematochezia) should undergo emergency EGD soon after medical resuscitation. In general, emergency endoscopy is best performed once the patient has reached an ICU bed, rather than in the emergency department, because resources (personnel, medications, and space) are more readily available in the ICU. Patients suspected of having cirrhosis or

Fig 20.3  Algorithm for the management of severe hematochezia. RBC, Red blood cell. *Deep enteroscopy includes double-balloon enteroscopy, single-balloon enteroscopy, and spiral enteroscopy.

an aortoenteric fistula, or who rebleed in the hospital, should undergo emergent endoscopy as soon as they are hemodynamically resuscitated. Patients who are hemodynamically stable without evidence of ongoing bleeding can undergo urgent endoscopy (within 24 hours), often in the GI endoscopy unit rather than the ICU. Middle-of-the-night endoscopy should be avoided, except for the most severely bleeding or high-risk patients, because well-trained endoscopy nurses, optimal endoscopic equipment, and angiographic backup may not be available at night. In the rare patient with massive bleeding and refractory hypotension, endoscopy can be performed in the operating room, with the immediate availability of surgical management, if necessary. In patients with severe UGI bleeding, lavage with a large (34 Fr) orogastric tube may help evacuate blood and clots from the stomach to prevent aspiration and allow adequate endoscopic visualization (see also Chapter 42). Special lavage systems can help remove blood rapidly. IV administration of a gastric prokinetic

CHAPTER 20  Gastrointestinal Bleeding

281

Severe hematochezia Ongoing hemodynamic resuscitation History, physical examination, NG tube History of cirrhosis, ulcers, melena, or hematemesis EGD and/or push enteroscopy Source identified: Treat

No source identifed

History of hemorrhoids, pelvic or abdominal radiation, colitis, diarrhea

No identifiable risk factors, painless hematochezia

Anoscopy and flexible sigmoidoscopy Source identified: Treat

No source identified

Colonic purge and urgent colonoscopy

No source identified: Push enteroscopy

Fig. 20.4  Algorithm for the management of severe hematochezia modified according to patient’’s history. RBC, Red blood cell. *Deep enteroscopy includes double-balloon enteroscopy, single-balloon enteroscopy, and spiral enteroscopy.

medication (e.g., erythromycin, metoclopramide) 30 to 90 minutes before EGD to induce gastric contraction and propel blood from the stomach into the small intestine helps endoscopic visualization and decreases the need for repeat endoscopy but does not reduce the transfusion requirement, length of hospitalization, or need for surgery.23-25 Therapeutic single- or double-channel endoscopes with large-diameter suction channels should be used to allow rapid removal of fresh blood from the GI tract during endoscopy. Additionally, a water pump is useful for irrigating target lesions through an accessory channel and for diluting blood to allow suctioning, thereby facilitating visualization. Iced saline lavage is of no value in the management of UGI bleeding and may impair coagulation and cause hypothermia. NG lavage with lukewarm tap water is as safe as lavage with sterile saline and much less expensive. A clear plastic cap placed on the tip of the endoscope can help to visualize bleeding sites behind mucosal folds, deploy endoscopic clips by modifying the angle of endoscopic approach (see later), avoid mucosal “white-out” at corners, and remove blood clots.26 In patients with severe hematochezia and suspected active colonic bleeding, urgent colonoscopy can be undertaken after a rapid purge (see Chapter 42, and Figs. 20.3 and 20.4).27,28 Patients should receive 6 to 8 L of polyethylene glycol (PEG) purge orally or via an NG tube over 4 to 6 hours until the rectal effluent is clear of stool, blood, and clots. Additional PEG purge may be required in some patients, particularly those with active bleeding, severe constipation, or the onset of hematochezia in the hospital. Metoclopramide, 10 mg given intravenously before the purge and repeated every 4 to 6 hours, may facilitate gastric emptying and reduce nausea. In patients with severe or ongoing

Source identified: Treat

Source identified: Treat

No source identified: Capsule endoscopy or RBC scintigraphy or angiography

Source identified: Treat (may require deep enteroscopy*)

No source identified: Deep enteroscopy* or surgery

active hematochezia, urgent colonoscopy should be performed within 12 to 14 hours, but only after thorough cleansing of the colon. Patients with mild or moderate self-limited hematochezia should undergo colonoscopy within 24 hours of admission after a colonic purge. Patients with maroon stool in whom there is pretest uncertainty about the bleeding source should be considered for an urgent PEG preparation as well. Colonoscopy immediately after push enteroscopy (see later) while the patient is still sedated will expedite a patient’s care if push enteroscopy does not provide a diagnosis (Fig. 20.5). Wireless video capsule endoscopy (see later) is useful in patients with overt GI bleeding who have normal push enteroscopy and colonoscopy results and in whom a small bowel source of bleeding is suspected.29 Capsule endoscopy has the advantage of directly visualizing the small intestine to identify potential sources or active bleeding. Disadvantages are that the procedure takes 8 hours to complete and additional time to download and review the images, does not permit therapeutic hemostasis, and may be difficult to perform in inpatients because of limited availability of staff trained to place the capsule during off hours. A follow-up endoscopic procedure, such as single- or double-balloon enteroscopy or retrograde ileoscopy, may be indicated for definitive diagnosis and treatment if a focal bleeding site is found on capsule endoscopy. Complications related to emergency endoscopy and endoscopic hemostasis may occur in up to 1% of patients, depending on the type of endoscopy and treatment performed.30,31 The most common complications include aspiration pneumonia, induced hemorrhage, an adverse medication reaction, hypotension, hypoxia, and GI tract perforation (see Chapter 42). 

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Severe obscure overt GI bleeding Hematochezia

Melena

Urgent colonoscopy after colonic purge

EGD and/or push enteroscopy

Source identified: Treat

No source identified

Source identified: Treat

No source identified: Colonoscopy with examination of terminal ileum

Source identified: Treat

No source identified: Capsule endoscopy

Source identified No source identified: Deep endoscopy* In proximal small intestine

In distal small intestine

Deep enteroscopy*

Retrograde ileoscopy (via deep enteroscopy* or colonoscopy)

Source identified: Treat or laparotomy and intraoperative enteroscopy

Endoscopic Hemostasis Thermal contact probes have been the mainstay of endoscopic hemostasis since the 1970s. These probes come in diameters of 7 and 10 Fr and in lengths that can fit through panendoscopes, enteroscopes, or colonoscopes. Contact probes can physically tamponade a blood vessel to stop bleeding and interrupt underlying blood flow; thermal energy is then applied to seal the underlying vessel (coaptive coagulation). The most commonly used probe is a multipolar electrocoagulation (MPEC) probe, also referred to as a bipolar electrocoagulation probe, with which heat is created by current flowing between intertwined electrodes on the tip of the probe. In animal studies, optimal coagulation has been shown to occur with low-power settings (12 to 16 W) applied for a moderate amount of time (8 to 10 seconds) with moderate pressure on the bleeding site.32 Heater probes provide a predetermined amount of joules of energy, which does not vary with tissue resistance and can effectively coagulate arteries up to 2 mm in diameter, a diameter considerably larger than most secondary or tertiary branches of arteries (usually 1 mm) found in resected bleeding human peptic ulcers.33,34 The main risk of using a thermal probe is perforation with excessive application of coagulation or pressure, especially in acute or nonfibrotic lesions. Thermal probes can also cause a coagulation injury that can make lesions larger and deeper and may induce delayed bleeding in patients with a coagulopathy. Argon plasma coagulation is a noncontact thermal therapy (see later). Injection therapy is most commonly performed with a sclerotherapy needle and submucosal injection of epinephrine, diluted to a concentration of 1:10,000 or 1:20,000, into or around the bleeding site or stigma of hemorrhage (see later). The advantages of this technique are its wide availability, relatively low cost, and safety in patients with a coagulopathy, and lower risk of

No source identified: Supportive care

Fig. 20.5  Algorithm for the management of severe obscure overt GI bleeding. *Deep enteroscopy includes doubleballoon enteroscopy, single-balloon enteroscopy, and spiral enteroscopy.

perforation (and absence of thermal burn damage) than thermal techniques. Epinephrine injection is not as effective, however, for definitive hemostasis as thermal coagulation, hemostatic clip placement (hemoclipping [see later]), or combination therapy.35,36 Injection therapy can also be performed with a sclerosant, such as ethanolamine or alcohol, but these agents are associated with increased tissue damage and other risks. Endoscopic hemoclips (or clips) have been available since 1974, and have become popular following technical improvements.37 Hemoclips serve to apply mechanical pressure to a bleeding site. The first-generation endoscopic hemoclips could not stop bleeding in vessels larger than a diameter of 1 mm,38 but subsequent hemoclips have been larger and stronger and have had a grasp-and-release mechanism that improves endoscopic deployment and hemostasis. Hemoclips are especially useful for patients with malnutrition or coagulopathy39 but can also be difficult to deploy depending on the location of the bleeding site, the degree of fibrosis of the underlying lesion, and limitations to endoscopic access. Newer, large, over-the-endoscope hemoclips grasp more tissue, adhere to fibrotic ulcers better, and can control severe ulcer bleeding better than standard ulcer hemostatic techniques.40 With band ligation, mucosal (with or without submucosal) tissue is suctioned into a cap placed on the end of the endoscope, and a rubber band is rolled off the cap and over the lesion to compress its base. This technique is widely used for the treatment of esophageal varices (see Chapter 92) and can occasionally be used for other bleeding lesions. It is relatively easy to perform, but sufficient mucosa must be suctioned into the cap for ligation to be successful. Depending on the manufacturer, some band ligation devices can only fit on diagnostic endoscopes, and switching from a larger therapeutic endoscope to a smaller diagnostic endoscope is necessary.

CHAPTER 20  Gastrointestinal Bleeding

Hemostatic spray is a inorganic powder with clotting abilities that can create a mechanical barrier that adheres to and covers a bleeding site.41-44 The technique can be used for temporary control of bleeding from peptic ulcers, tumors, and diffusely bleeding lesions; however, for patients with severe nonvariceal bleeding (such as from ulcers or Dieulafoy lesions [see later]) or varices (esophageal or gastric), subsequent definitive hemostasis is usually required with repeat endoscopy, angiography, or surgery. 

Imaging Angiography may be used to diagnose and treat severe bleeding, especially when the cause cannot be determined by upper and lower endoscopy. Angiography is generally diagnostic of extravasation into the intestinal lumen only when the arterial bleeding rate is at least 0.5 mL/min.45 The sensitivity of mesenteric angiography is 30% to 50% (with higher sensitivity rates for active GI bleeding than for recurrent acute or chronic occult bleeding), and the specificity is 100%.46 Angiography permits therapeutic intra-arterial infusion of vasopressin or transcatheter embolization for hemostasis if active bleeding is detected, without the need for bowel cleansing. The rate of major complications, including hematoma formation, femoral artery thrombosis, contrast dye reactions, acute kidney injury, intestinal ischemia, and transient ischemic attacks, is 3%.47 Moreover, angiography does not usually identify the specific cause of bleeding, only its location. Radionuclide imaging is occasionally helpful for patients with unexplained GI bleeding, although it is used less frequently now than in the past because of the widespread use of endoscopy and lack of availability of nuclear medicine services for emergencies, particularly at night and on weekends. Radionuclide imaging can be performed relatively quickly and may help localize the general area of bleeding and thereby guide subsequent endoscopy, angiography, or surgery. The technique involves IV injection of a radiolabeled substance into the patient’s bloodstream, followed by serial scintigraphy to detect focal collections of radiolabeled material. Radionuclide imaging has been reported to detect bleeding at a rate of 0.04 mL/min.48 RBCs are generally labeled with technetium pertechnetate because they remain in the circulation for up to 24 hours so that scanning can be repeated in patients with either active or intermittent GI bleeding.49 The overall rate of a tagged RBC scan for the diagnosis of hematochezia is low (3

≤72 hr

70-80

40-50

4-7 days

10-15

15-20

8-30 days

1-5

15-20

>30 days

0

5-10

Frequency (%) American Society of Anesthesiologists Physical Status score* Time to rebleeding (%)

  

*One point signifies a healthy person; 5 points signifies high likelihood of mortality within 24 hr. Data from the UCLA CURE database. CURE, Center for Ulcer Research and Education; UCLA, University of California, Los Angeles.   

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despite the older age and more serious medical problems of patients treated by angiography.158,159 These studies suggest that angiography can be considered after failure of endoscopic therapy. If embolization therapy does not control the bleeding, surgery remains an option. A randomized controlled trial has suggested that OTSC hemoclipping for recurrent peptic ulcer bleeding was more effective than standard endoscopic hemostasis (mostly by hemoclipping). This new treatment has the potential to reduce the need for surgery or angiography for recurrent ulcer bleeding. OTSC hemoclipping is also more effective than standard hemostasis in eradicating underlying artieral blood flow, which, when present, correlates with a risk of rebleeding.106,111 Immediate surgical intervention is indicated for patients who have exsanguinating bleeding and those who cannot be medically resuscitated. Surgery should also be considered if the endoscopist does not feel comfortable treating a large or pulsating visible vessel (e.g., one in a deep, posterior duodenal ulcer that may represent the gastroduodenal artery) or if a bleeding malignant ulcerated mass is found on endoscopy. 

Immediate Postendoscopic Management High-Risk Endoscopic Stigmata Patients who have undergone endoscopic hemostasis for active arterial bleeding, an NBVV, or an adherent clot should be observed in the hospital for 72 hours while they receive high-dose IV infusions of a PPI. After successful endoscopic treatment and recovery from sedation, the patient can be started on a liquid diet, with subsequent advancement of the diet. For patients who have been on and need to continue antiplatelet agents or an anticoagulant, a cardiologist or vascular physician should be consulted to help determine whether, and for how long, these agents can be held.116,160 For patients with severe atherosclerotic cardiovascular disease who require aspirin, however, a dose of 81 mg/day should be started within 7 days.  Intermediate-Risk Stigmata Patients with flat spots and arterial blood flow detected underneath, those with oozing bleeding from an ulcer and no other stigmata (e.g., spurting, NBVV, clot), and those with severe comorbidity or shock on presentation should undergo endoscopic hemostasis. Initiation of a twice-daily oral PPI and observation in the hospital for 24 to 48 hours after successful endoscopic hemostasis are recommended. Such patients do not benefit from highdose IV PPIs after successful endoscopic hemostasis.106,135  Low-Risk Endoscopic Stigmata Patients with a clean-based ulcer or flat spot with no arterial blood flow detected in the ulcer base can generally resume a normal diet immediately, begin an oral PPI once daily, and be discharged early after endoscopy when stable. 132 These patients can often avoid hospitalization entirely or be discharged early. 10,11,74,161 Generally, they are young and hemodynamically stable with no severe coexisting medical illnesses, a hemoglobin level higher than 10 mg/dL, normal coagulation parameters, and good social support systems at home in case bleeding recurs. 

Prevention of Recurrent Ulcer Bleeding Hp Infection All patients with peptic ulcer bleeding should be tested for Hp infection (see earlier) and, if the result is positive, should receive standard therapy for Hp infection (see Chapter 52).88 One caveat is that bleeding can lead to a false-negative rapid urease test result, and the patient may need to undergo an alternative method of testing for Hp in this setting. Antibiotic therapy does not have to

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be started immediately and can be initiated on an outpatient basis when the patient has resumed a normal diet. In patients who are found to have an Hp-induced ulcer, confirmation of the eradication of Hp after treatment is recommended (see Chapter 52).  Aspirin, Other NSAIDs, and Antiplatelet Drugs Ideally, patients with ulcer bleeding caused by aspirin or another nonselective NSAID should stop the drug. If the patient is also positive for Hp, the organism should be eradicated with standard therapy (see Chapter 52).162 In patients with a history of ulcer bleeding who are positive for Hp and need to continue taking low-dose aspirin (81 mg daily), eradication of Hp alone results in ulcer rebleeding rates similar to those associated with daily PPI therapy (if Hp is not eradicated).163 By contrast, in patients with a history of ulcer bleeding who are positive for Hp and need to continue full-dose NSAID therapy, eradication of Hp alone without a PPI leads to a significantly higher rebleeding rate than use of a daily PPI in conjunction with the NSAID. In patients with ulcer bleeding who do not have Hp infection but who need to continue daily aspirin, co-therapy with a daily PPI significantly reduces the rebleeding rate compared with placebo.164 Patients who require an antiplatelet medication such as clopidogrel and have a history of ulcer bleeding will have less chance of recurrent bleeding if they take aspirin (81 mg) and a PPI daily compared with taking clopidogrel alone.165 Patients who require an NSAID after an ulcer bleed may be considered for a selective COX-2 inhibitor. Selective COX-2 inhibitors cause fewer ulcers than nonselective NSAIDs but are associated with a greater rate of cardiovascular complications. Because selective COX-2 inhibitors result in rebleeding rates similar to those associated with a nonselective NSAID and PPI co-therapy, their use may not be worth the increased cardiovascular risk.166 

Repeat Endoscopy to Confirm Gastric Ulcer Healing Repeat EGD should be considered in patients with a gastric ulcer after 6 to 10 weeks of acid suppressive therapy to confirm healing of the ulcer and absence of malignancy (see Chapters 53 and 54). In areas of the world where the population is at intermediate risk for gastric cancer, 2% to 4% of repeat upper endoscopies to confirm ulcer healing have been reported to disclose gastric cancer.167-169 Some experts have suggested that when the index endoscopy with biopsies is negative for malignancy and the ulcer appears benign endoscopically, a followup endoscopy is unnecessary.170 A small retrospective study has found that when gastric cancer is detected on repeat endoscopy to evaluate gastric ulcer healing, survival is no better than that for patients who did not undergo the recommended follow-up endoscopy.171 

Other Nonvariceal Causes Esophagitis Patients with severe erosive esophagitis can present with hema­ temesis or melena. A multivariate analysis from a center in France, in which 8% of all UGI bleeding was caused by erosive esophagitis, found that independent risk factors for bleeding esophagitis were grade 3 or 4 (moderate to severe) esophagitis by the Savary-Miller grading system (see Chapter 46), cirrhosis, a poor performance status, and anticoagulant therapy.171 A history of heartburn was obtained in only 38% of patients. Severe bleeding from gastroesophageal reflux-induced esophagitis is treated medically with a PPI (see Chapter 46). EGD is essential for diagnosing severe erosive esophagitis, but endoscopic therapy generally has no role unless a focal ulcer with a SRH is found. These

patients should be treated with a daily PPI for 8 to 12 weeks and undergo repeat endoscopy to exclude underlying Barrett’s esophagus (see Chapter 47). Patients can sometimes present with mild UGI bleeding from esophagitis not related to GERD but to infections (e.g., Candida, HSV, CMV) or pill-induced esophagitis. Endoscopy with biopsies and brushings is critical for making these diagnoses and determining the appropriate pharmacologic therapy (see Chapter 45). 

Ulcer Hemorrhage in Hospitalized Patients Hemorrhage from an ulcer or erosions in hospitalized patients typically falls into 2 categories. The classic cause is stress-related mucosal injury (SRMI, or stress ulcers), characterized by diffuse bleeding from erosions and superficial ulcers. The second category is inpatient ulcers, which are large, focal, chronic-appearing ulcers that are painless and present with severe UGI hemorrhage manifested by hematochezia, melena, or bloody emesis. On emergency endoscopy, focal inpatient ulcers are often actively bleeding or demonstrate a visible vessel or adherent clot and are marked by high rebleeding rates, despite combination endoscopic therapy, and delayed healing on a high-dose PPI. SRMI occurs in the UGI tract of severely ill inpatients in an ICU and is likely caused by a combination of decreased mucosal protection and mucosal ischemia. SRMI usually occurs in the stomach but can also be seen in the duodenum, esophagus, and even rectum. Diffuse oozing is common, and patients have a poor prognosis and high rebleeding rate, often related to impaired wound healing and multiple organ failure. Bleeding from SRMI is now uncommon, with a frequency of approximately 1.5% of patients in an ICU. The 2 main risk factors are severe coagulopathy and mechanical ventilation for longer than 48 hours.172 The frequency of clinically significant GI bleeding with either or both of these risk factors is 3.7%, compared with 0.1% when neither risk factor is present. Other proposed risk factors include a history of UGI bleeding, sepsis, an ICU admission longer than 7 days, occult GI bleeding for more than 5 days, and treatment with high-dose ­glucocorticoids. ICU patients with risk factors for bleeding are the main target groups for pharmacologic prevention of bleeding SRMI. Therapy with an H2RA has been shown to decrease the rate of clinically significant bleeding in ICU patients at high risk of SRMI.173 One large multicenter study found that prophylactic treatment with oral omeprazole or IV cimetidine results in similar bleeding rates, but that omeprazole is more effective than cimetidine in maintaining the luminal gastric pH above 4.174 A potential harmful effect of gastric acid suppression to prevent stress ulcers is proliferation of bacteria in the stomach secondary to the increased gastric pH, and the associated risk of aspiration and ventilator-associated pneumonia; however, randomized trials in which acid suppression (with an H2RA or antacids) and sucralfate (which does not lower gastric pH) were compared have not shown convincingly that raising gastric pH increases the risk of pneumonia.175,176 Generally, if a patient with SRMI or an inpatient ulcer is supported hemodynamically and medically, the lesion will heal as the patient’s overall medical status improves. Because SRMI is diffuse, endoscopic therapy is generally not feasible. By contrast, focal inpatient ulcer hemorrhage often requires endoscopic hemostasis for severe hemorrhage (see Fig. 20.9); however, rebleeding rates are higher and healing is slower than in patients in whom bleeding starts before hospitalization (see Table 20.7).177,178 A study in which epinephrine injection plus hemoclip placement was compared with epinephrine injection plus MPEC in a cohort of patients who had a high frequency of in-hospital ulcers found a significantly lower rebleeding rate in the group that underwent injection and hemoclip placement.133 

CHAPTER 20  Gastrointestinal Bleeding

Dieulafoy Lesion A Dieulafoy lesion is a large (1- to 3-mm) submucosal artery that protrudes through the mucosa, is not associated with a peptic ulcer, and can cause massive bleeding. It is usually located in the gastric fundus, within 6 cm of the gastroesophageal junction, although lesions in the duodenum, small intestine, and colon have been reported. The cause is unknown, and congenital and acquired (related to mucosal atrophy or an arteriolar aneurysm) causes are thought to occur (see Chapter 38). Dieulafoy lesion can be difficult to identify at endoscopy because of the intermittent nature of the bleeding; the overlying mucosa may appear normal if the lesion is not bleeding. An NBVV or adherent clot without an ulcer may be seen on endoscopy. If a massive UGIB seems to be emanating from the stomach, careful inspection of the proximal stomach should be carried out to look for a protuberance that might be a Dieulafoy lesion. DEP has been used to help identify a Dieulafoy lesion not visualized on endoscopy.179 Owing to the difficulty of identifying the bleeding site and because rebleeding is not uncommon, we recommend that if a Dieulafoy lesion is found and treated, the site should be marked with submucosal injection of ink to tattoo the area in case of rebleeding and the need for retreatment. Endoscopic hemostasis of a Dieulafoy lesion can be performed with injection therapy, a thermal probe, hemoclipping, OTSC hemoclipping, or rubber band ligation.111,179-185 Large case series have reported an initial hemostasis rate of approximately 90%, with the need for surgery in 4% to 16% of cases.182 Rebleeding rates may be lower with combination therapy or OTSC hemoclipping because underlying arterial blood flow is eradicated more effectively than by injection or monotherapy.111 Although all the endoscopic hemostasis techniques seem to be effective, perforation and delayed rebleeding have been reported after band ligation (see Chapter 42). 

Mallory-Weiss Tears Mallory-Weiss tears are mucosal or submucosal lacerations that occur at the gastroesophageal junction and usually extend distally into a hiatal hernia (Fig. 20.14). Patients generally present with hematemesis or coffee-ground emesis and a history of nonbloody vomiting followed by hematemesis, although some patients do not recall vomiting. The tear is thought to result from increased intra-abdominal pressure, in combination with a shearing effect caused by negative intrathoracic pressure above the diaphragm, which is often related to vomiting. Mallory-Weiss tears have

295

been reported in patients who vomit while taking a bowel purge before colonoscopy.186 Endoscopy usually reveals a single tear that begins at the gastroesophageal junction and extends several millimeters distally into a hiatal hernia sac. Occasionally, more than one tear is seen. A retroflexed view in the stomach may provide better visualization than a forward view. The bleeding stigmata of Mallory-Weiss tears can include a clean base, adherent clot, NBVV, oozing, or, rarely, active spurting. Usually, the bleeding is self-limited and mild, but occasionally it can be severe, especially in patients with esophageal varices or coagulopathies. Mucosal (superficial) Mallory-Weiss tears can start healing within hours and can heal completely within 48 hours. Although approximately 50% of patients hospitalized with UGI bleeding from a Mallory-Weiss tear receive blood transfusions, the tear manifests as mild, self-limited hematemesis in most patients, who do not seek medical care.187 The rebleeding rate among patients hospitalized for a Mallory-Weiss tear is approximately 10%; risk factors for rebleeding include shock at presentation and active bleeding at endoscopy.188 Owing to the risk of continued and recurrent bleeding, patients with active bleeding from a Mallory-Weiss tear should undergo endoscopic therapy, which can be performed successfully with epinephrine injection, MPEC, hemoclip placement, or band ligation. Randomized trials that compared MPEC and medical therapy with an H2RA have found that endoscopic therapy reduces the rates of rebleeding, blood transfusions, and emergency surgery.189 Our current endoscopic technique for treating actively bleeding Mallory-Weiss tears in patients without portal hypertension or esophageal varices is to apply endoscopic hemoclips to stop the bleeding and close the tear. If hemoclips are unavailable, epinephrine injection to slow bleeding and focal hemostasis of the bleeding site with MPEC at a low-power setting (12 to 14 W) and with light pressure applied for 1 to 2 seconds are recommended. The management of patients with esophageal varices caused by portal hypertension who also have a Mallory-Weiss tear should be targeted toward the esophageal varices, with esophageal band ligation or variceal sclerotherapy (see later and Chapter 92). Patients with a Mallory-Weiss tear are also treated with antiemetics if they have nausea or vomiting, and a PPI to accelerate mucosal healing. Long-term treatment with a PPI is not required. 

Cameron Lesions Cameron lesions are linear erosions or ulcerations in the proximal stomach at the end of a large hiatal hernia, near the diaphragmatic pinch (Fig. 20.15).190 Cameron lesions are thought to be caused by mechanical trauma and local ischemia as the hernia moves against the diaphragm and only secondarily by acid and pepsin. They can be a source of acute UGI bleeding but more commonly may present as chronic GI bleeding and iron deficiency anemia. Cameron lesions are a common cause of obscure GI bleeding (see later) and, not uncommonly, are missed by an unsuspecting endoscopist. Endoscopic management has been reported.191 Long-term medical management is usually with iron supplements and an oral PPI.192,193 Surgical repair of the hiatal hernia may be needed for patients with severe acute or chronic GI bleeding and failure of medical management (see Chapter 27).192 

UGI Malignancy

Fig. 20.14  Endoscopic appearance of a Mallory-Weiss tear with mild oozing.  Note that the tear starts at the gastroesophageal junction (long arrow) and extends distally into the hiatal hernia (short arrow).

Malignancy accounts for 1% of severe UGIBs. The tumors are usually large, ulcerated masses in the esophagus, stomach, or duodenum. Endoscopic hemostasis with MPEC, laser, injection therapy, or hemoclips can temporarily control acute bleeding in most patients and allow time to determine the appropriate long-term management.194,195 Patients with an ulcerated subepithelial mass (usually a GIST or leiomyoma) should undergo surgical resection of the mass to prevent rebleeding and, in the case of a GIST,

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the risk of metastasis. Angiography with embolization should be considered for patients with severe UGI bleeding caused by malignancy who do not respond to endoscopic therapy. External beam radiation can provide palliative hemostasis for patients with bleeding from advanced gastric or duodenal cancer (see Chapter 54). Hemospray has been used to manage oozing bleeding from UGI tumors in a small case series (see earlier).42 

GAVE GAVE, also described as “watermelon stomach,” is a variant of gastric vascular ectasia (see Chapter 92) characterized by rows or stripes of ectatic mucosal blood vessels that emanate from the pylorus and extend proximally into the antrum (Fig. 20.16). The cause is uncertain, and the lesion may represent a response to mucosal trauma from contraction waves in the antrum. GAVE

has been associated with cirrhosis and systemic sclerosis (scleroderma) (see Chapters 37, 38, and 92). Patients with GAVE who do not have portal hypertension demonstrate linear arrays of angiomas (classic GAVE), whereas those with portal hypertension have more diffuse antral angiomas.196 The diffuse type of antral angiomas and, occasionally, classic GAVE are sometimes mistaken for gastritis by an unsuspecting endoscopist. Such cases are a common cause of obscure GI bleeding in referral centers (see later).57 Patients usually present with iron deficiency anemia or melena, with a mildly decreased hematocrit value suggestive of a slow UGIB. GAVE is most commonly reported in older women196 and also seems to be more common in patients with end-stage renal disease. Endoscopic hemostasis with thermal heat modalities such as laser, MPEC, or argon plasma coagulation has been used successfully. Endoscopic hemostasis and ablation with thermal modalities can result in good palliation with an increase in the hematocrit value and a decrease in the need for blood transfusions and hospitalization.196,197 Usually, several sessions approximately 4 to 8 weeks apart are required to achieve eradication of the lesions and a reduction in bleeding from the antral ectasias. Endoscopic therapy with argon plasma coagulation has been shown to be equally (80%) effective in cirrhotic and noncirrhotic patients with GAVE.198 Pilot studies have demonstrated that mucosal band ligation, radiofrequency ablation, and cryotherapy can also lead to eradication of GAVE in selected patients.199-201 Placement of a TIPS in patients with portal hypertension and cirrhosis does not decrease bleeding from GAVE or diffuse antral angiomas. Patients who have ongoing severe chronic bleeding from GAVE rarely require surgical antrectomy to control symptoms (see Chapters 38 and 92).202 

Portal Hypertensive Gastropathy

Fig. 20.15  Endoscopic appearance of Cameron lesions.  Note that these linear ulcerations (arrows) are located at the distal end of a hiatal hernia.

Portal hypertensive gastropathy (PHG) is caused by increased portal venous pressure and severe mucosal hyperemia that results in ectatic blood vessels in the proximal gastric body and cardia and oozing of blood. Less severe grades of PHG appear as a mosaic or snakeskin pattern and are not associated with bleeding.203 Usually, patients with severe PHG present with chronic blood loss, but they can occasionally present with acute bleeding. Severe PHG with diffuse bleeding is treated by measures that decrease portal pressure, usually with β-adrenergic receptor blocking agents or possibly with placement of a TIPS or surgical portacaval shunt. Endoscopic management has no role unless an obvious focal bleeding site is identified. The best treatment is LT (see Chapter 92). 

Hemobilia Hemobilia may occur in patients who have experienced liver trauma, undergone a liver biopsy or manipulation of the hepatobiliary system (as occurs with ERCP, percutaneous transhepatic cholangiography, or TIPS), or have HCC or a biliary parasitic infection.204 Patients may present with a combination of GI bleeding and elevated liver biochemical test levels. The diagnosis can be confirmed by using a side-viewing duodenoscope to identify bleeding from the ampulla (Fig. 20.17). Ongoing or recurrent bleeding is treated with arterial embolization via arteriography. 

Hemosuccus Pancreaticus

Fig. 20.16  Endoscopic appearance of GAVE, or watermelon stomach.  The pattern seen in this view is considered classic, with rows of ectatic mucosal blood vessels emanating from the pylorus.

Hemosuccus pancreaticus is a rare form of UGI bleeding that occurs most commonly in patients with acute pancreatitis, chronic pancreatitis, pancreatic pseudocyst, or pancreatic cancer or after ERCP with pancreatic duct manipulation (see Chapters 42, 58, 59, 60, and 61). It can also result from rupture of a splenic artery aneurysm into the pancreatic duct.205 CT can demonstrate

CHAPTER 20  Gastrointestinal Bleeding

297

Patients with an acute UGIB and a history of an aortic aneurysm repair should undergo urgent CT with IV contrast or MR angiography first. CT or MRI may show inflammation around the graft and may demonstrate the fistula. If these are not diagnostic, push enteroscopy should be considered to evaluate the third portion of the duodenum for compression, blood, or graft material, as well as to exclude other bleeding sources. A vascular surgery consultation should also be obtained. Surgical treatment is required to remove the infected graft. Therapeutic endoscopy plays no role in the management of bleeding from an aortoenteric fistula (see Chapter 38). 

Varices

Fig. 20.17  Endoscopic appearance of the ampulla of Vater and hemobilia.  Note fresh red blood on the right side exuding from the ampulla of a patient who earlier that day had undergone a percutaneous liver biopsy.

pancreatic pathology if previously unsuspected. Endoscopy with a side-viewing duodenoscope reveals blood coming out of the ampulla. Management of severe hemorrhage is usually with angiographic embolization or surgery. 

Postsphincterotomy Bleeding Bleeding following endoscopic sphincterotomy occurs in approximately 2% of patients (see Chapter 42).206 Potential risk factors include coagulopathy, use of anticoagulants, portal hypertension, renal failure, and the type and length of sphincterotomy. Successful hemostasis of postsphincterotomy bleeding is usually achieved with endoscopic methods such as injection of epinephrine, hemoclips, or MPEC (see Chapter 42). 

Aortoenteric Fistula Bleeding from an aortoenteric fistula is usually acute and massive, with a high mortality rate.207 A primary aortoenteric fistula is a communication between the native abdominal aorta (usually an atherosclerotic abdominal aortic aneurysm) and, most commonly, the third portion of the duodenum.208 Often, a self-limited herald bleed occurs hours to months before a more severe exsanguinating bleed. Occasionally, the diagnosis of an aortoenteric fistula is suspected by a history of an abdominal aortic aneurysm or by palpation of a pulsatile abdominal mass. The diagnosis can be difficult to make on endoscopy in the absence of active bleeding. Demonstration of an aortic aneurysm on abdominal CT or MRI (with IV contrast) suggests the diagnosis of a fistula.58 Secondary aortoenteric fistulas are more common and usually occur between the small intestine and an infected abdominal aortic surgical graft. The fistula typically occurs between the third portion of the duodenum and the proximal end of the graft but may occur elsewhere in the GI tract. The fistula usually forms between 3 and 5 years after graft placement. Patients often experience a herald bleed that is mild and self-limited, and occasionally intermittent, before massive bleeding occurs.209 A secondary fistula can also occur between the third part of the duodenum and an endovascular stent, in which case the fistula may be caused by pressure from the stent against the duodenum, infection of the stent, or possibly expansion of the native aneurysm.210

Variceal hemorrhage is an important cause of UGI bleeding and is discussed in more detail in Chapter 92. Esophageal variceal bleeding related to portal hypertension is the second most common cause of severe UGI bleeding (after PUD). The acute mortality rate with each bleed is approximately 30%, and the long-term survival rate is less than 40% after 1 year with medical management alone.211 Despite advances in medical therapy, endoscopic hemostasis, and angiographic procedures and TIPS, overall long-term survival rates have not improved for patients with variceal bleeding. Survival in nontransplanted patients with variceal bleeding is heavily influenced by the severity of underlying liver disease, with poorer survival rates for patients with higher MELD scores or Child-Pugh class C cirrhosis than for those with Child-Pugh class A or B cirrhosis (see Chapters 74, 92, and 97). LT can improve survival in selected patients. Bleeding gastric varices are a difficult therapeutic problem because in contrast to bleeding esophageal varices, most available nonsurgical treatments are ineffective, except when isolated gastric varices are found without accompanying esophageal varices, as occurs with splenic vein thrombosis and often in association with pancreatitis or pancreatic cancer. The diagnosis of splenic vein thrombosis can be made with Doppler US, MRI, or routine angiography. Bleeding from gastric varices caused by splenic vein thrombosis is treated by splenectomy. Focal gastric varices with bleeding can be treated with injection of cyanoacrylate glue or radiologic procedures such as balloon-occluded retrograde transvenous obliteration (see Chapter 92).  Medical Management of Acute Variceal Bleeding Somatostatin and its long-acting analog, octreotide, cause selective splanchnic vasoconstriction and lower portal pressure without causing the cardiac complications seen with vasopressin (even in combination with nitroglycerin). Studies have shown mixed results as to whether somatostatin is more effective than placebo in managing variceal bleeding, but it seems to be at least as effective as vasopressin and is much safer. A meta-analysis has shown that vasoactive drugs (e.g., octreotide, somatostatin, terlipressin [a long-acting vasopressin analog]) are as effective as sclerotherapy for controlling variceal bleeding and cause fewer adverse events.21 No studies have shown a survival benefit to vasopressin or somatostatin in patients with variceal bleeding. Given the potential ability of octreotide to control acute variceal hemorrhage, its low toxicity, and its availability in the USA, octreotide has been the pharmacologic drug of choice as an adjunct to endoscopic therapy for the treatment of variceal hemorrhage. The dose of octreotide for acute variceal hemorrhage is a 50 μg bolus followed by a continuous IV infusion of 50 μg/hr for up to 5 days. Patients with a prolonged PT that does not correct with fresh frozen plasma may benefit from infusion of human recombinant factor VIIa, although prolongation of the PT does not correlate with bleeding risk (see Chapters 92 and 94). In one uncontrolled trial, a single 80 μg/kg dose of recombinant factor VIIa

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normalized the PT in all 10 patients within 30 minutes, with immediate control of bleeding in all patients.212 In a large randomized, placebo-controlled study, administration of recombinant factor VIIa in addition to endoscopic hemostasis decreased rebleeding rates in patients with Child-Pugh class B and C cirrhosis who had bled from varices.213 Because recombinant factor VIIa is expensive and associated with a risk of thrombosis, its use should be reserved for patients with severe ongoing bleeding and irreversible coagulopathy, pending the results of additional clinical and cost-effectiveness studies. Up to 20% of cirrhotic patients who are hospitalized with GI bleeding have a bacterial infection at the time of admission to the hospital, and infection develops during the hospitalization in up to 50% (see Chapter 93). Meta-analyses suggest that administration of an antibiotic to cirrhotic patients with variceal bleeding is associated with a decrease in the rates of mortality and bacterial infections.214,215 Commonly prescribed antibiotics are fluoroquinolones, such as oral norfloxacin (400 mg twice daily) (not available in the USA), IV ciprofloxacin (400 mg every 12 hours), IV levofloxacin (500 mg every 24 hours), and, most commonly, IV ceftriaxone, 1 g every 24 hours, administered for 7 days.  Balloon Tamponade Although balloon tamponade of varices is seldom used now to control gastroesophageal variceal bleeding, it may be used to stabilize a patient with massive bleeding prior to definitive therapy (see Chapter 92). Three types of tamponade balloons are available. The Sengstaken-Blakemore tube has gastric and esophageal balloons, with a single aspirating port in the stomach. The Minnesota tube also has gastric and esophageal balloons and has aspiration ports in the esophagus and stomach. The LintonNachlas tube has a single large gastric balloon and aspiration ports in the stomach and esophagus. Most reports suggest that balloon tamponade provides initial control of bleeding in 85% to 98% of cases, but variceal rebleeding recurs soon after the balloon is deflated in 21% to 60% of patients.216 The major problem with tamponade balloons is a 30% rate of serious complications such as aspiration pneumonia, esophageal rupture, and airway obstruction. Patients should be intubated before placement of a tamponade balloon to minimize the risk of pulmonary complications. Clinical studies have not shown a significant difference in efficacy between vasopressin administration and balloon ­tamponade.  Endoscopic Sclerotherapy Endoscopic variceal sclerotherapy involves injecting a sclerosant into or adjacent to esophageal varices. The most commonly used sclerosants are ethanolamine oleate, sodium tetradecyl sulfate, sodium morrhuate, and ethanol. Cyanoacrylate, a glue that effectively stops bleeding when injected into esophageal or gastric varices, is difficult to use and not approved by the FDA. Various techniques are used; their common goals are to achieve initial hemostasis and reduce the risk of rebleeding by performing sclerotherapy on a scheduled basis until the varices are obliterated. Esophageal varices are much more amenable than gastric varices to eradication with endoscopic therapy. Prospective randomized trials have suggested that immediate hemostasis is improved and the risk of acute rebleeding is reduced with sclerotherapy compared with medical therapy alone for bleeding esophageal varices.217-220 Hemostasis can be achieved in 85% to 95% of cases, with a rebleeding rate of 25% to 30%.221 Complications of endoscopic variceal sclerotherapy include esophageal ulcers that can bleed or perforate, esophageal strictures, mediastinitis, pleural effusions, aspiration pneumonia, acute respiratory distress syndrome, chest pain, fever, and bacteremia and account, in part, for the use of esophageal variceal band ligation as the preferred endoscopic therapy for variceal bleeding. 

Endoscopic Band Ligation The technique of endoscopic band ligation is similar to that used for band ligation of internal hemorrhoids (see Chapter 129). A rubber band is placed over a varix, which subsequently undergoes thrombosis, sloughing, and fibrosis. Prospective randomized controlled trials have shown that endoscopic band ligation is as effective as sclerotherapy in achieving initial hemostasis and reducing the rate of rebleeding from esophageal varices. Acute hemostasis can generally be achieved in 80% to 85% of cases, with a rebleeding rate of 25% to 30%. Band ligation is associated with fewer local complications, especially esophageal strictures, and in one study required fewer endoscopic treatment sessions than sclerotherapy.222 A meta-analysis has reported that variceal band ligation reduces the rates of rebleeding, overall mortality, and death from bleeding compared with sclerotherapy.223 Band ligation, however, may be more technically difficult to perform than sclerotherapy during active variceal bleeding. Devices used for band ligation allow up to 10 bands to be placed, without the need to remove the endoscope to reload the banding device. The recommended strategy is to control active bleeding first and then place 2 bands on each esophageal variceal column, one distally near the gastroesophageal junction and another 4 to 6 cm proximally.224,226  TIPS Placement of a TIPS is an interventional radiologic procedure in which an expandable metal stent is placed via percutaneous insertion between the hepatic and portal veins, thereby creating an intrahepatic portosystemic shunt. TIPS is effective for shortterm control of bleeding gastroesophageal varices, especially those that fail endoscopic therapy.226,227 Initially envisioned as a bridge to LT, it has been used with increased frequency in nontransplantation situations. Randomized trials that have compared TIPS with endoscopic sclerotherapy suggest that TIPS is more effective for the long-term prevention of rebleeding.228 The main problems with TIPS are a rate of shunt occlusion of up to 80% (less with use of polytetrafluoroethylene-coated stents) within 1 year and development of new or worsening hepatic encephalopathy in approximately 20% of patients.229 Most relevant studies have shown that TIPS does not prolong survival of patients with variceal bleeding compared with endoscopic treatment. In the management of acute variceal bleeding, TIPS is generally reserved for patients who fail endoscopic treatment. In one study of patients with predominantly alcoholic cirrhosis and active drinking, those with Child-Pugh class B cirrhosis who were stabilized with vasoactive and endoscopic therapy were randomized to either urgent TIPS within 72 hours after initial stabilization or therapy with a β-adrenergic receptor blocking agent and endoscopic band ligation as maintenance therapy, and those who underwent a TIPS had a lower rate of rebleeding and improved 1-year survival.230 The findings may not be as applicable to patients with nonalcoholic cirrhosis (see also Chapter 92).  Portosystemic Shunt Surgery A variety of portosystemic shunt operations have been performed to reduce portal venous pressure. When compared with sclerotherapy, surgical shunts decrease the rebleeding rate significantly but do not improve survival.221,231-234 Surgical shunts may be associated with hepatic encephalopathy and can make future LT technically more difficult, but they have an advantage over endoscopic variceal therapy in reducing portal hypertension and treating gastric variceal bleeding. Surgical shunts are performed infrequently now but are considered for selected patients who have failed endoscopic therapy and are not expected to become candidates for LT (see Chapters 92 and 97). 

CHAPTER 20  Gastrointestinal Bleeding

LOWER GASTROINTESTINAL BLEEDING LGI bleeding generally signifies bleeding from the colon or anorectum. The annual incidence of LGI bleeding is approximately 20 cases/100,000 population, with an increased risk in older adults.235 The rate of hospitalization for LGI bleeding is lower than that for UGI bleeding. Most patients are older than 70 years of age. Patients usually present with painless hematochezia and a decrease in the hematocrit value but without orthostasis. If orthostasis is associated with hematochezia, a briskly bleeding UGI source should be excluded (see earlier); severe painless hematochezia results from a foregut source in approximately 15% of noncirrhotic patients.236 The sites of origin within the GI tract of severe hematochezia at UCLA CURE are shown in Fig. 20.18. Patients with LGI bleeding should initially be resuscitated medically. After they have been stabilized, they should generally undergo urgent colonoscopy after a PEG purge.27 For patients with cirrhosis, a recent history of melena or hematemesis, or a history of PUD, “panendoscopy” (upper and lower endoscopy) is recommended first.236,237 In early reports, urgent colonoscopy resulted in a diagnosis in approximately 70% of cases;238,239 however, in subsequent reports, the combination of urgent colonoscopy and, if necessary, push enteroscopy, anoscopy, and capsule endoscopy has resulted in a diagnosis in 95% of cases (see Fig. 20.4).236,237 The most common causes of LGI bleeding are shown in Table 20.8. Diverticulosis is the most common cause of acute LGI bleeding and occurs in approximately 30% of cases.2 Colonic polyps or cancer, colitis, and anorectal disorders each account for approximately 20% of cases.240 In most cases, acute LGI bleeding will stop spontaneously, thereby allowing nonurgent diagnosis and treatment. For patients with ongoing or recurrent hematochezia, urgent diagnosis and treatment are required to control the bleeding. In a large series of patients at the UCLA Medical Center and Wadsworth Veterans Small intestine 5% (n = 30) No source identified 3% (n = 18)

Colon 75% (n = 486)

UGI tract 17% (n = 113) Fig. 20.18  Frequencies of sources of severe hematochezia in patients seen at UCLA CURE.  Note that in most cases (75%), severe hematochezia is from the colon, 17% is from a UGI (esophagus, stomach, or duodenum) source, and 5% is from a small intestinal source. CURE, Center for Ulcer Research and Education; UCLA, University of California, Los Angeles.

299

Administration Hospital, 64% of patients with severe hematochezia required a therapeutic intervention to control continued bleeding or rebleeding27: 39% underwent endoscopic hemostasis, 1% underwent angiographic embolization, and 24% underwent surgery.

Risk Factors and Risk Stratification Nonselective NSAIDs increase the risk of LGI bleeding compared with placebo.241,242 The main risk factors for NSAIDassociated LGI bleeding appear to be an age of 65 years or older and prior history of LGI bleeding.243 Whether use of long-term selective COX-2 inhibitors is associated with a lower risk of LGI bleeding than nonselective NSAIDs is uncertain. Table 20.9 shows clinical factors that are predictive of severe LGI bleeding (defined as continued bleeding within the first 24 hours of hospitalization, with a transfusion requirement of at least TABLE 20.8  Colonic Causes of Severe Hematochezia (%) Study Lesion

Reference 239

Reference 240

UCLA CURE* (2018)

Diverticulosis

30

33

33

Colon cancer or polyps

18

21

5.2

Colitis

17

17

N/A

Ischemic colitis

N/A

7

11.9

IBD

N/A

4

3.6

Noninfectious colitis

N/A

5

2.7

Infectious colitis

N/A

1

1.2

Angioectasia

7

6

5.0

Postpolypectomy ulcer

6

N/A

7.8

Rectal ulcer

N/A

1

8.4

Hemorrhoids

N/A

20

10.3

Anorectal source (other)

4

3

1.8†

Radiation colitis

0

0.5

2.2

Colon anastomotic ulcer

N/A

N/A

2.1

Other

8

3

4.1

Unknown

16

0

0

  

*N = 823. fissure following rubber band ligation, ulcer, rectal cancer, or other anorectal lesion. CURE, Center for Ulcer Research and Education; UCLA, University of California, Los Angeles; N/A, not available.

†Anal

  

TABLE 20.9  Clinical Prediction Score and Outcomes of Severe Acute LGI Bleeding Total Risk Points*

Frequency (%)

Risk of Severe Bleeding (%)

Need for Surgery (%)

Mortality Rate (%)

Hospital Days

Mean Number of Units Transfused (Packed Red Blood Cells)

0

6

6

0

0

2.8

0

1-3

75

43

1.5

2.9

3.1

1

≥4

19

79

7.7

9.6

4.6

3

  

*Risk factors (1 point each): aspirin use; more than 2 comorbid illnesses; heart rate ≥100/min; nontender abdominal examination; rectal bleeding within the first 4 hr of evaluation; syncope; systolic blood pressure ≤115 mm Hg. Severe LGI bleeding is defined as continued bleeding within the first 24 hr of hospitalization (transfusion of 2 or more units of packed red blood cells and/ or hematocrit value drop of 20% or more) and/or recurrent bleeding after 24 hr of stability (need for additional transfusions, further hematocrit value decrease of 20% or more, or readmission to the hospital for LGI bleeding within 1 week of discharge). Data from Strate LL, Saltzman JR, Ookubo R, et al. Validation of a clinical prediction rule for severe acute lower intestinal bleeding. Am J Gastroenterol 2005; 100:1821–7.   

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2 units of packed RBCs or a decrease in the hematocrit value of 20% or more) or recurrent bleeding after 24 hours of stability (defined as the need for additional transfusions, a further decrease in the hematocrit value of at least 20%, or readmission for LGI bleeding within 1 week of discharge). Predictive factors include tachycardia, hypotension, syncope, a nontender abdomen, witnessed rectal bleeding on presentation, aspirin use, and more than 2 comorbid illnesses.244,245 These risk factors are used in a prognostic scoring system that identifies patients at the highest risk for severe LGI bleeding, who account for 19% of patients with LGI bleeding and may benefit most from urgent colonoscopy. A single-institution case series of 94 patients admitted for LGI bleeding246 found that 39% of all cases of LGI bleeding requiring hospitalization were severe, as defined by the passage of red blood after the patient had left the emergency department and associated hypotension or tachycardia or the need for a transfusion of more than 2 units of packed RBCs during hospitalization. Independent risk factors for severe LGI bleeding were an initial hematocrit value of 35% or lower, abnormal vital signs (a systolic blood pressure 100/min) on admission, and gross blood on initial rectal examination. Artificial neural networks have also been used to develop prediction models for severe LGI bleeding,247,248 but from a clinical point of view, the large number of variables that have to be entered into a computer program for analysis limit their widespread use. 

Mortality A large U.S. database study of 227,000 patients with a discharge diagnosis of LGI bleeding reported an overall mortality rate of 3.9% in 2008.240 Multivariate analysis found that independent predictors of in-hospital mortality are age older than 70 years, intestinal ischemia, at least 2 comorbid illnesses, onset of bleeding after hospitalization for an unrelated condition, coagulopathy, hypovolemia, transfusion of packed RBCs, and male gender. Colorectal polyps and hemorrhoids were associated with a lower mortality risk. The low risk of death from LGI bleeding identified in this study is consistent with data from smaller series such as those from Kaiser San Diego (2.4%) and the University of California, San Francisco (3.2%).235,246 The Kaiser study also found an increased risk of death with in-hospital LGI bleeding. 

Diagnostic and Therapeutic Approach Patients with hematochezia should undergo the same careful history taking, physical examination, and laboratory testing described earlier for the general approach to the patient with acute GI bleeding (see Table 20.1). The history should focus specifically on identifying sources of LGI bleeding. Diverticular bleeding should be suspected in patients with painless, severe, acute hematochezia and a history of diverticulosis, although ischemic colitis may also be painless.249 Patients should be medically resuscitated. Because LGI bleeding is generally less severe than UGI bleeding, blood transfusions may not be required. Most patients should undergo initial evaluation with colonoscopy after bowel preparation, although in selected cases anoscopy or flexible sigmoidoscopy without any bowel cleansing or after an enema may be performed. Other diagnostic tests, including radionuclide bleeding scans or angiography, may be used in selected cases or when colonoscopy fails to detect a source of bleeding.

Anoscopy Anoscopy can be useful for patients in whom bleeding internal hemorrhoids or other anorectal disorders (e.g., fissures, fistulas, proctitis) are suspected from the medical history. For internal hemorrhoids, immediate treatment with rubber band ligation is

recommended (see Chapter 129). Most patients, however, especially if older than 50 years of age, will also require colonoscopy, at least electively, to evaluate the remainder of the colon. 

Flexible Sigmoidoscopy Flexible sigmoidoscopy can evaluate the rectum and left side of the colon for a bleeding site and can be performed without a standard colonoscopy bowel preparation. Although not adequate for evaluation of the anal canal, flexible sigmoidoscopy alone will result in a diagnosis in approximately 9% of cases.250 If the distal colon can be adequately cleansed with enemas, an urgent flexible sigmoidoscopy can be useful for patients suspected of having a solitary rectal ulcer, UC, radiation proctitis, postpolypectomy bleeding (in the rectosigmoid), or internal hemorrhoids (see Chapters 41, 116, 119, 126, 128, and 129). Therapeutic hemostasis can be provided with injection therapy, hemoclip placement, band ligation, or MPEC. Monopolar electrocautery (e.g., argon plasma coagulation, snare polypectomy, hot biopsy forceps) should not be used if a bowel preparation has not been administered to avoid the risk of ignited flammable colonic gas (see Chapter 17). 

Radionuclide Imaging Radionuclide imaging involves injecting a radiolabeled substance into the patient’s bloodstream and performing serial scintigraphy to detect focal collections of radiolabeled material (see earlier). This technique has been reported to detect bleeding at a rate as low as 0.04 mL/min,48 with an overall positive diagnostic rate of approximately 45% and an accuracy rate of 78% for localizing the true bleeding site.238 The disadvantages of radionuclide imaging are that delayed scans may be misleading, and determining the specific cause of bleeding often depends on endoscopy or surgery. False-positive results are most likely to occur when transit of luminal blood is rapid, so that radiolabeled blood is detected in the colon even though it originated in the UGI tract. Radionuclide imaging may be helpful in cases of obscure GI bleeding (see later) or prior to angiography to help localize a lesion, particularly if an early scan (e.g., 30 minutes to 4 hours after injection of the radiolabeled material) is positive for RBC extravasation. 

Angiography Angiography is most likely to detect a site of bleeding when the rate of arterial bleeding is at least 0.5 mL/min.45 The diagnostic yield depends on patient selection, the timing of the procedure, and the skill of the angiographer, with positive results in 12% to 69% of cases. An advantage of angiography is that embolization can be performed to control some bleeding lesions. Major complications, however, occur in 3% of cases and include bowel ischemia, hematoma formation, femoral artery thrombosis, contrast dye reactions, acute kidney injury, and transient ischemic attacks.47 Other disadvantages of angiography are the absence of active bleeding in most patients at the time of angiography, inability to detect nonbleeding SRH (NBVV, clot, or spot), expense of the test, and inability to determine the specific lesion responsible for bleeding in many cases.236,237 A small retrospective case series of 11 patients with colonic bleeding who underwent angiographic embolization reported that the bleeding ceased in 10, mesenteric ischemia developed in 7, and 6 died.251 Another study of 65 patients with acute LGI bleeding who did not undergo colonoscopy as a first diagnostic step found that diagnostic angiography provided little additional clinical information because the bleeding stopped spontaneously in most patients. Moreover, angiography did not help guide subsequent surgery and was associated with a complication rate of 11%.252 

CHAPTER 20  Gastrointestinal Bleeding

CT and CT Colonography Multidetector CT can identify abnormalities in the colon that could be a source of bleeding, such as diverticulosis, colitis, masses, and varices. CT is often performed if the patient is having hematochezia with abdominal pain. One study from France reported that CT accurately identified 17 of 19 LGI bleeding sites, including diverticula, tumors, angiomas, and varices.253 Multidetector CT has been shown to be more accurate than technetium-tagged RBC scanning in patients with LGI bleeding.254 CT colonography is being used increasingly to screen persons for colonic polyps and cancer and may be of some benefit in patients with LGI bleeding (see Chapter 127). CT colonography detects large polyps (>1 cm) or cancers with a sensitivity rate of 90%.255 Faster multidetector scanners also allow CT angiography to be performed, as well as evaluation of the small bowel. This capability could allow detection of masses and vascular lesions and is a potential advantage of CT angiography over other radiologic imaging techniques. Multidetector CT has been proposed as an early diagnostic step in patients with suspected colonic bleeding to help direct colonoscopic evaluation.256 Because this approach may expose the patient to unnecessary radiation, and because nearly all patients will undergo either urgent or elective colonoscopy anyway, CT colonography is unlikely to play an important role in the acute evaluation of patients with LGI bleeding. Moreover, CT angiographic IV contrast can cause acute kidney injury in patients with renal insufficiency. 

Colonoscopy Urgent colonoscopy following a rapid bowel purge has been shown to be safe, provide important diagnostic information, and allow therapeutic intervention.236,237 Patients usually ingest 6 to 8 L of PEG solution orally or via an NG tube over 4 to 6 hours until the rectal effluent is clear of stool, blood, and clots. Metoclopramide, in a dose of 10 mg, may be given intravenously before the purge and repeated every 3 to 4 hours to facilitate gastric emptying and reduce nausea. Owing to the potential risks of high sodium and phosphate loads, sodium phosphate bowel preparations should probably be avoided in patients with suspected LGI bleeding. Urgent colonoscopy for LGI bleeding is generally performed 6 to 24 hours after the patient is admitted to the hospital. Most bleeding stops spontaneously, and thus, colonoscopy is often performed semi-electively on the day after initial hospitalization to allow the patient to receive blood transfusions and the bowel preparation on the first day of hospitalization. The overall rate of detecting a presumed or definite cause of LGI bleeding by colonoscopy ranges from 48% to 90%, with an average of 68%, based on a review of 13 studies.238 The problem with interpreting these data, however, is that making a definite diagnosis of the cause of the bleeding is often not possible unless a bleeding stigma such as active bleeding, a visible vessel, an adherent clot, a flat spot, mucosal friability or ulceration, or the presence of fresh blood limited to a specific segment of the colon is seen. The optimal time for performing urgent bowel preparation and colonoscopy is unknown. Theoretically, the sooner an endoscopy is performed, the higher the likelihood of finding a lesion (e.g., bleeding diverticulum, polyp stalk) with stigmata that might be amenable to endoscopic hemostasis. A retrospective study from the Mayo Clinic, however, suggested that in patients with diverticular bleeding, the timing of endoscopy (0 to 12 hours, 12 to 24 hours, or more than 24 hours after admission) is not significantly associated with the finding of active bleeding or other stigmata that would prompt colonoscopic hemostasis.257

301

A prospective study revealed no difference between urgent (≤12 hours after presentation) and elective (36 to 60 hours after presentation) colonoscopy in terms of further bleeding, blood transfusions, hospital days, or hospital charges.9 Early colonoscopy (soon after admission) has been associated with a shorter length of hospitalization, principally because of improved diagnostic yield rather than therapeutic intervention.258 A consensus on a single approach to patients with severe hematochezia has not been reached, and the approach used depends on local resources and expertise. In large centers, the approach detailed in Fig. 20.4 is recommended. With use of an urgent endoscopic approach for diagnosis and treatment, the diagnostic yield of definitive and presumptive bleeding sites is more than 90%, and the estimated direct costs are significantly less than the costs associated with an elective evaluation.28 

Barium Enema Emergency barium enema has no role in patients with LGI bleeding. This test is rarely diagnostic because it cannot demonstrate vascular lesions and may be misleading if only diverticula are seen. It fails to detect 50% of polyps larger than 10 mm.259 In addition, the barium contrast liquid can make urgent colonoscopy more difficult by impairing visualization and delaying other studies such as angiography. Subsequent colonoscopy is required for any suspicious lesions seen on barium enema or for lesions that require therapy. 

Role of Surgery Surgical management is rarely needed in patients with LGI bleeding because most bleeding is self-limited or easily managed with medical or endoscopic therapy. The main indications for surgery are malignancy, diffuse bleeding that fails to cease with medical therapy (as in ischemic colitis or UC), and recurrent bleeding from a diverticulum. At present, most patients are managed on a medical service rather than on a surgical service. 

Causes and Management Visualizing active bleeding during colonoscopy is not always possible, but colonoscopy permits identification of SRH (visible vessels, adherent clot, or spots) and provides information on the location of the lesion and on risk stratification. The earlier a colonoscopy is carried out, the higher the chance of detecting an actively bleeding lesion or SRH. A definite diagnosis of a bleeding lesion can usually be made if active bleeding, a visible vessel, or a clot is seen. A presumptive diagnosis of the cause of bleeding can be made if a lesion that is a potential cause of bleeding is seen and no other possible sources are identified by anoscopy, full colonoscopy with intubation of the terminal ileum, and, in some cases, push enteroscopy.28

Diverticulosis Colonic diverticula are herniations of colonic mucosa and submucosa through the muscular layers of the colon (see Chapter 121). Histopathologically, diverticula in the colon are actually pseudodiverticula because they do not contain all layers of the colonic wall. Diverticula form when colonic tissue is pushed out by intraluminal pressure at points of entry of the small arteries (vasa recta), where they penetrate the circular muscle layer of the colonic wall. The entry points of the vasa recta are areas of relative weakness through which the mucosa and submucosa can herniate when intraluminal pressure is increased.261 Diverticula vary in diameter from a few millimeters to several centimeters and are located most commonly in the left colon. Most colonic diverticula are asymptomatic and

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PART III  Symptoms, Signs, and Biopsychosocial Issues

remain uncomplicated. Bleeding may occur from vessels at the neck or base of a diverticulum.261 In our experience with definitive diverticular hemorrhage (see later), bleeding was from the base in 52% and from the neck in 48% of diverticula.262 Diverticula are common in Western countries, with a frequency of 50% in older adults.263 By contrast, diverticula are found in fewer than 1% of continental African and Asian populations.264 It has been hypothesized that the regional differences in prevalence rates can be explained by the low amount of dietary fiber in Western diets (see Chapter 121). Diverticular bleeding develops in an estimated 3% to 5% of patients with diverticulosis.265 Although most diverticula are in the left colon, several series have suggested that diverticula in the right colon are more likely to bleed.265,267,268 Two thirds of definitive diverticular bleeds (with SRH) emanate from the region of the splenic flexure of the colon or proximally.262 Diverticular hemorrhage should be classified carefully based on findings at colonoscopy, angiography, or surgery,28 particularly in the case of older patients with severe hematochezia who are likely to have colonic diverticulosis. Definitive diverticular hemorrhage is diagnosed when SRH (e.g., active bleeding, visible vessel, adherent clot) are seen on colonoscopy or active bleeding is demonstrated on angiography or radionuclide imaging, with later confirmation of a diverticulum in that location as the source of bleeding by colonoscopy or surgery. Presumptive diverticular hemorrhage is diagnosed when colonoscopy reveals diverticulosis without stigmata, and no other significant lesions are seen in the colon and by anoscopy, terminal ileum examination, and push enteroscopy. The term incidental diverticulosis is used when another lesion is identified as the cause of hematochezia, and colonic diverticulosis is evident. In a large prospective cohort study in which the management algorithm shown in Fig. 20.4 was used in our institutions to classify patients with hematochezia, colonic diverticulosis was incidental in 52%, presumptive diverticular hemorrhage occurred in 31%, and definitive diverticular hemorrhage was established in 17% of cases.237 Patients with diverticular bleeding are typically older, have been taking aspirin or other NSAID, and present with painless hematochezia.269,270 In at least 75% of patients with diverticular bleeding, the bleeding stops spontaneously, and these patients require transfusion of fewer than 4 units of packed RBCs. In one surgical series, surgical segmental colonic resection was performed in 60% of patients, most of whom had had continued bleeding despite transfusion of 4 units of blood.267 Patients who underwent resection for a bleeding diverticulum had a rebleeding rate of 4%. Among patients who stopped bleeding spontaneously, the rebleeding rate from colonic diverticulosis has been reported to range from 25% to 38% over the next 4 years, with most patients having mild rebleeding.235,267 These data, however, are not based on colonoscopic documentation of diverticular bleeding, and the

A

B

actual rate of rebleeding appears to be lower. In a large prospective cohort study of patients with documented colonic diverticular hemorrhage (definitive or presumptive) by our group, the overall rate of rebleeding was 18% in 4 years—9% from recurrent diverticular hemorrhage and 9% from other GI sources.262 Endoscopic Stigmata About one third of patients with true diverticular hemorrhage (presumptive or definitive) during urgent colonoscopy following adequate cleansing have a stigma of recent bleeding, such as active bleeding, a visible vessel, an adherent clot, or a flat spot in a single diverticulum.237,262 As noted, earlier colonoscopy for LGI bleeding is likely to result in a greater frequency of finding SRH, although a small case series study from the Mayo Clinic did not find any difference in the rate of detection of these stigmata whether colonoscopy was performed between 0 and 12 hours, 12 and 24 hours, or more than 24 hours from the time of hospital admission.257 Stratifying the risk of diverticular rebleeding by applying the same endoscopic stigmata used in high-risk peptic ulcer bleeding (active bleeding, NBVV, and clot) has been advocated. For example, as in histopathologic examination of resection specimens of bleeding ulcers with visible vessels, the pigmented protuberance found on the edge of some diverticula is an organized clot over an underlying ruptured blood vessel on histopathology (Fig. 20.19).271 The short-term natural history associated with each of these stigmata has been reported to be similar to that for stigmata associated with peptic ulcer hemorrhage.272 Of medically treated patients with active bleeding from a diverticulum, 83% (15 of 18) rebled and 56% required intervention (surgery or angiographic embolization) for hemostasis. In patients with an NBVV in a single diverticulum, the rate of rebleeding was 60% and the rate of intervention for hemostasis was 40%. In patients with an adherent clot treated medically, the rebleeding rate was 43% and the rate of intervention was 29%. For the entire group of 37 patients with these high-risk stigmata, the rebleeding rate on medical therapy was 65% and the rate of intervention was 43%. These rebleeding and intervention rates are worse than those for peptic ulcer hemorrhage because there are no drugs similar to PPIs that can be used to reduce the rebleeding risk in patients with highrisk SRH. UCLA CURE hemostasis studies using a DEP have detected underlying blood flow in 91% of patients with major SRH (active bleeding, NBVV, or adherent clot) but in no patient without these stigmata. The DEP has also been used for risk stratification of patients with flat spots in diverticula during urgent colonoscopy for hemorrhage and as a guide to the completeness of hemostasis in patients with SRH.273 With DEP guidance to obliterate blood flow, the rebleeding rates have been less than 5% in 30 days.272,273 

C

Fig. 20.19  Endoscopic stigmata of recent colonic diverticular bleeding.  A, Active bleeding (arrow). B, Adherent clot (arrow). C, Nonbleeding visible vessel (arrow).

CHAPTER 20  Gastrointestinal Bleeding

Endoscopic Hemostasis Colonoscopic hemostasis of actively bleeding diverticula has been reported using MPEC, epinephrine injection, hemoclips, fibrin glue, rubber band ligation, endoloops, or combinations of epinephrine and MPEC or hemoclips.28,271,274-278 If fresh red blood is seen in a focal segment of colon, that segment should be irrigated vigorously with water to remove the blood and identify the underlying bleeding site. If bleeding is coming from the edge of a diverticulum or a pigmented protuberance is seen on the edge, a sclerotherapy needle can be used for submucosal injection of epinephrine (diluted 1:20,000 in saline) in 1 mL aliquots into 4 quadrants around the bleeding site. Subsequently, MPEC at a low power setting (10 to 15 W) and light pressure can be carried out for a 1-second pulse duration to cauterize the diverticular edge and stop bleeding or flatten the visible vessel, or hemoclips can be applied. A nonbleeding adherent clot can be injected with 1:20,000 epinephrine into 4 quadrants, 1 mL/quadrant, after which the clot can be removed piecemeal by guillotining it with a cold polyp snare until it extends 3 mm above the diverticulum. The underlying stigma is treated with MPEC or hemoclips (see earlier). After endoscopic hemostasis of a bleeding diverticulum is completed, a permanent submucosal tattoo should be placed around the lesion to allow identification of the site in case colonoscopy is repeated or surgery is performed for recurrent bleeding. After colonoscopic hemostasis, patients should be told to avoid aspirin and other NSAIDs and take a daily fiber supplement on a longterm basis. In 2000, Jensen and the UCLA CURE group published their results on urgent colonoscopy for the diagnosis and treatment of severe diverticular hemorrhage28 and reported that 20% of patients with severe hematochezia had endoscopic stigmata, suggesting a definitive diverticular bleed. This group of patients, who underwent colonoscopic hemostasis, had a rebleeding rate of 0% and an emergency hemicolectomy rate of 0%, compared with 53% and 35%, respectively, in a historical control group of patients who had high-risk stigmata but did not undergo colonoscopic hemostasis. No rebleeding had occurred after 3 years of follow-up in the patients who underwent colonoscopic ­hemostasis. In another report from the UCLA CURE group of 63 patients with definitive diverticular hemorrhage who were treated with endoscopic hemostasis, the rebleeding rate was 4.8%, and the rate of surgery or angiographic embolization for rebleeding was only 3.2%.273 The investigators carried out treatment with injection of epinephrine and hemoclipping of the SRH in the base of the diverticulum (and on either side of a stigma to obliterate the underlying arterial blood flow) and injection of epinephrine and MPEC of SRH at the neck. Approximately 50% of the diverticular SRH were located at the neck and 50% at the base; more than 55% of the diverticula with SRH were found at or proximal to the splenic flexure. Complete hemostasis was documented with a DEP by absence of blood flow after treatment, and absence of blood flow correlated with lack of rebleeding. A 2012 study from Japan of 87 patients who underwent endoscopic clip placement at the mouth of a diverticulum for acute bleeding revealed a 34% early rebleeding rate, with the majority of rebleeding episodes occurring from diverticula located in the ascending colon.279 The high rebleeding rate in this study279 can be explained by the vascular anatomy of colonic diverticula and the placement of hemoclips away from SRH that lie in the base of a diverticulum. Because there is bidirectional arterial flow in diverticula and an arcade of 2 different arteries, treating with hemoclips at the neck of the diverticulum when the SRH is in the base will not seal the artery under the stigma; therefore rebleeding rates would be expected to be high. The acute rebleeding rate in this study279 is similar to that for the medically treated patients in a report from UCLA CURE of the natural history of

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diverticular bleeding in which 65% of patients rebled and 43% required surgery or interventional radiology.272 Endoscopic band ligation has also been reported as treatment of colonic diverticular hemorrhage. A 2012 study from Japan of 29 patients showed that band ligation was successful and safe, with an 11% rate of early rebleeding and the need for surgical resection in only one patient with bleeding from an ascending colon diverticulum.280 Owing to the potential risk of full-thickness wall entrapment in the right colon, however, band ligation may increase the risk of perforation.281 Diverticulitis has also been reported after band ligation. In a Japanese study, banding was reported to yield lower rebleeding rates than hemoclipping;282 however, many of the patients were treated by remote hemoclipping treatment, that is, placement of the clips at the neck for diverticular closure when the bleeding point was in the base of the diverticulum.  Angiography and Surgery Angiographic embolization can be performed in selected cases of diverticular bleeding, but with a risk of bowel infarction, contrast dye reactions, and acute kidney injury. One study found that routine angiography prior to surgical resection is not helpful in reducing the overall risk of complications.252 Surgical resection for diverticular bleeding is rarely needed and is reserved for recurrent bleeding. The decision to operate is best guided by colonoscopic, angiographic, or radionuclide imaging studies that demonstrate the likely segment of colon from which the bleeding is emanating, and by the presence of medical comorbidities. Diverticular bleeding is usually mild in patients without major SRH, and the risk of surgical complications is increased in older patients. Blind subtotal colectomy, often performed in the past when a definite bleeding site could not be identified, should be avoided if possible. 

Colitis The term colitis refers to any form of inflammation of the colon. Severe LGI bleeding may be caused by ischemic colitis, IBD, or infectious colitis. Ischemic colitis can present as painless or painful hematochezia with mild left-sided abdominal discomfort (see Chapter 118). The painless subtype usually results from mucosal hypoxia and is thought to be caused by hypoperfusion of the intramural vessels of the intestinal wall, rather than by large-vessel occlusion or embolization, which is often painful and clinically more severe with worse outcomes. The incidence of ischemic colitis is estimated to be 4.5 to 44 cases/100,000 person-years.283 Most cases do not have a recognizable cause. Risk factors associated with ischemic colitis have been reported to include older age, shock, cardiovascular surgery, heart failure, chronic obstructive pulmonary disease, ileostomy, colon cancer, abdominal surgery, IBS, constipation, laxative use, oral contraceptive use, and use of an H2RA.283-286 The superior mesenteric artery supplies blood to the right colon (cecum, ascending colon, hepatic flexure, proximal transverse colon, and midtransverse colon), whereas the inferior mesenteric artery supplies blood to the left colon (distal transverse colon, splenic flexure, descending colon, sigmoid colon, and rectum). The colon has an abundant blood supply, but the watershed area between the superior and inferior mesenteric arteries has the fewest collateral vessels and is at most risk for ischemia. The colon normally receives 10% to 35% of cardiac output, and ischemia can occur if blood flow decreases by more than 50%. Although ischemia is most likely to occur in the watershed area of the splenic flexure, it can occur anywhere in the colon.287 The diagnosis of ischemia is usually made by colonoscopy, but in severe cases of large-vessel ischemia, “thumbprinting” may be noted on plain films or colonic wall thickening on CT.

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The colonoscopic appearance of the mucosa includes erythema, friability, and exudate. Mucosal biopsy specimens may suggest ischemic changes but are generally used to exclude infectious or Crohn colitis. Ischemic colitis usually resolves in a few days and generally does not require colonoscopic hemostasis or antibiotic therapy. In the UCLA CURE experience, approximately 10% of patients with ischemic colitis and severe hematochezia had a focal ulcer with a major stigma of hemorrhage on urgent colonoscopy.288 After detection of arterial blood flow with DEP, the recommended treatment in these cases is epinephrine injection and hemoclipping, similar to that for other ulcers. In a large retrospective series from Kaiser, no episodes of rebleeding from ischemic colitis occurred over a 4-year follow-up period.235 On the other hand, patients with large-vessel mesenteric ischemia usually have worse outcomes, including higher rates of rebleeding, perforation, surgery, and death. IBD that involves the colon can rarely cause severe acute LGI bleeding (see Chapter 115). In a case series from the Mayo Clinic, most of these patients had Crohn disease, and most were successfully treated medically.289 Three of the 31 patients in this series underwent endoscopic therapy with epinephrine injection alone or with MPEC for an adherent clot or an oozing ulcer. These 3 patients had no rebleeding, but 23% of the other 28 patients had rebleeding at a median of 3 days (range, 1 to 75 days) after the initial bleed; 39% of the patients with severe bleeding eventually required surgery. Infectious colitis should be excluded in any patient with severe LGI bleeding and colitis (see Chapters 110 and 112). LGI bleeding can occur with infection caused by Campylobacter jejuni, Salmonella, Shigella, enterohemorrhagic Escherichia coli (O157:H7), CMV, or Clostridiodes difficile. Significant blood loss is rare except in patients with severe coagulopathy. The diagnosis is made by stool cultures and flexible sigmoidoscopy or colonoscopy. Treatment is with medical management; the use of antibiotics depends on the causative organism. Endoscopic management generally has no role in infectious colitis. 

Postpolypectomy Bleeding Painless bleeding occurs after approximately 1% of colonoscopic polypectomies. It is most common 5 to 7 days after polypectomy but can occur from 1 to 14 days after the procedure. It is generally self-limited and mild to moderate, with 50% to 75% of patients requiring blood transfusions.290-293 Reported risk factors for postpolypectomy bleeding include a large polyp size (>2 cm), thick stalk, sessile type, location in the right colon, use of anticoagulants, and use of aspirin or another NSAID. During urgent colonoscopy of patients with severe delayed postpolypectomy bleeding, an ulceration with a major stigma of hemorrhage is usually found at the site of the polypectomy (Fig. 20.20). In patients with severe bleeding in whom a SRH is found in the ulceration,294,295 a DEP can be used to detect underlying arterial blood flow and the need for endoscopic hemostasis. Endoscopic management techniques for delayed postpolypectomy bleeding depend on the stigma found and are similar to those used for peptic ulcer hemorrhage, including epinephrine injection, thermal coagulation, hemoclip placement, and combination therapy. Most major SRH in postpolypectomy ulcers are treated with hemoclipping (with or without epinephrine injection) because hemoclips do not cause tissue damage, as is seen with thermal coagulation. 

Colon Neoplasia Patients with colon polyps and cancer can present with acute hematochezia. Often, these patients have a microcytic iron deficiency anemia consistent with slow GI blood loss (see later) before more overt bleeding occurs. Colonic neoplasia was the eighth most common cause of severe hematochezia in a large CURE series.296 At colonoscopy, epinephrine can be injected into the

Fig. 20.20  Endoscopic appearance of postpolypectomy bleeding in the colon. Bleeding occurred 7 days after snare polypectomy of a large pedunculated polyp. Note the nonbleeding visible vessel (arrow) in the ulcerated polypectomy site.

lesion to slow active bleeding, and hemoclips can be applied to treat SRH on ulcerated lesions that cannot be resected endoscopically. Hemostatic powder may have a palliative role in reducing acute bleeding, prior to definitive treatment (see earlier).43When possible, colon polyps can be removed to stop bleeding. Surgical resection is usually required to prevent rebleeding from a large, ulcerated sessile lesion (see Chapters 126 and 127); however, most patients with colon polyps or cancer and severe hematochezia have advanced stage disease and high early mortality and should be considered for nonsurgical therapies.296 

Radiation Proctitis Radiation proctitis usually causes mild chronic hematochezia but occasionally can cause acute severe LGI bleeding. Ionizing radiation can cause acute and chronic damage to the normal colon and rectum when used to treat pelvic tumors—gynecologic, prostatic, bladder, or rectal (see Chapter 41). Acute self-limited diarrhea, tenesmus, abdominal cramping, and, rarely, bleeding develops for a few weeks in approximately 75% of patients who have received a radiation dose of 4000 cGy. Chronic radiation effects occur 6 to 18 months after completion of treatment and manifest as bright red blood with bowel movements. Bowel injury resulting from chronic radiation is related to vascular damage, with subsequent mucosal ischemia, thickening, and ulceration. Much of this damage is thought to result from chronic hypoxic ischemia and oxidative stress. Flexible sigmoidoscopy or colonoscopy reveals telangiectasias, friability, and sometimes ulceration in the rectum (Fig. 20.21). Oozing bleeding is common, and often other nonbleeding rectal telangiectasias are seen. Internal hemorrhoids are often seen as well and are frequently misdiagnosed as the cause of the rectal bleeding by those unfamiliar with radiation telangiectasias. Treatment initially focuses on avoidance of aspirin and other NSAIDs, consumption of a high-fiber diet, and iron supplementation if the patient is anemic. Medical therapy with topical or oral 5-aminosalicylic acid (mesalamine), sucralfate, or glucocorticoids may be prescribed but are not generally effective.297 Thermal therapy is usually successful, but repeated treatments with MPEC or argon plasma coagulation are necessary to achieve good outcomes.289 Topical formalin applied directly to the rectal mucosa can reduce bleeding,299 as can the use of hyperbaric oxygen.300 Antioxidant vitamins, such as vitamins E and C, have also been reported to decrease bleeding from chronic radiation proctitis (see Chapter 41).301 

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techniques. A topical calcium channel blocker (e.g., 2% topical diltiazem cream) and control of constipation with fiber supplementation and stool softeners plus sitz baths will heal most anal fissures (see Chapter 129). 

Rectal Varices

Fig. 20.21  Endoscopic appearance of radiation proctitis. Note diffuse oozing and telangiectasias.

Colonic Angioectasia

Ectopic varices may develop in the rectal mucosa between the superior hemorrhoidal veins (portal circulation) and middle and inferior hemorrhoidal veins (systemic circulation) in patients with portal hypertension. On sigmoidoscopy, rectal varices are seen during retroflexion as venous structures located several centimeters above the dentate line and extending into the rectum. They are distinct from internal hemorrhoids. The frequency of rectal varices increases with the degree of portal hypertension. Approximately 60% of patients with a history of bleeding esophageal varices have rectal varices, but they are a rare cause of severe hematochezia.27,230,294 The treatment of bleeding rectal varices is similar to that for esophageal varices, with sclerotherapy, band ligation, or a portosystemic shunt (see Chapter 92).303-305 

Rectal Dieulafoy Lesions

Colonic bleeding from angioectasia, an important cause of LGI bleeding in the older adults, is discussed in the section on small bowel and obscure bleeding (see later). When angioectasia is the cause of bleeding in the colon, the lesions are often multiple, making endoscopic hemostasis a challenge (see also Chapter 38). 

Dieulafoy lesions are large submucosal arteries without overlying mucosal ulceration that can cause massive bleeding. They can occur anywhere in the GI tract, although usually in the foregut (see earlier). Bleeding Dieulafoy lesions in the rectum, which have been treated successfully with endoscopic hemostasis, have been described in several reports.179,306 

Internal Hemorrhoids

Rectal Ulcers

Hemorrhoidal bleeding is painless and characterized by bright red blood per rectum that can coat the outside of the stool, drip into the toilet bowl, be seen on tissue after wiping, and often appear as a large amount of fresh blood in the toilet. Usually, bleeding is mild, intermittent, and self-limited but, occasionally, severe transfusion-requiring bleeding may occur from hemorrhoids.302 In a large study of patients with hematochezia discharged from the hospital, 20% were thought to have had bleeding from hemorrhoids.240 In the UCLA CURE series of patients hospitalized for severe hematochezia (see earlier), internal hemorrhoids were the second most common cause (see Table 20.8).237 Hemorrhoids were documented by urgent anoscopy and colonoscopy after a colonic cleansing preparation. The diagnosis can be made with anoscopy, sigmoidoscopy, or colonoscopy, especially if performed while bleeding is ongoing. The treatment of internal hemorrhoids usually starts with medical therapy consisting of fiber supplementation, stool softeners, lubricant rectal suppositories (with or without glucocorticoids), and warm sitz baths. Anoscopic therapy can also be used and includes injection sclerotherapy, rubber band ligation, cryosurgery, infrared photocoagulation, MPEC, and direct current electrocoagulation. Although most patients with mild hemorrhoidal bleeding respond to medical therapy, those with severe or recurrent bleeding are likely to require rubber band ligation, some other endoscopic treatment, or, if these measures fail, surgery (see Chapter 129). 

Several case series have described seriously ill hospitalized patients with the sudden onset of painless severe hematochezia from a solitary or multiple rectal ulcer(s) located 3 to 10 cm above the dentate line. In one series of 19 cases from Taiwan, 2.7% of patients evaluated for severe hematochezia were diagnosed with acute hemorrhagic rectal ulcer syndrome.307 The patients had a mean age of 71 years and had been hospitalized for other medical problems from 3 to 14 days (average 7.5 days) prior to the onset of bleeding. All developed hypotension and required transfer to an ICU and blood transfusions. Colonoscopy revealed an equal number of cases of multiple and solitary ulcers located 1 to 7 cm from the dentate line; most of the ulcers were large (more than 1 cm) and circumferential or geographic in appearance. The patients were treated with combinations of thermal coagulation, injection therapy, and suture ligation and had a mortality rate of 26% because of multiorgan failure. The pathology of the lesions revealed necrosis suggestive of mucosal ischemia, as seen with gastric stress ulcers (see earlier). This entity appears to be a different disease from solitary rectal ulcer syndrome, colitis cystica profunda, infectious ulcers, radiation ulcer, NSAID ulcers, or constipation-induced stercoral ulcer and can be considered a type of stress ulcer of the rectum, similar to that seen in the duodenum, in extremely ill, hospitalized patients (see Chapter 128). Solitary or multiple painless rectal ulcers were the third most common cause of severe hematochezia developing in inpatients in the UCLA CURE study (see Table 20.8). In contrast to solitary rectal ulcer syndrome, they occur in older patients with severe constipation, ICU patients, and persons who are bedridden. On colonoscopy, ulcers are chronic-appearing, large, and single or multiple. They often have SRH and can be treated endoscopically (Fig. 20.22).308 Patients with inpatient hematochezia from a rectal ulcer have a higher rate of rebleeding than those who present from home. For acute hemostasis of large, firm ulcers with stigmata, treatment with OTSC hemoclips is recommended. 

Anal Fissures Patients with an anal fissure usually present with constipation followed by painful bowel movements with or without hematochezia. The hematochezia is usually mild and is noticed with wiping; rarely, hematochezia is moderate to severe. Treatment focuses on healing the anal fissure, rather than using specific hemostasis

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BOX 20.2 Causes of Obscure GI Bleeding UPPER GI TRACT Cameron lesions Dieulafoy lesions GAVE  SMALL INTESTINE Angioectasia Aortoenteric fistula Dieulafoy lesion Diverticulosis Meckel diverticulum Neoplasm Pancreatic or biliary disease Ulceration  Fig. 20.22  Endoscopic appearance of bleeding from a solitary rectal ulcer with a visible vessel (arrow) seen on a retroflexed view.

OBSCURE OVERT GASTROINTESTINAL BLEEDING Obscure GI bleeding is traditionally defined as GI bleeding of uncertain cause after a nondiagnostic EGD, colonoscopy, and barium small bowel follow-through.309 Obscure GI bleeding may have an overt or occult presentation. Obscure overt GI bleeding refers to visible acute GI bleeding (e.g., melena, maroon stool, hematochezia) in patients with a nondiagnostic EGD, colonoscopy, and small bowel series. Obscure occult GI bleeding refers to a positive FOBT result, usually in association with unexplained iron deficiency anemia. In most large series, the cause of bleeding is not found on EGD and colonoscopy in 5% of hospitalized patients with overt GI bleeding. In 75% of these patients, a bleeding site is located in the small intestine. In patients with obscure GI bleeding, the following possibilities exist: (1) the lesion was within reach of a standard endoscope and colonoscope but not recognized as the bleeding site (e.g., Cameron lesions, angioectasias, internal hemorrhoids); (2) the lesion was within reach of the endoscope and colonoscope but was difficult to visualize (e.g., a blood clot obscured visualization of the lesion; varices became inapparent in a hypovolemic patient; a lesion was hidden behind a mucosal fold) or presented with intermittent bleeding (e.g., Dieulafoy lesion, angioectasias); or (3) the lesion was in the small intestine beyond the reach of standard endoscopes (e.g., neoplasm, angioectasias, Meckel diverticula). In several series, 50% or more patients referred to a tertiary medical center for evaluation of obscure bleeding were found to have a lesion within reach of standard endoscopes (i.e., a missed lesion or difficult-to-see lesion that accounted for the bleeding) (Box 20.2).310 In a patient with recurrent severe unexplained hematochezia without hypotension, a colonic source should be suspected, and a repeat colonoscopy with a good colon preparation by an experienced endoscopist is warranted. Colonic lesions that can bleed profusely and then stop, such as diverticulosis or hemorrhoids, should be considered. In patients with recurrent severe melena, push enteroscopy to re-examine the esophagus, stomach, and duodenum, as well as the proximal jejunum, for a missed or unrecognized lesion should be considered. Duodenoscopy may be useful for blood or lesions in the second to fourth portions of the duodenum.57 Once it is certain that a bleeding lesion in the UGI or LGI tract was not missed, the evaluation should focus on the small intestine. In the past, the principal imaging modality of the small intestine was barium radiography, but this technique was limited by the length, mobility, and motility of the small bowel and by overlying loops of bowel. Because small bowel bleeding is often intermittent, radionuclide imaging or angiography has limited value in the diagnostic evaluation. Since the late 1990s, diagnostic

COLON Angioectasia Diverticulosis Hemorrhoids *After exclusion of common causes of UGI bleeding.

options for evaluating the small intestine have expanded greatly and have been revolutionized by the development of new small bowel imaging techniques, including wireless video capsule endoscopy, deep enteroscopy, and CT enterography, which now allow greater visualization and more therapeutic options than in the past (see later).311

Causes A number of lesions can cause obscure GI bleeding (see Box 20.2). In persons younger than age 40, bleeding is more likely to be caused by a tumor, Meckel diverticulum, or Crohn disease. Angioectasias or an NSAID-induced ulcer are common causes in persons 40 years of age and older.

Angioectasia A variety of vascular lesions may cause bleeding from the GI tract (see Chapter 38). Angioectasia, also referred to as angiodysplasia, is the formation of aberrant blood vessels found throughout the GI tract that develop with advancing age. The lesions are distinct from arteriovenous malformations (AVMs), which are congenital, and angiomas, which are neoplastic. Telangiectasia is the lesion that results from dilatation of the terminal aspect of a blood vessel. Any of the vascular lesions may cause overt or obscure GI bleeding in adults, particularly in older adults and those who take antiplatelet and anticoagulant drugs. Acquired vascular lesions (angioectasia and telangiectasia) occur in association with various disorders, such as chronic kidney disease, cirrhosis, rheumatologic disorders, and severe heart disease.57 Although angioectasia may present as overt bleeding, they often manifest as occult bleeding or iron deficiency anemia. The most common locations are the colon and small intestine. The histopathology of angioectasias in the colon is characterized by ectatic, dilated submucosal veins.312,313 A proposed mechanism for their formation in the colon is that partial, intermittent, low-grade obstruction of submucosal veins during muscular contraction and distention of the cecum results in dilatation and tortuosity of the submucosal veins. Over time, the increased pressure also results in dilatation of the venules, capillaries, and arteries of the mucosal vasculature. Finally, precapillary sphincters can become incompetent, thereby causing arteriovenous communications to develop and possibly result in local mucosal

CHAPTER 20  Gastrointestinal Bleeding

ischemia. Because angioectasia can occur elsewhere in the GI tract, other mechanisms are postulated, including a response to mucosal irritation or local ischemia, as occurs after radiation. Most angioectasias occur in patients older than 60 years of age and can involve any segment of the GI tract. Usually, the lesions are multiple in a given segment of intestine. Approximately 20% (and probably more) of patients have angioectasias in at least 2 sections of the GI tract.314,315 In studies of asymptomatic persons who underwent colonoscopy, angioectasias were found in 1% to 3%.316,317 In these persons, the angioectasias were mostly in the right colon, with the following distribution: cecum, 37%; ascending colon, 17%; transverse colon, 7%; descending colon, 7%; sigmoid colon, 18%; and rectum, 14%. Among asymptomatic persons found incidentally to have colonic angioectasia, no bleeding occurred during a 3-year follow up. Several conditions appear to be associated with an increased frequency of angioectasia. Patients with chronic kidney disease and uremia have an increased rate of intestinal angioectasias. A study of patients with and without chronic kidney disease who had obscure GI bleeding found angioectasia as the presumptive source in 47%, compared with 18% of those without kidney disease.318 The increased risk of bleeding from angioectasia in patients with chronic kidney disease may be associated with uremia-induced platelet dysfunction. von Willebrand disease (congenital or acquired) has also been associated with bleeding angioectasia.319 von Willebrand’s factor is needed for effective platelet aggregation. A well-controlled prospective study found that almost all patients with bleeding UGI and colonic angioectasias, as opposed to nonbleeding angioectasias or bleeding diverticulosis, had acquired von Willebrand disease associated with selective loss of the largest multimeric forms of von Willebrand factor, as well as with aortic stenosis.320 Because the large von Willebrand multimers promote primary hemostasis in a microcirculation characterized by high shear forces, as occurs in angioectasia, the loss of the large multimers may explain why bleeding occurs in some patients with angioectasias. Aortic stenosis has been associated with GI bleeding from angioectasia (Heyde syndrome).321 This association is controversial because both conditions are common, and an association may not imply cause and effect.322 Nevertheless, aortic stenosis has been shown to be associated with an acquired form of von Willebrand disease in 67% to 92% of patients because of mechanical

A

disruption of von Willebrand proteins during passage through the stenotic aortic valve; the acquired von Willebrand disease, in turn, increases the risk of bleeding from angioectasia.323,324 Several series have reported cessation of bleeding from angioectasia after aortic valve replacement, even though the angioectasias persisted, an observation consistent with the hypothesis that bleeding was the result of the damaged von Willebrand factors that normalized after aortic valve replacement.325 Overt or obscure GI bleeding occurs in approximately 20% of patients with a left ventricular assist device, especially in older patients, with angioectasia as one of the most frequent causes of bleeding.326-328 Possible pathophysiologic mechanisms for angioectasia formation and bleeding include loss of von Willebrand factor related to shear stress, which results in impaired platelet aggregation, and intestinal hypoperfusion related to increased vascular luminal pressure and lowered pulse pressure.328 Because many older persons with bleeding from intestinal angioectasia have cardiovascular disease but not severe aortic stenosis, other cardiovascular disorders such as mild to moderate aortic stenosis, aortic sclerosis, hypertrophic cardiomyopathy, and peripheral vascular disease may result in sufficiently high shear stress to disrupt von Willebrand factors and contribute to bleeding angioectasias.325 On endoscopy, an angioectasia appears as a 2 to 10 mm red lesion, with arborizing ectatic blood vessels that emanate from a central vessel (Fig. 20.23). Application of pressure on an angioectasia with an endoscopic probe may cause the lesion to blanch. One study has suggested that sedation of a patient with a narcotic during endoscopy can make visualization of angioectasia difficult because of transient mucosal or submucosal hypoperfusion, which leads to decreased filling or causes vasoconstriction, and that reversal with naloxone, an opioid antagonist, can make the angioectasia more prominent.329 In practice, however, this maneuver is unlikely to be useful clinically and might make the patient more uncomfortable. Angioectasias can be treated endoscopically with various modalities, including epinephrine injection, thermal probe coagulation, argon plasma coagulation, hemoclips, and band ligation. Assessing efficacy can be difficult, given the heterogeneity of affected patients and intermittent nature of the blood loss. One series of 16 patients with transfusion-requiring bleeding from angioectasia found no difference in the frequency of continued bleeding (50%) whether treatment was with surgery, endoscopic therapy, or blood transfusions alone, presumably because of the

B Fig. 20.23 Endoscopic appearance of jejunal angioectasia before (A) and after (B) multipolar probe electrocoagulation.  

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diffuse locations of the angioectasias.330 In another study of 33 patients with iron deficiency anemia and small bowel angioectasias seen on push enteroscopy, no changes in clinical or endoscopic findings were found in most patients 1 year after endoscopic therapy.331 By contrast, in another study of patients with GI bleeding suspected from small bowel angioectasia, treatment with electrocoagulation led to a significant decrease in (but not elimination of) the need for blood transfusions compared with observation alone.332 In a pilot study of double-balloon enteroscopy, endoscopic treatment was performed in approximately one half of patients with angioectasia, and rebleeding rates during follow up were similar in the treated and nontreated patients.333 In a small case series, hormonal therapy with estrogen was suggested to have a benefit in controlling bleeding from telangiectasia in patients with chronic kidney disease.334 Case reports have suggested that estrogen also decreases bleeding in patients with HHT (Osler-Weber-Rendu disease [see later]) and von Willebrand disease. A multicenter randomized controlled trial involving 72 patients, however, found no difference between an estrogen-progesterone combination and placebo in the rates of rebleeding, which were 39% and 46%, respectively.335 Therefore routine use of hormones for managing bleeding from angioectasia cannot be recommended. Thalidomide is an angiogenesis inhibitor that may be effective in selected patients with vascular malformations. A randomized trial that compared thalidomide with oral iron in patients with angiodysplasia or GAVE revealed that thalidomide-treated patients experienced a significant decrease in the number of bleeding episodes, transfusions, and hospitalizations and in vascular endothelial growth factor levels.336 Until these data are confirmed, however, caution is required in the use of thalidomide, given its potential for serious side effects including birth defects. Most patients with intermittently bleeding GI angioectasia require medical treatment in addition to endoscopic hemostasis. Medications that can exacerbate chronic low-level bleeding (in particular, aspirin, other NSAIDs, warfarin, other antiplatelet agents such as clopidogrel, and direct-acting oral anticoagulants) should be avoided or at least minimized. Many patients can be managed with chronic administration of iron (orally or intravenously) and, occasionally, those with renal insufficiency may need erythropoietin injections as well to maintain adequate blood counts, despite ongoing bleeding. 

HHT HHT, also known as Osler-Weber-Rendu disease, is a hereditary condition characterized by diffuse telangiectasias and large AVMs (see also Chapters 38 and 85). The most striking clinical feature is telangiectasias on the lips, oral mucosa, and fingertips. Additionally, up to one third of patients have pulmonary, hepatic, or cerebral AVMs (see Chapter 85). Patients generally present with recurrent severe nosebleeds, GI bleeding, and iron deficiency anemia. Usually the epistaxis, rather than GI bleeding, causes the more profound blood loss and anemia. HHT can be life-threatening because of embolic strokes or brain abscesses related to the pulmonary and cerebral AVMs. Symptoms of HHT generally develop in childhood or early adulthood. HHT is inherited as an autosomal dominant trait, with varying phenotypic expression. Mutations occur in at least 4 genes (ENG [encodes endoglin, type 1 HHT or HHT1], ALK-1 [encodes activin receptor-like kinase 1, type 2 HHT or HHT2], SMAD4, and HHT3) that encode proteins needed to maintain the integrity of the vascular endothelium; defects in these proteins allow the formation of AVMs. The diagnosis of HHT is based on 4 criteria: (1) spontaneous and recurrent epistaxis, (2) multiple mucocutaneous telangiectasias, (3) visceral AVMs (GI, pulmonary, brain, liver), and

(4) a first-degree relative with HHT.337 Genetic testing to detect mutations in the ENG, ALK-1, or SMAD4 genes may be helpful in selected cases. Patients suspected of having HHT should be screened for cerebral and pulmonary AVMs, and family members of the patient should consider genetic testing. Telangiectasias can occur anywhere in the small intestine in patients with HHT. In a case series in which capsule endoscopy was performed in 32 patients with and 48 patients without HHT who were being evaluated for small bowel bleeding, small bowel telangiectasias were found in 81% of patients with HHT compared with 29% of those without HHT.338 The telangiectasias were evenly distributed throughout the small bowel, but all actively bleeding lesions were found in the duodenum or proximal jejunum and within reach of a standard push enteroscope. The detection of 5 or more telangiectasias had a sensitivity of 75% and a positive predictive value of 86% for a diagnosis of HHT. The treatment of HHT is generally focused on the control of acute bleeding (epistaxis and GI bleeding), prevention of rebleeding, and treatment of anemia (with iron supplements). Patients with GI bleeding should undergo endoscopy (or push enteroscopy) and colonoscopy to look for any GI tract lesions that may be bleeding. Focal GI tract bleeding can be treated with endoscopic coagulation. Hormonal therapy has also been reported as a treatment for small bowel bleeding in HHT.339 Patients who have symptomatic or large cerebral or pulmonary AVMs should be considered for radiologic embolization of these lesions (see Chapter 38). 

Blue Rubber Bleb Nevus Syndrome Blue rubber bleb nevus syndrome is rare and characterized by venous malformations in the skin, soft tissues, and GI tract.340,341 Bleeding usually occurs in childhood and continues into adulthood and results in chronic iron deficiency requiring iron replacement and transfusions. On endoscopy, lesions appear as large protuberant polypoid blue venous blebs; they can occur anywhere in the GI tract, but especially in the small bowel and colon, and can be treated by endoscopic band ligation or surgical resection (see Chapter 38). 

Meckel Diverticulum A Meckel diverticulum is a congenital, blind, intestinal pouch that results from incomplete obliteration of the vitelline duct during gestation (see Chapter 98).342 Characteristic features of Meckel diverticula have been described by the “rule of 2s”: they occur in 2% of the population, are found within 2 feet of the ileocecal valve, are 2 inches long, result in a complication in 2% of cases, have 2 types of ectopic tissue (gastric and pancreatic) within the diverticulum, present clinically most commonly at age 2 (with intestinal obstruction), and have a male-to-female ratio of more than 2:1. The most common complications of Meckel diverticula are bleeding, obstruction, and diverticulitis, which can occur in children or adults. Histopathologic evaluation of bleeding diverticula reveals ectopic gastric mucosa, which can lead to acid secretion and ulceration in up to 75% of patients. The diagnostic test for a Meckel diverticulum is a 99mTc-pertechnetate scan (Meckel scan) because technetium pertechnetate has an affinity for gastric mucosa. Meckel scans have a high specificity (almost 100%) and positive predictive value but can be negative in the 25% to 50% of patients in whom the diverticulum does not contain ectopic gastric mucosa.343 The accuracy of the Meckel scan can be improved with administration of an H2RA for 24 to 48 hours before the test. Meckel diverticula also have been diagnosed by CT enterography, capsule endoscopy, or double-balloon enteroscopy (via an oral or rectal approach). 

CHAPTER 20  Gastrointestinal Bleeding

NSAID–Induced Small Intestinal Erosions and Ulcers Mucosal erosions or ulcers that can be seen on capsule endoscopy develop in 25% to 55% of patients who take full-dose nonselective NSAIDs.344-348 Patients who take selective COX-2 inhibitors have lower rates of mucosal ulcers on capsule endoscopy (see Chapter 119). 

Small Intestinal Neoplasms Tumors of the small intestine comprise only 5% to 7% of all GI tract neoplasms but are the most common cause of obscure GI bleeding in patients younger than age 50.349 The most common small intestine neoplasms are adenomas (usually duodenal), adenocarcinomas (Fig. 20.24), carcinoid tumors (usually ileal), GISTs, lymphomas, hamartomatosis polyps (Peutz-Jeghers syndrome), and juvenile polyps (see Chapters 32 to 34, 125, and 126). 

Small Intestinal Diverticula The duodenum is the most common site of small intestinal diverticula. In one large series,350 79% of small intestinal diverticula occurred in the duodenum, 18% were in the jejunum or ileum, and only 3% were in all 3 segments—duodenum, jejunum, and ileum. Duodenal diverticula are noted in up to 20% of the population, with an increasing frequency with age.350-353 They are usually located along the medial wall of the second part of the duodenum within 1 to 2 cm of the ampulla of Vater. Bleeding from a duodenal diverticulum is rare. Several reports have described bleeding from a duodenal diverticulum that was managed endoscopically.353,354 Jejunal and ileal diverticula occur in 1% to 2% of the population, are most commonly associated with scleroderma, another motility disorder, or SIBO, and only rarely have been associated with bleeding (see Chapters 26, 37, and 105). 

Dieulafoy Lesion of the Small Intestine Several reports have described Dieulafoy lesions of the duodenum, jejunum, and ileum (see Chapter 38).355 Most affected persons are younger than age 40, in contrast to those with gastric Dieulafoy lesions, who tend to be older (see earlier). The lesions are often challenging to find, and in the past were detected by angiography and intraoperative endoscopy. Capsule endoscopy can also localize and diagnose these lesions, which can be treated via a single- or double-balloon enteroscope. 

Fig. 20.24  Ileal adenocarcinoma detected on deep enteroscopy in a patient with a history of hereditary nonpolyposis colorectal cancer who had obscure overt GI bleeding. The lesion was initially visualized on a capsule endoscopy study.

309

Diagnostic Tests Imaging Barium small bowel follow-through is no longer utilized because it has a low yield for determining the cause of obscure GI bleeding (with limited ability to distend the bowel and visualize mucosal lesions such as angiodysplasia). Barium studies are not recommended for patients with acute bleeding; residual barium contrast in the GI tract can make urgent endoscopy, colonoscopy, or angiography more difficult to perform. CT of the abdomen has the advantage of imaging extraluminal structures as well as mucosal and intramural lesions in the small bowel. High-quality abdominal CT (with and without oral contrast) can show thickening of the small bowel, suggestive of Crohn disease or malignancy. Standard CT is less accurate than barium enteroclysis for the diagnosis of low-grade bowel obstruction, mucosal ulcerations, and fistulas. CT enteroclysis using a multidetector scanner provides better views of the small intestine than standard CT. Because placement of a nasoduodenal tube is usually required, patients sometimes receive moderate sedation for CT enteroclysis.356 CT enterography with a high volume of an oral contrast agent to distend the small bowel may have a diagnostic yield similar to that for CT enteroclysis, without the need for a nasoduodenal tube. MRI enteroclysis and enterography have also been described, but preliminary studies suggest that results to date are inferior to those with a multidetector CT. MRI techniques have the advantage of not exposing the patient to radiation. Nuclear medicine studies and angiography can be used to evaluate obscure GI bleeding. A Meckel (99mTc-pertechnetate) scan can be useful for the diagnostic evaluation of a Meckel diverticulum, particularly in younger patients, as discussed earlier. Radionuclide scanning with technetium-labeled RBCs has limited utility because of its poor ability to localize the bleeding site in the small bowel. Angiography can be useful for patients with active, acute small bowel bleeding because of the possibility of therapeutic embolization. Small case series have described provocative angiography, in which heparin or another anticoagulant is administered to provoke GI bleeding that has been intermittent. The technique increases the yield of detecting a bleeding lesion but at the risk of causing a life-threatening complication.357 

Endoscopy Push Enteroscopy Push enteroscopy can be performed with a colonoscope (160 to 180 cm in length) or dedicated push enteroscope (220 to 250 cm in length).358 These endoscopes can be used to evaluate the esophagus, stomach, duodenum, and proximal jejunum approximately 50 to 150 cm beyond the ligament of Treitz. Insertion is often limited by looping of the endoscope in the stomach. Push enteroscopy identifies a potential bleeding site in 50% or more patients, and roughly 50% of lesions found are within reach of a standard upper endoscope, suggesting that the lesion was missed or unrecognized on the initial examination.309,310,358 The overall diagnostic yield of push enteroscopy is approximately 40%, with a range of 3% to 80% in various studies; the most commonly detected lesions are angioectasias.309 In the UCLA CURE hemostasis experience in patients with recurrent severe, obscure, overt GI bleeding manifesting as melena, the diagnostic yield has been 80%.57 The lesions were categorized as those missed by EGD, those in the duodenum (first to fourth portion), and those in the jejunum; most lesions were within reach of a push enteroscope. Focal lesions were treated endoscopically, biopsied, or tattooed. Patients in whom a diagnosis was not made by push enteroscopy underwent further studies (see Fig. 20.5).  Intraoperative Endoscopy and Surgical Exploration Surgical exploration of the small intestine can be performed when other studies are nondiagnostic. At surgery, the small bowel

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should be palpated (“running the bowel”) to detect mass lesions. In general, a standard exploratory laparotomy or laparoscopy is performed first to lyse any adhesions and look for obvious tumors, a Meckel diverticulum, or large vascular lesions. The small bowel is usually extracted through the abdominal incision to allow the surgeon to assist with advancement of an endoscope within the lumen of the GI tract, which allows mucosal visualization as well as transillumination. Various endoscopes can be used (standard upper endoscope and colonoscope, pediatric colonoscope, or push enteroscope), depending on the route of access. The endoscope can be passed transorally for a natural orifice luminal examination or via an enterotomy with use of a sterile endoscope.359 Because air insufflation will distend the entire small intestine and thereby make laparoscopic or open visualization difficult, the surgeon should pinch the intestine, manually or with an atraumatic clamp, distal to the tip of the endoscope, to trap enough air to permit visualization. Additionally, insufflation of the bowel with carbon dioxide, rather than room air, allows faster diffusion of gas out of the bowel. The surgeon helps advance the endoscope by pleating the small bowel over the endoscope. Any lesion identified can be addressed surgically or endoscopically, depending on the nature of the lesion. Most series report complete enteroscopy of the entire small bowel in 50% to 75% of cases.360,361 The diagnostic yield of intraoperative enteroscopy ranges from 58% to 88%, but rebleeding after intraoperative enteroscopy has also been reported in 13% to 60% of patients.309 The moderate performance characteristics, as well as risks of surgical exploration, limit this procedure as a diagnostic tool, but in selected patients, combined endoscopic and surgical evaluation can be useful and definitive. The role of intraoperative endoscopy in the management of severe obscure GI bleeding before versus after the introduction of capsule endoscopy and deep enteroscopy has been reported.361 Before an operation in the precapsule endoscopy era, a presumptive diagnosis or localization of bleeding site was achieved in 36% of patients compared with 63% in the postcapsule endoscopy era. In the precapsule endoscopy era, a definitive diagnosis was made intraoperatively in 100% of patients compared with 76% in the postcapsule endoscopy era. For lesions that were surgically resectable—small bowel tumors, Meckel diverticula, aortoenteric fistula, and focal ischemic ulcers—no patient experienced postoperative bleeding during long-term follow up; however, rebleeding rates were high in other patients—67% with vascular lesions, 44% with small bowel ulcers, 50% with Crohn disease, and 63% with no definitive diagnosis.361 Preoperative diagnosis with capsule endoscopy or deep enteroscopy has become more important, particularly in older patients who may have significant complications or death from surgery. Careful selection of patients is required (see Fig. 20.5).363  Capsule Endoscopy With capsule endoscopy, the patient ingests a pill camera that transmits images of the small intestine for 8 hours or more. In patients with severe recurrent GI bleeding, this technique can identify a transition point at which fresh blood appears in the small bowel, and thereby localize the bleeding site and sometimes identify a specific source lesion.363 Capsule endoscopy does not permit the application of therapy and can only localize a lesion in the small bowel on the basis of the time of passage down the small intestine, as determined by sensors on the abdomen and telemetry. The information can be useful, however, in directing subsequent therapeutic procedures such as deep enteroscopy, angiography, or surgery. Although capsule endoscopy may occasionally detect gastric, duodenal, or colonic lesions, it is not a substitute for EGD and colonoscopy. Compared with small bowel barium studies, capsule endoscopy has significantly improved detection rates for small bowel lesions (67% vs. 8%) and findings that influence clinical management

(42% vs. 6%).363,364 A small series has found capsule endoscopy to be superior to CT enteroclysis for the diagnosis of obscure GI bleeding because of its ability to identify angioectasias.365 An evaluation of published studies that have compared push enteroscopy with capsule endoscopy in patients with obscure bleeding (79% overt, 21% occult) found that the average rate of positive findings was 23% for push enteroscopy and 63% for capsule endoscopy.309 A similar result was found in a metaanalysis of published trials and abstracts; the diagnostic yield for push enteroscopy was 28% and 63% for capsule endoscopy.364 A randomized trial that compared push enteroscopy with capsule endoscopy as a first-line approach to obscure GI bleeding reported identification of a bleeding source in 24% of the push enteroscopy examinations and 50% of the capsule studies (P = .02).366 In this study, capsule endoscopy missed lesions in 8% of patients, and all the missed lesions were within reach of a standard upper endoscope. A study of patients with acute, overt, unexplained GI bleeding (melena or hematochezia with nondiagnostic EGD and colonoscopy) who were randomized to capsule endoscopy or angiography reported a significantly higher diagnostic rate for capsule endoscopy than for angiography (53% vs. 20%) but no difference in the long-term outcomes, including transfusions, hospitalizations, and mortality.367 Capsule endoscopy was compared with intraoperative endoscopy in one study of 47 patients who underwent both procedures, primarily for obscure overt GI bleeding.368 Using intraoperative endoscopy as the gold standard, capsule endoscopy had a sensitivity of 95%, specificity of 75%, positive predictive value of 95%, and negative predictive value of 85%. Most of the bleeding lesions were angioectasias. Several studies have found that the diagnostic yield of capsule endoscopy increases in the setting of ongoing or recent (6000 U/L) developed acute bilateral ankle pain with redness and swelling. Three days later he noticed painful red bumps in his right posterior forearm and right ankle area, with later spread to the right ankle. He had pain and swelling in several metacarpophalangeal and interphalangeal joints, and bilateral swelling of the Achilles tendon. Biopsy of one of the subcutaneous nodules showed fat necrosis. The lesions and arthritis gradually resolved without scarring over several weeks. (Courtesy Ann Malbas, MD.)  

and knees, may accompany the nodules or occur without skin lesions (Fig. 25.17). Abdominal pain may be absent when the skin lesions or arthritis occur. In addition to the expected elevations of serum lipase (and amylase), eosinophilia is common. Histopathologic evaluation of skin lesions usually reveals diagnostic findings—pale staining necrotic fat cells (ghost cells) and deposits of calcium in the necrotic fat. The mortality rate in cases not associated with carcinoma can approach 50%. In PPP syndrome, subcutaneous nodules usually manifest on the anterior shins. A bluish discoloration of the skin (ecchymosis) around the umbilicus, sometimes associated with hemorrhagic pancreatitis, is called Cullen sign; when a similar process occurs in the flank, it is called the Grey-Turner sign (see Chapter 58). Some cutaneous markers historically thought to be associated with internal malignancies have more recently been dismissed as having no direct relationship. These include Bowen disease (cutaneous squamous cell carcinoma in situ) and skin tags. Leser-Trélat sign (sudden appearance of multiple seborrheic keratoses) remains controversial but may be more specific for a GI or lung adenocarcinoma when associated with another paraneoplastic finding, such as malignant acanthosis nigricans.25 Sweet syndrome (acute febrile neutrophilic dermatoses) might be associated with a lymphoproliferative neoplasm. 

Cutaneous metastases occur rarely with GI adenocarcinomas. They may appear anywhere on the skin and are often nonspecific, very firm, dermal or subcutaneous nodules. When metastasis to the umbilicus occurs, intra-abdominal GI carcinoma is found in more than half of cases and gastric carcinoma in 20%. This lesion is called Sister Mary Joseph nodule. Immunoperoxidase markers have assisted pathologists in predicting the primary site of origin from biopsy specimens of metastatic nodules. 

CUTANEOUS MANIFESTATIONS OF LIVER DISEASE Liver disease can result in a variety of cutaneous manifestations, especially in relation to hepatitis B and C (Boxes 25.1 and 25.2). Pruritus is a distressing complication of cholestatic, inflammatory, and malignant liver diseases. The itching of liver disease is not relieved by scratching or topical glucocorticoids, may be especially prominent in the palms and soles, and can be difficult to manage. Amelioration of pruritus with ultraviolet B light treatment, cholestyramine, or rifampin does not help in elucidating the pathogenesis of this distressing condition. Opiate antagonists may relieve pruritus of liver disease, and the pruritus associated with metastatic disease to the liver has been successfully treated with ondansetron, a 5-HT3 receptor antagonist. Intense ongoing research is being applied to the field of itch and multiple potential itch pathways have been proposed including receptor activations of TRPV1, opioid receptor, 5-HT, histamine receptor, GABA receptor, neurokinin-1, TRPA1, and others.27 Frequently administered to patients with liver disease and hypoprothrombinemia, vitamin K cutaneous reactions, although rare, may occur after subcutaneous, intramuscular, or intravenous administration. Large, erythematous, indurated, pruritic plaques occur within a few days to a few weeks. These reactions may be a delayed hypersensitivity reaction, in that dermal testing can reproduce the reactions. When tested, patients have been found to be allergic to the vitamin K, not the benzoyl alcohol vehicle. However, vitamin K3 (Synkayvite), which is water-soluble, has not been reported to cause similar reactions. If reactions occur after buttock injections of vitamin K, there is an almost diagnostic tendency of these plaques to spread around the waist and down the thigh, reproducing what has been called a “cowboy gun belt and holster” pattern. These reaction sites resolve over days to weeks but may persist for months to years. After

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an erythematous reaction, or without prior reaction, expanding sclerotic plaques with violaceous borders similar to those of morphea have occurred months to years after injections. The latter pattern usually occurs after large parenteral doses of vitamin K. In addition to these local reactions, anaphylaxis after intravenous administration that may be fatal may occur. The association between polyarteritis nodosa and hepatitis B is well documented. Urticaria and serum sickness classically occur in patients with hepatitis B, although both have been reported in association with hepatitis C (see Chapters 79 and 80). Chronic hepatitis C virus is associated with leukocytoclastic vasculitis with cryoglobulinemia. Petechiae and palpable purpura are noted on the skin. Porphyria cutanea tarda (PCT) is a disorder of porphyrin metabolism characterized by skin fragility, blisters, hypertrichosis, and hyperpigmentation in sun-exposed skin (Fig. 25.18). PCT is the commonest form of porphyria and is characterized by a deficiency of uroporphyrinogen decarboxylase. Diagnosis is typically made with a 24-hour urine collection demonstrating elevated uroporphyrin levels. Alcohol consumption, estrogens, iron, and sunlight all are known to exacerbate PCT. There is a clear and substantial link between PCT and hepatitis C.28 The prevalence of hepatitis C in patients with PCT demonstrates regional variation, ranging from 65% in southern Europe and North America

BOX 25.2 Cutaneous Manifestations of Hepatitis B and C

to 20% in northern Europe and Australia.29 Treatment involves phlebotomy and antimalarial agents. LP is a common idiopathic inflammatory disorder that can affect skin, hair, mucous membranes, and nails (see earlier). The prototypical presentation of LP is violaceous, polygonal, flattopped papules of flexural areas of the wrists, arms, and legs. The papules often have an overlying reticulated white scale known as Wickham striae. An association between LP and hepatitis C exists but is not as prominent as the link between PCT and hepatitis C.30 

DRUG-INDUCED LIVER DISEASE IN PATIENTS WITH SKIN DISEASE Dermatologists frequently consult gastroenterologists for evaluation of patients who are being treated with methotrexate or retinoids, because these medications can cause acute and chronic liver disease (see Chapter 88). Methotrexate is commonly used for severe psoriasis and psoriatic arthritis but is also used for cutaneous T cell lymphoma, connective tissue diseases such as rheumatoid arthritis, and other inflammatory disorders. Methotrexate is usually given as a single weekly dose of 10 to 25 mg, but may be used in higher dosages in selected patients. A grading system for liver biopsies has been established and is generally followed by dermatologists, with decisions on continuation or discontinuation of treatment frequently based on the results of these biopsies (Table 25.2).26 Latest consensus guidelines from the American Academy of Dermatology recommend less frequent liver biopsies than those previously prescribed

HEPATITIS B MORE THAN IN HEPATITIS C Polyarteritis nodosa Urticaria Serum sickness Infantile papular acrodermatitis (Gianotti-Crosti syndrome) Erythema nodosum  BOTH HEPATITIS B AND C Small vessel vasculitis Urticarial vasculitis Pruritus Erythema multiforme  HEPATITIS C MORE THAN IN HEPATITIS B Leukocytoclastic vasculitis with cryoglobulinemia Porphyria cutanea tarda  HEPATITIS C Lichen planus Livedo reticularis Necrolytic acral erythema

Fig. 25.18  Porphyria cutanea tarda characterized by noninflammatory blisters and erosions of the dorsa of the hands. Affected patients are frequently infected with HCV. (Courtesy Dr. Timothy Berger, San Francisco, CA.)

TABLE 25.2  Grading System for Liver Biopsy Findings in Patients Taking Methotrexate and Guidelines for Continuation/Discontinuation of Methotrexate Grade

Criteria

Guidelines

I

Normal; mild fatty infiltration; nuclear variability, portal inflammation

May continue to receive methotrexate.

II

Moderate to severe fatty infiltration; nuclear variability; portal tract expansion, portal tract inflammation, and necrosis

May continue to receive methotrexate.

IIIA

Mild fibrosis (formation of fibrotic septa extending into the lobules)

May continue to receive methotrexate but should have a repeat liver biopsy after approximately 6 more months of methotrexate. Alternative therapy should be considered.

IIIB

Moderate to severe fibrosis

Should not administer further methotrexate. Exceptional circumstances, however, may require continued methotrexate, with follow-up liver biopsies.

IV

Cirrhosis (regenerative nodules as well as bridging of portal tracts)

Should not administer further methotrexate. Exceptional circumstances, however, may require continued methotrexate, with follow-up liver biopsies.

  

Modified from Roenigk HH Jr, Auerbach R, Maibach H, Weinstein GD. Methotrexate in psoriasis: revised guidelines. J Am Acad Dermatol 1988;19:145–56.   

CHAPTER 25  Cutaneous Manifestations of Gastrointestinal and Liver Diseases

and no longer suggest pretreatment liver biopsies in patients without risk factors for additive hepatotoxicity (e.g., chronic alcohol use, obesity, diabetes mellitus, active or chronic hepatitis). Notably, liver biopsy is still recommended for monitoring in psoriasis (every 3.5 to 4 g total cumulative dose)32 due to the chronic liver damage caused by the inherent metabolic disorder that accompanies severe psoriasis, but a growing body of work suggests that liver elastography or other non-invasive tests may supplant the need for as many biopsies as are performed today.33 Retinoids (e.g., isotretinoin, acitretin, bexarotene), derivatives of vitamin A, are currently used for the treatment of certain forms of severe psoriasis, cystic acne, and other disorders of keratinization. Regular evaluation of liver chemistry tests is required during this treatment. Mild elevations of serum triglyceride, cholesterol, ALT, and AST levels are common (20% to 30% of patients treated), usually transient, or easily managed by reducing the dose. Severe or even fatal hepatitis has been reported, however. Retinoids may be used for patients with psoriasis who were previously treated with methotrexate or who have preexisting liver disease contraindicating the use of methotrexate. Limited experience suggests that these patients do not suffer progression of their liver disease with such retinoid therapy. As with methotrexate, there is a poor correlation between liver chemistry test results and liver histology during retinoid therapy. Therefore, pretreatment and intermittent liver biopsies may be required for certain high-risk patients being chronically treated with oral retinoids. 

PARASITIC DISEASES OF THE SKIN AND GASTROINTESTINAL TRACT The larval forms of human and animal nematodes may cause migratory erythematous skin lesions called creeping eruptions (see Chapter 114). The most common pattern is cutaneous larva migrans, caused by dog and cat hookworms (Fig. 25.19). Pruritic linear papules migrate at a rate of 1 to 2 cm daily on skin sites that have come in contact with fecally contaminated soil, usually the feet, buttocks, or back. Lesions resolve spontaneously over weeks to months. Larva currens is due to Strongyloides stercoralis larva migrating in the skin. It occurs in 2 forms, one localized to the perirectal skin in immunocompetent hosts and another disseminated form occurring in immunosuppressed hosts. S. stercoralis has the unique capacity among nematodes to develop into infective larvae within the intestine. These infective larvae may invade the perirectal skin in infected immunocompetent individuals, causing urticarial, erythematous, linear lesions that migrate up to 10 cm a day, usually within 30 cm of the anus. Skin lesions may occur intermittently, making diagnosis difficult. In immunosuppressed hosts, repeated autoinfection through the

Fig. 25.19  Cutaneous larva migrans characterized by a serpiginous erythematous migratory lesion caused by an infection with dog hookworm. (Courtesy Dr. Timothy Berger, San Francisco, CA.)

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intestine leads to a tremendous parasite burden (hyperinfection), manifested most commonly by pulmonary disease. In association with hyperinfection, disseminated larva currens–type lesions may appear over the whole body, especially the trunk. Petechial or purpuric serpiginous lesions may also occur periumbilically. Parasitic infections are classically considered in the differential diagnosis of urticaria. Except for fascioliasis and hydatid disease, however, a direct relationship with urticaria has rarely been proved. If blood eosinophilia and GI symptoms are absent, stool examination for parasites is rarely beneficial. 

DERMATITIS HERPETIFORMIS AND CELIAC DISEASE Dermatitis herpetiformis (DH) is an extremely pruritic skin disorder most commonly appearing during early adulthood (see Chapter 107). The cutaneous eruption consists of urticarial, vesicular, or bullous lesions characteristically localized to the scalp, shoulders, elbows, knees, and buttocks.34 The disorder is so pruritic that often all the skin lesions have been excoriated, and the diagnosis must be suspected on the basis of this and the distribution (Fig. 25.20). The diagnosis of DH is established by skin biopsy and direct immunofluorescence examination of the skin. Deposits of IgA are found in the dermal papillae at sites of itching and where vesicles are forming. Patients with DH commonly have an enteropathy indistinguishable from celiac disease (CD). Their HLA patterns, including haplotypes B8, DR3, and DQw2, intestinal malabsorption, presence of antibodies to endomysium (EMA), gliadin (AGA), and tissue transglutaminase (TG), and small bowel biopsy findings are similar to those of patients with CD. Despite these striking similarities, fewer than 5% of patients with DH have symptomatic GI disease. Gluten has been shown to be the dietary trigger of DH. Even patients with such minimal bowel disease that bowel biopsy findings are normal improve on a gluten-free diet. Reintroduction of gluten in a symptom-free patient on a gluten-free diet leads to the reappearance of pruritus and skin lesions.

Fig. 25.20  Dermatitis herpetiformis characterized by pruritic, urticarial papules, and small blisters concentrated over the elbows, knees, and buttocks. (Courtesy Dr. Benjamin Lockshin, Silver Spring, MD.)

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A pathogenic mechanism has been proposed to explain the relationship between DH and CD. In patients with CD, IgA antibodies are produced in response to tissue TG2 that is cross-linked to deamidated gliadin peptides (derived from dietary wheat, barley, or rye and presented by HLA-DQ2 or -DQ8 molecules on antigen-presenting cells). IgA antibodies to the epidermal form of TG, TG3, are then thought to form as a result of epitope spreading, and these antibodies eventually form antigen-antibody complexes with TG3 in the papillary dermis, resulting in the clinical and pathologic findings of DH. This model would explain why DH more commonly presents at a later age than symptomatic

Fig. 25.21  Lower extremities of an older man with Whipple disease. Perifollicular hemorrhage is apparent. Plasma vitamin C levels were decreased. The skin lesions rapidly disappeared after vitamin C supplementation. (Courtesy Dr. Mark Feldman, Dallas, TX.)

Fig. 25.22  Infant girl with acrodermatitis enteropathica secondary to nutritional zinc deficiency. She was subsisting on a diet of rice cereal and water. (Courtesy Dr. Genevieve Wallace, Dallas, TX.)

TABLE 25.3  Nutritional Abnormalities and Associated Skin Findings Nutritional Abnormality

Causes

Clinical Features

Treatment

Niacin deficiency (pellagra)

Inadequate diet Medication (isoniazid) Carcinoid syndrome

Symmetrical brown-red, blistering, or scaling plaques in sun-exposed areas Glossodynia, atrophic glossitis 4 Ds: dermatitis, diarrhea, dementia, death

Nicotinic acid: Mild: 50 mg orally 3 times daily Symptomatic: 25 mg intravenously or intramuscularly 3 times daily Advanced: 50-100 mg intravenously or intramuscularly 3 times daily × 3-4 days, followed by oral therapy

Zinc deficiency (acrodermatitis enteropathica if genetic) Deficiency of essential fatty acids Biotin deficiency

Congenital metabolic abnormalities Alcoholics with cirrhosis Hyperalimentation without adequate supplementation Crohn disease

Superficial scaling eruption, accentuated in groin and around the mouth Alopecia

Zinc: 1-2 mg/kg/day orally for acquired form; 3 mg/kg/day for congenital form, acrodermatitis enteropathica Biotin: 10-40 mg/day orally, intramuscularly

Vitamin C deficiency (scurvy)

Alcohol abuse Crohn disease Whipple disease

Follicular hyperkeratosis and perifollicular hemorrhage Ecchymoses Xerosis Poor wound healing Corkscrew body hairs Gingivitis with gum hemorrhage

Ascorbic acid, 800 mg/day orally

Glucagonoma syndrome (necrolytic migratory erythema)

Glucagon-secreting neuroendocrine tumors of the pancreas Also in setting of cirrhosis and subtotal villus atrophy of the jejunal mucosa

Intense erythema progressing to flaccid bullae and crusting with rupture Most commonly on the central face, intertriginous sites, thighs, buttocks, and distal limbs Often painful or pruritic

Surgical removal of the tumor Somatostatin analog or zinc supplementation sometimes beneficial while awaiting surgery

  

Modified from Nieves D, Goldsmith L. Cutaneous changes in nutritional disease. In: Freedberg I, Eisen A, Wolff F, editors. Fitzpatrick’s dermatology in general medicine. New York: McGraw-Hill; 2003. pp 1399-1412.   

CHAPTER 25  Cutaneous Manifestations of Gastrointestinal and Liver Diseases

CD, and with less severe intestinal disease, in that epitope spreading likely requires time and continued exposure to gluten.35 Because it is occasionally difficult to distinguish DH from other blistering skin diseases, a patient with an extremely pruritic eruption may be referred for endoscopy. The finding of an abnormal small intestine consistent with CD in a patient with a pruritic eruption would be highly suggestive of DH (see Chapter 107). The skin lesions of DH respond dramatically to sulfa drugs (dapsone or sulfapyridine), but the gut pathology and skin immunofluorescence are unchanged by sulfa drugs. Treatment with a gluten-free diet leads to gradual clearing of skin lesions, improvement of the intestinal abnormality, disappearance of the IgA from

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the skin, and decreased dependence on dapsone for control of the cutaneous eruption.36 

VITAMIN AND MINERAL DEFICIENCIES Though many vitamin deficiencies result in various skin findings (Figs. 25.21 and 25.22), those of most relevance to GI and liver disease are summarized in Table 25.3, along with treatment algorithms.31 (Also see Chapters 6 and 104.) Full references for this chapter can be found on www.expertconsult.com

.

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Diverticula of the Pharynx, Esophagus, Stomach, and Small Intestine Kerry B. Dunbar, D. Rohan Jeyarajah

CHAPTER OUTLINE ZENKER DIVERTICULA�������������������������������������������������������372 Epidemiology, Etiology, and Pathophysiology�������������������372 Clinical Features and Diagnosis���������������������������������������372 Complications�����������������������������������������������������������������373 Treatment and Prognosis�������������������������������������������������373 DIVERTICULA OF THE ESOPHAGEAL BODY������������������������374 Epidemiology, Etiology, and Pathophysiology�������������������374 Clinical Features and Diagnosis���������������������������������������374 Complications�����������������������������������������������������������������375 Treatment and Prognosis�������������������������������������������������375 ESOPHAGEAL INTRAMURAL PSEUDODIVERTICULA����������375 Epidemiology, Etiology, and Pathophysiology�������������������375 Clinical Features and Diagnosis���������������������������������������375 Complications�����������������������������������������������������������������375 Treatment and Prognosis�������������������������������������������������375 GASTRIC DIVERTICULA������������������������������������������������������377 Epidemiology, Etiology, and Pathophysiology�������������������377 Clinical Features and Diagnosis���������������������������������������377 Complications�����������������������������������������������������������������377 Treatment and Prognosis�������������������������������������������������377 DUODENAL DIVERTICULA��������������������������������������������������377 Extraluminal Diverticula���������������������������������������������������377 Intraluminal Diverticula����������������������������������������������������378 JEJUNAL DIVERTICULA�����������������������������������������������������379 Epidemiology, Etiology, and Pathophysiology�������������������379 Clinical Features and Diagnosis���������������������������������������379 Complications�����������������������������������������������������������������379 Treatment and Prognosis�������������������������������������������������380

Diverticula are outpouchings from tubular structures. True diverticula involve all layers of the intestinal wall, whereas false diverticula are due to herniation of mucosa and submucosa through the muscular wall. Many diverticula contain attenuated portions of the muscular wall of the intestine, and hence may be difficult to define as true or false. True diverticula are often assumed to be congenital lesions, and false diverticula are assumed to be acquired, but this is not always the case. Some authors reserve the terms false diverticula or pseudodiverticula for diverticula caused by an inflammatory process. This chapter addresses diverticula of all parts of the GI tract, with the exception of Meckel diverticulum and colonic diverticula, which are covered in Chapters 98 and 121.

ZENKER DIVERTICULA Ludlow first described a patient with a hypopharyngeal diverticulum in 1767, and in 1877 Zenker and Von Ziemssen reported 23 such patients.1,2

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Epidemiology, Etiology, and Pathophysiology The prevalence of Zenker diverticula has been estimated to be between 0.1% and 0.01%. Patients generally present in the seventh or eighth decade of life. Twice as many men as women develop Zenker diverticula.3,4 Zenker diverticula are acquired. They develop when abnormally high pressures occur during swallowing, leading to mucosa that protrudes through an area of anatomic weakness in the pharynx known as Killian triangle (see Chapter 43). Killian triangle is located posteriorly where the transverse fibers of the cricopharyngeus muscle of the upper esophageal sphincter (UES) intersect with the oblique fibers of the inferior pharyngeal constrictor muscle. The size of this area of weakness varies among individuals. Relatively large defects may predispose to the development of Zenker diverticula.4 With a Zenker diverticulum, opening of the UES is impaired, generating high pressures with swallowing. In patients with Zenker diverticula, several pathophysiologic changes have been documented in the cricopharyngeus, including inflammation and fibrosis leading to poor compliance and abnormal relaxation of the cricopharyngeus.5,6 These changes lead to a reduction in compliance and decreased opening of the UES.3 Other types of diverticula similar in appearance to Zenker diverticula have been reported as a complication of anterior cervical spine surgery.7,8 Killian-Jamieson diverticula are seen just below the cricopharyngeus and have a similar presentation to Zenker diverticula.9 

Clinical Features and Diagnosis Common presenting symptoms are listed in Box 26.1, with dysphagia and regurgitation as the most common complaints. Patients with small diverticula may be asymptomatic. In some patients, Boyce sign, a palpable nodule or swelling on the left anterior neck that may gurgle on palpation, can be found.10 Zenker diverticulum can be suspected from a careful history. Barium swallow is the most useful diagnostic study. The radiologist should be alerted in advance so that proper views are taken (Fig. 26.1B; see also Chapter 44). Small diverticula may be seen only transiently. Barium swallow in the lateral view using video fluoroscopy is helpful for detecting small diverticula. The opening of a large Zenker diverticulum often becomes aligned with the axis of the esophagus. Oral contrast will preferentially fill the diverticulum and empty slowly from it. Large diverticula are therefore often obvious, even on delayed images. Zenker diverticula more often on the left side of the neck. Zenker diverticula may be discovered incidentally during barium swallow or upper endoscopy (see Fig. 26.1A) carried out for investigation of unrelated problems. When evaluating patients with symptoms suspicious for the presence of a Zenker diverticulum, consider obtaining a barium swallow prior to endoscopic evaluation. During endoscopy, Zenker diverticulum should be suspected if, on entering the pharynx, the UES cannot be located. In such cases, the endoscopy should be stopped, and the patient sent for a barium study. 

CHAPTER 26  Diverticula of the Pharynx, Esophagus, Stomach, and Small Intestine

BOX 26.1 Presenting Symptoms in Patients with a Zenker Diverticulum Aspiration Choking Dysphagia Halitosis Regurgitation Voice changes Weight loss

A

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Bleeding may occur from ulcerated Zenker diverticula.12 Aspiration of retained food contents may lead to aspiration pneumonia.13,14 Medications may become lodged in Zenker diverticula and can cause ulceration and pain, as well as decreased medication effectiveness.15,16 Because a Zenker diverticulum is occasionally palpable on physical exam, it can be difficult to distinguish from a large thyroid nodule, and accumulation of radioactive iodine tracer in a Zenker diverticulum has been reported to lead to erroneous diagnosis of metastatic thyroid cancer.17 The videocapsules used for capsule endoscopy may also become lodged in Zenker diverticula and should be delivered into the stomach with an endoscope when such studies are required.18 Intubation of the trachea or the esophagus may be complicated by the presence of a Zenker diverticulum. A large diverticulum displaces the lumen of the esophagus. The tip of the intubation instrument is often directed preferentially into the diverticulum. At endoscopy, it may be difficult to distinguish the lumen of the diverticulum from the true lumen of the esophagus (see Fig. 26.1A). Endotracheal intubation, placement of a nasogastric tube, and intubation of the esophagus for upper endoscopy, endoscopic retrograde cholangiopancreatography, or transesophageal echocardiography may be difficult. Perforation can occur. Intubation of the esophagus in patients with Zenker diverticula should be performed under direct vision. When a large Zenker diverticulum causes marked anatomic distortion or when intubation with a side-viewing endoscope is required, direct intubation is not prudent. In such cases, a forward-viewing endoscope can be used to pass a soft-tipped guidewire into the esophageal lumen.19 The guidewire is then back-loaded into the endoscope, and the endoscope is advanced into the esophagus over the guidewire. An alternative technique consists of passing a forward-viewing endoscope loaded with an overtube. Once the endoscope has been passed into the esophagus, the overtube is advanced, the forwardviewing endoscope is withdrawn, and the side-viewing or ultrasound endoscope is passed through the overtube.20 

Treatment and Prognosis

B Fig. 26.1  Zenker diverticulum.  A, Endoscopic view. It is often difficult to distinguish the lumen of the esophagus from the lumen of the diverticulum. B, Barium esophagogram showing a diverticulum large enough to cause esophageal obstruction when it fills. (A, Courtesy of the late Dr. David Langdon; B, Courtesy Dr. Charles E. Pope, Seattle, WA.)

Complications Squamous cell cancer may develop in Zenker diverticula; the estimated incidence is 0.4% to 1.5%.3,11 If myotomy without diverticulectomy is planned, it is prudent to carefully inspect the lining of the diverticulum for any evidence of cancer.

Patients with small asymptomatic or minimally symptomatic diverticula can be followed, because progressive enlargement is uncommon.21,22 Patients with large and symptomatic Zenker diverticula should be offered treatment.22,23 Zenker diverticula may be treated by open surgical procedures or by transoral endoscopic techniques using rigid or flexible endoscopes. Open surgery for Zenker diverticula is typically performed through the left neck in patients with large (>5 cm) diverticula that extend into the thorax.24 Young patients and patients with small diverticula may also be candidates for open surgery.25 Large diverticula can be resected, inverted, or suspended (diverticulopexy). Cricopharyngeal myotomy is performed to treat the hypertonic cricopharyngeus muscle, and is the key aspect to treating this disorder; the hypertonic cricopharyngeus muscle must be divided to relieve distal obstruction. If diverticula are resected without myotomy, there is an increased risk of postoperative leaks and an increased frequency of recurrence.25,26 Complications of open surgery include anastomotic leaks, mediastinitis, esophagocutaneous fistula, and vocal cord paralysis from injury to the recurrent laryngeal nerve, which runs in the tracheoesophageal groove. One review of 22 research studies including 1793 patients who underwent open surgery for Zenker diverticulum found an initial success rate of 96%, a morbidity rate of 11%, a 5% perforation or leak rate, and a 3.5% symptom recurrence rate over a median of 36 months of follow-up.23 Endoscopic treatment of Zenker diverticulum can be performed using a rigid endoscope or flexible endoscope, with division of the fibrotic septum between the esophagus and the diverticulum.25,27 Compared with open surgical approaches, endoscopic approaches are associated with shorter anesthesia

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PART IV  Topics Involving Multiple Organs Diverticuloscope

Esophageal lumen

Fig. 26.3  Endoscopic view of a midesophageal diverticulum. These diverticula are most apparent when the esophagus is well insufflated. Zenker’s diverticulum Fig. 26.2 Diverticuloscope. The instrument is positioned to expose the common wall between the lumen of the esophagus and the Zenker diverticulum.

times, lower complication rates, and shorter hospital stays. Endoscopic techniques are suitable for patients with medium-sized diverticula (2 to 5 cm). Rigid diverticuloscopes and flexible endoscopes have been used. The diverticuloscope provides visualization of the lumen of the esophagus and diverticulum and the septum between them (Fig. 26.2). This septum is composed of the posterior wall of the esophagus and the anterior wall of the diverticulum and includes the UES. The muscular layers of this septum (and UES) are incised, restorating a single lumen. The incision can be performed by a number of techniques. With a rigid diverticuloscope, CO2 laser, surgical stapling, argon plasma coagulation, electrocautery, or harmonic scalpel can be used for the procedure.22,25 During endoscopic stapling, one leg of the stapler is placed in the esophagus and the other into the diverticulum. The septum is then divided and stapled with 2 rows of staples on each side of the division line. The Zenker diverticulum must be at least 3 cm in length to be able to seat an adequate length of the stapler. Modifications of the stapler and other techniques may improve results in short diverticula.28 Complications of endoscopic procedures include bleeding, perforation, and leaks, but these are uncommon if a stapler-assisted technique is used. In a review of rigid endoscopic treatment of Zenker diverticulum, combining 11 studies of 494 patients, the median initial success rate was 95%, with a 4% rate of conversion to open surgery, a 3% rate of major morbidity, with recurrence of symptoms in 5% over a median follow-up of 16 months.23 Flexible endoscopic techniques also have a role in the treatment of Zenker diverticula because rigid diverticuloscopes cannot be used in patients who have limited neck extension or limited ability to open their mouth.26 Transparent caps or a soft diverticuloscope may be attached to the endoscope to improve visualization.29-31 A variety of techniques can be used to perform the endoscopic myotomy, including needle knife, argon plasma coagulation, monopolar forceps, or harmonic scalpel.22,29 Complications of flexible endoscopic techniques include cervical and mediastinal air dissection, which are common, as well as perforation and mediastinitis. In a review of 20 studies of flexible endoscopic treatment of 813 patients with Zenker diverticula, the initial success rate was 91%, with an 11% adverse event rate, and an 11% recurrence rate after a median of 23 months of follow-up.32 Flexible endoscopic treatment of Zenker diverticula has typically been performed by surgeons, but some expert endoscopists have begun performing these procedures (Video 26.1).4 

DIVERTICULA OF THE ESOPHAGEAL BODY Diverticula of the esophageal body are most commonly located in the middle or lower third of the esophagus (Fig. 26.3).

Epidemiology, Etiology, and Pathophysiology Estimates of the frequency of esophageal body diverticula vary from a prevalence of 0.015% seen on autopsy to 2% in patients referred for radiologic evaluation of swallowing disorders.33,34 These diverticula can be divided into 2 types: traction and pulsion diverticula. Traction diverticula are related to an inflammatory, fibrotic, or neoplastic process outside of the esophagus. Traction diverticula are often related to mediastinal inflammation associated with tuberculosis or histoplasmosis.35 Enlarged mediastinal lymph nodes from lung malignancies can also lead to traction diverticula. Pulsion diverticula are typically caused by motility disorders. The most common type of pulsion diverticula is an epiphrenic diverticula, which is located near the diaphragmatic hiatus (Fig. 26.4). About 80% of epiphrenic diverticula are associated with esophageal motility disorders such as achalasia or distal esophageal spasm, which are discussed in Chapter 43.36,37 Epiphrenic diverticula have been reported as a complication of band-based obesity surgery, due to obstruction of the esophagus and upper stomach by the band (see Chapter 8).38,39 Congenital bronchopulmonary-foregut malformations can also present with esophageal diverticula.40 

Clinical Features and Diagnosis Congenital and traction diverticula of the esophagus are usually asymptomatic, particularly when in the mid and lower esophagus. If symptoms are not present at diagnosis, they rarely occur during follow-up. When symptoms occur, the most common are dysphagia, food regurgitation, reflux, weight loss, and chest discomfort.41 Dysphagia may be caused by an underlying motility disorder or by extrinsic compression of the esophagus by a large diverticulum, with preferential filling of the diverticulum.36,37,42 Bronchopulmonary-foregut fistulas can develop, however, leading to cough, pneumonia, and recurrent bronchopulmonary infections.43 Diagnosis of epiphrenic diverticulum can be made during endoscopy or barium radiography. An epiphrenic diverticulum may be mistaken for a diaphragmatic hernia or duplication cyst on chest radiography. Endoscopy may show an empty diverticulum or the presence of food debris (Fig. 26.5A). Diagnosis is best made by barium swallow, which serves to visualize the diverticulum and localizes it more precisely than endoscopy (see Fig. 26.5B). The radiologist must be alerted to the possibility of this diagnosis, because oblique views will be required to demonstrate

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that there is no staple line to heal, decreasing the risk of a leak. It must be understood that the symptoms are usually related to the underlying motility disorder and not the diverticulum itself. Therefore, treating the underlying condition, usually with myotomy, is the key component of the surgery. To prevent gastroesophageal reflux after myotomy, a partial posterior (Toupet) or anterior (Dor) fundoplication may be performed.41,49 The prognosis for patients who undergo surgery for esophageal diverticula is good, with rates of symptom improvement of 88.5%, with better symptom response rates when diverticulectomy is performed.49 

ESOPHAGEAL INTRAMURAL PSEUDODIVERTICULA Esophageal intramural pseudodiverticula (EIP) were first described in 1960.51 The pseudodiverticula are flask-shaped outpouchings from the lumen of the esophagus, ranging in size from 1 to 4 mm.

Epidemiology, Etiology, and Pathophysiology

Fig. 26.4  Barium esophagogram showing an epiphrenic diverticulum immediately above the stomach. In this projection, the diverticulum may be confused with a hiatal hernia. (Courtesy Dr. Charles A. Rohrmann and Dr. Charles E. Pope, Seattle, WA.)

the diverticulum. CT should also be considered to ensure no associated pathologic adenopathy or mass lesions that might be causative of a pulsion diverticulum. 

Complications Squamous cell carcinoma has been reported in epiphrenic diverticula.44,45 As with Zenker diverticula, accumulation of radioactive iodine tracer in esophageal diverticula has been mistaken for metastatic thyroid cancer.46 Bleeding from an ulcerated esophageal diverticulum has been reported.47 Regurgitation and aspiration of the contents of the diverticulum may complicate induction of anesthesia. Perforation is possible during nasogastric intubation or UGI endoscopy 

Treatment and Prognosis Asymptomatic diverticula of the esophagus need no treatment. Only patients with symptoms clearly related to their diverticula should be treated. Preoperative endoscopy and manometry are advisable. It can be difficult to pass a manometry catheter beyond the diverticulum and into the stomach, but documentation of achalasia or distal esophageal spasm is helpful for guiding treatment.48 Surgical treatment of esophageal diverticula can be performed by open, laparoscopic, combined laparoscopic-thoracoscopic, or robotic techniques.49,50 Epiphrenic diverticula are often amenable to a laparoscopic approach, which has the advantages of a shorter hospital stay and a quicker return to normal activities (see Fig. 26.5C). Large diverticula may be inverted or resected. Given the high prevalence of associated motility disorders such as achalasia, esophageal myotomy is performed in most cases.41,49 Small diverticula can be treated by myotomy without resection. The advantage to forgoing the diverticulectomy is

EIP are more common than the small number of published case reports would imply. EIP have been demonstrated in 0.09% to 0.15% of barium swallow studies.52,53 Patients are found to have EIP most commonly in their sixth or seventh decades. The condition is slightly more common in men than in women.54 EIP are abnormally dilated ducts of submucosal glands. They are thought to be acquired and are often associated with conditions that cause chronic esophageal inflammation. The ducts may become dilated because of periductal inflammation or fibrosis.55 Esophageal strictures are commonly associated with EIP, but GERD, chronic candidiasis, caustic ingestion, esophageal cancer, and eosinophilic esophagitis are also associated with EIP.52-54,56,57 Marked thickening of the esophageal wall has been noted in some cases by CT or EUS.58,59 

Clinical Features and Diagnosis EIP can be discovered on a barium swallow done for dysphagia or heartburn (Fig. 26.6A). EIP may also be an incidental finding in patients without related symptoms. The esophageal pseudodiverticula are localized in most cases but are diffusely scattered throughout the esophagus in 40% of cases.54 Strictures are common and tracking or communication between adjacent pseudodiverticula can also occur.60,61 The differential diagnosis on barium swallow examination includes esophageal ulceration. Although the endoscopic appearance of EIP is characteristic (see Fig. 26.6B), the openings of EIP are small and are often missed. EIP located within an area of stricture are particularly difficult to see at endoscopy. Symptoms, when present, are generally related to the associated condition, such as stricture or candidiasis, rather than to the EIP. 

Complications Complications due to EIP are rare. Cancer must be excluded by upper endoscopy if a stricture is present; increased rates of esophageal cancer have been found in patients with EIP.52 There have been rare case reports of perforation of EIP leading to mediastinitis.62,63 

Treatment and Prognosis Treatment of EIP should be directed at the underlying condition, such as stricture, acid reflux, or candidiasis. Dilation of the esophagus has been reported to provide symptomatic improvement of dysphagia in EIP. In one series of 22 patients with EIP, all had improvement in dysphagia symptoms with esophageal

26

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PART IV  Topics Involving Multiple Organs

A B

C Fig. 26.5  Giant esophageal diverticulum. A, Endoscopic view of a large esophageal diverticulum with food and liquid (arrows). B, Barium esophagogram showing a large esophageal diverticulum. C, Laparoscopic resection of a large diverticulum (arrows) of the esophagus (arrowheads). (B and C, Courtesy Dr. Thai Pham, Dallas, TX.)

A

B

Fig. 26.6  Esophageal intramural pseudodiverticula. A, Barium esophagogram showing small outpouchings. B, Endoscopic view. Tiny openings of the pseudodiverticula are seen in this patient, who also has a distal esophageal peptic stricture.

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26

A

B Fig. 26.7 A, Juxtacardiac gastric diverticulum. This wide-mouthed diverticulum (arrows) was seen on a retroflexed view of the cardia. The mucosa within the diverticulum was normal. B, Prepyloric gastric diverticulum.  

bougienage, but multiple dilation sessions were often required. In addition, 57% required repeat dilation due to recurrence of dysphagia symptoms.61 The EIP may persist even if treatment relieves symptoms.54 

GASTRIC DIVERTICULA Gastric diverticula are uncommon and are typically incidental findings identified during endoscopy or imaging studies.

Epidemiology, Etiology, and Pathophysiology Gastric diverticula are found in only 0.04% of UGI x-rays and 0.02% of autopsies.64 Juxtacardiac diverticula make up 75% of all gastric diverticula. These are most often located near the gastroesophageal junction on the posterior aspect of the lesser curvature (Fig. 26.7A).65 They are most commonly found in middle-aged patients, although cases have been reported in children and adolescents.66 They typically range in size from 1 to 3 cm in diameter but are occasionally larger. Intramural or partial gastric diverticula are formed by projection of the stomach mucosa through the muscularis. These diverticula are found most commonly on the greater curvature.67,68 Deformities caused by peptic ulcers or other inflammatory processes can resemble prepyloric diverticula on barium studies or at endoscopy (see Fig. 26.7B). Gastric diverticula have been reported as a complication of obesity surgery, particularly from vertical banded gastroplasty, although they have also been seen after Roux-en-Y gastric bypass.69,70 

Clinical Features and Diagnosis Juxtacardiac diverticula are almost always asymptomatic. Rarely, patients may complain of pain or dyspepsia attributable to a diverticulum. During endoscopy, juxtacardiac diverticula are best seen on a retroflexed view. They may be missed on barium study unless lateral views are taken. On CT, they may appear as air- or contrast-filled suprarenal masses and can be mistaken for an adrenal mass or cyst.71 The structure can lead to a dilemma in diagnosis if it is fluid-filled alone; this can be mistaken for a pancreatic cystic lesion. The combination of air and fluid leads the radiologist to consider a pancreatic abscess in the differential. Intramural diverticula do not usually cause symptoms. They are often mistaken for ulcers on barium studies. 

Complications Complications of gastric diverticula are rare. Cancer has rarely been reported.72,73 Bleeding rarely occurs and may require combination therapy for hemostasis, such as hemoclips and epinephrine injection.74,75 Perforation is also very rare.75 Bleeding that cannot be controlled with endoscopic techniques may require referral for surgery. 

Treatment and Prognosis Intramural diverticula require no intervention. Juxtacardiac diverticula almost never require treatment. A clear association with a specific symptom complex should be firmly established before considering resection, because more common diagnoses (e.g., dyspepsia, reflux) can cause unexplained UGI symptoms. If a patient with a juxtacardiac diverticulum is referred for surgery, it may be prudent to place an endoscopic tattoo near the diverticulum, to assist with localization during surgery. Laparoscopic diverticulectomy can be used for simple resections for symptoms or perforation.76 In these cases, the stomach is mobilized laparoscopically and the diverticulum is stapled, leaving the majority of the stomach intact. Proximal diverticula near the esophagogastric junction are handled with care to avoid narrowing this area with the stapler. Placement of a bougie can help avoid narrowing of the gastroesophageal junction. 

DUODENAL DIVERTICULA Duodenal diverticula can be extraluminal or intraluminal.

Extraluminal Diverticula Epidemiology, Etiology, and Pathophysiology Extraluminal duodenal diverticula are noted in about 5% of UGI x-rays and seen in roughly 20% to 30% of ERCP studies.77,78 They are thought to be acquired and are typically seen in patients older than age 50.78 They arise in an area of the duodenal wall where a vessel penetrates the muscularis or where the dorsal and ventral pancreas fuse in embryologic development. About 75% are located within 2 cm of the ampulla, on the medial wall of the duodenum, and are termed juxtapapillary diverticula (JPD) (Fig. 26.8A). 

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B

A

Fig. 26.8 A, Juxtapapillary diverticulum identified during ERCP (arrow). A sphincterotome is inserted into the nearby ampulla (arrowhead). B, Upper GI radiograph showing multiple large duodenal diverticula. (A, Courtesy Dr. Zeeshan Ramzan, Dallas, TX.)  

Clinical Features and Diagnosis Duodenal diverticula are sometimes diagnosed on UGI x-rays. They are easily missed on endoscopy unless a side-viewing endoscope is used. A duodenal diverticulum may be mistaken for a pancreatic pseudocyst, peripancreatic fluid collection, pancreatic abscess, cystic pancreatic tumor, hypermetabolic mass, or distal bile duct stone on various imaging modalities (ultrasonography, CT, MRI, or PET-CT).79-83 If a diverticulum is suspected on CT or MRI, the diagnosis can be clarified by having the patient drink water and repeating the scan, or by using negative contrast agents during MRI.84,85 

Complications Although extraluminal duodenal diverticula are relatively common, complications are rare. Complications associated with extraluminal duodenal diverticula include perforation or diverticulitis, bleeding, acute pancreatitis, and bile duct stones.77,86-88 Duodenal diverticulitis may present as a free or contained perforation. Patients present with pain in the upper abdomen, often radiating to the back, and may have signs and symptoms of sepsis. An abdominal CT scan may reveal thickening of the duodenum, retroperitoneal air, phlegmon, or abscess. Bleeding has been reported from Dieulafoy-like lesions or ulcers within duodenal diverticula.89,90 Bleeding from duodenal diverticula may be very difficult to diagnose, requiring examination with a side-viewing endoscope or angiography. In some patients, the site of bleeding is discovered only at the time of ­surgery. Patients with multiple duodenal diverticula may develop bacterial overgrowth and malabsorption (see Fig. 26.8B) (see Chapters 104 and 105).91 JPD have been associated with bile duct stones, cholangitis, SOD (see Chapter 63) and recurrent pancreatitis, thought to be caused by an abnormal entrance of the pancreatic duct into the diverticulum.77,92-95 Delayed emptying of the bile duct may occur, even after sphincterotomy. Stasis within diverticula can result in bacterial overgrowth, leading to bile salt deconjugation and increasing the risk of primary bile duct stones.77,96

JPD do not appreciably increase the difficulty of cannulation or the risk of complications at ERCP performed by experienced therapeutic endoscopists.78,97 Several techniques have been described to overcome difficulties associated with an ampulla situated deep within a diverticulum.78,97 

Treatment and Prognosis Extraluminal duodenal diverticula rarely require therapeutic intervention. Resection of duodenal diverticula should never be performed for vague abdominal complaints. Bleeding, diverticulitis, and perforation are the most common problems associated with duodenal diverticula. Endoscopic control of bleeding from diverticula has been accomplished using various techniques, including bipolar cautery, epinephrine injection, and hemoclips.89,90,98 If the diagnosis is not made preoperatively, surgical control of bleeding can be accomplished through a duodenotomy. Many patients with duodenal perforation or diverticulitis undergo surgery for diagnosis and treatment including drainage and resection of the involved diverticulum, if feasible. In resecting the diverticulum, the pancreatic duct and bile duct can be injured, leading to biliary and pancreatic duct leaks and pancreatitis. If the diagnosis of duodenal diverticulitis is made preoperatively, conservative therapy with percutaneous drainage and antibiotics is preferred.88 Whipple procedure is a last resort and may be needed in the patient who has undergone inadvertent transection of the bile duct and pancreatic duct at time of diverticulectomy. 

Intraluminal Diverticula Epidemiology, Etiology, and Pathogenesis Intraluminal duodenal diverticula are very rare. Most patients present between the ages of 30 and 60, with men and women equally affected.99 Intraluminal duodenal diverticula (windsock diverticula) are single saccular structures that originate in the second portion of the duodenum. They are connected to the entire circumference or only to part of the wall of the duodenum and may project as far distally as the fourth part of the duodenum.

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Fig. 26.9  Intramural duodenal diverticulum (windsock diverticulum). A, Diverticulum attached to entire duodenal circumference. B, Diverticulum attached to only part of the duodenal circumference.

Ampulla of Vater

Ampulla of Vater

A

There is often a second opening located eccentrically in the sac (Fig. 26.9). Both sides of the diverticulum are lined by duodenal mucosa. During early fetal development, the duodenal lumen is occluded by proliferating epithelial cells and later recanalized (see Chapter 49). Abnormal recanalization may lead to a duodenal diaphragm or web. Over time, peristaltic stretching may transform the diaphragm into an intraluminal diverticulum. 

Clinical Features and Diagnosis Intraluminal diverticula are often asymptomatic but may become symptomatic at any age. The most common symptoms are those of incomplete duodenal obstruction, including nausea, vomiting, and abdominal pain.99 The typical radiographic appearance is that of a barium-filled globular structure of variable length, originating in the second portion of the duodenum, with its fundus extending into the third portion and outlined by a thin radiolucent line. The CT appearance has been reported as a ring-like soft tissue density in the lumen of the second portion of the duodenum, outlined with oral contrast and containing oral contrast and a small amount of air (halo sign).100 At endoscopy, an intraluminal diverticulum is a sac-like structure with an eccentric aperture or a large, soft, polypoid mass if the diverticulum is inverted orad.101,102 Endoscopic diagnosis may be difficult. A long sac may be mistaken for the duodenal lumen, whereas an inverted diverticulum may be mistaken for a large polyp. 

Complications Obstruction may be precipitated by retention of vegetable material or foreign bodies within the diverticulum, which commonly include food and less commonly coins or marbles.103-105 Pancreatitis and bleeding have also been reported.92,101 Gastric retention or dilation of the duodenal bulb may result from chronic partial obstruction caused by the diverticulum. 

Treatment and Prognosis Treatment may include resection in patients with symptoms of obstruction or bleeding, which can be performed laparoscopically.99 Successful endoscopic resection of intraluminal duodenal diverticula has also been reported.106 

JEJUNAL DIVERTICULA In 1881, Sir William Osler wrote about a patient with jejunal diverticula who, for years, “had suffered much from loud rumbling noises in his belly, particularly after each meal. So loud were

B they that it was his habit, shortly after eating, to go out and take a walk to keep away from people, as the noises could be heard at some distance.”107

Epidemiology, Etiology, and Pathophysiology Diverticula of the small bowel (apart from duodenal and Meckel diverticula) are most commonly found in the proximal jejunum and are seen in approximately 1% of the population.108 About 80% of jejunoileal diverticula arise in the jejunum, 15% in the ileum, and 5% in both; small bowel diverticula have been found in about 0.5% to 5% of small bowel x-rays and autopsies.109,110 They are commonly multiple and can vary from a few millimeters to several centimeters in size. They are usually located on the mesenteric border of the small bowel. Small bowel diverticula generally lack a true muscular wall and are considered as acquired. The cause of jejunoileal diverticula is largely unknown. Many patients have an underlying intestinal motility disorder. Periodically elevated intraluminal pressures can lead to herniation through areas of weakness at the mesenteric border where blood vessels penetrate the muscularis. Visceral neuropathies and myopathies, including progressive systemic sclerosis, can lead to chronic atrophy and fibrosis of the intestinal wall, with resultant herniation and diverticula formation (see Chapter 37).111 

Clinical Features and Diagnosis Jejunal diverticula are best diagnosed by UGI radiography with small bowel follow-through or CT with oral contrast and can also be identified on small bowel enteroscopy and video capsule endoscopy.112-115 Jejunal diverticula most commonly occur on the mesenteric border of the bowel, in contrast to Meckel diverticula, which occur on the antimesenteric border. Many cases of jejunoileal diverticulosis are asymptomatic or associated with nonspecific symptoms for which patients may not seek medical attention. About 40% of cases are discovered incidentally.110 Various symptoms and clinical problems may occur with jejunal diverticula. The most common clinical features are recurrent abdominal pain, early satiety, and bloating. Loud borborygmi and intermittent diarrhea may occur, symptoms which may be caused by an underlying motility disorder.116 

Complications Similar to diverticula of the colon, complications of jejunal diverticula include bleeding, diverticulitis, and perforation. Bleeding jejunal diverticula have been treated during double-balloon enteroscopy, although there is some risk of perforation.117-119 Malabsorption may result from associated small bowel bacterial

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overgrowth (see Chapters 104 and 105).110,120 Patients with jejunal diverticulosis and severe dysmotility can develop intestinal pseudo-obstruction (see Chapter 124). Patients with intestinal pseudo-obstruction may periodically have small amounts of free intraperitoneal air (pneumoperitoneum) without overt perforation.121 If such patients are otherwise well, they should be carefully observed. Surgical intervention is often not necessary. Bleeding from small bowel diverticula may be difficult to localize.117,122 If a source of bleeding is discovered in the small bowel at angiography, it may be useful to leave a small catheter within the feeding vessel as the patient is taken to the operating room. When the patient is explored, a small amount of dye can be injected through the catheter, staining the involved bowel. This may help the surgeon localize an otherwise obscure lesion. Diverticulitis may result in free perforation or an abscess contained within the mesentery.123 The finding of an inflammatory mass in the mesentery should raise the possibility of a perforated small bowel diverticulum.124 Because jejunal diverticula usually project into the mesentery, they can be difficult to detect, even at surgery. Large enteroliths can form in jejunal diverticula and lead to mucosal erosion, with bleeding, diverticulitis, perforation, or

intestinal obstruction.123,125,126 Jejunal diverticulosis has also been associated with small bowel volvulus.127 

Treatment and Prognosis In patients with small bowel diverticulosis and suspected dysmotility, the use of oral antibiotics to treat associated bacterial overgrowth may lead to improvement in bloating and diarrhea, as well as malabsorption (see Chapters 104 and 105).128 In patients with bleeding, perforation, or diverticulitis, a limited surgical resection of the affected section of the bowel should be performed, but this may be difficult to localize with precision.123,129 In patients with symptoms of chronic intestinal pseudo-obstruction, surgery should generally be avoided, although carefully selected patients may benefit.130 If a long segment of bowel is resected in an attempt to remove all the diverticula, the patient may be left with short bowel syndrome, which can lead to severe disability (see Chapter 106). Full references for this chapter can be found on www.expertconsult.com

.

27

27

Abdominal Hernias and Gastric Volvulus D. Rohan Jeyarajah, Kerry B. Dunbar

CHAPTER OUTLINE DIAPHRAGMATIC HERNIAS�������������������������������������������� 381 Hiatal and Paraesophageal Hernias������������������������������ 381 Congenital Diaphragmatic Hernias������������������������������� 384 Traumatic and Posttraumatic Diaphragmatic Hernias���� 386 GASTRIC VOLVULUS 386 INGUINAL AND FEMORAL HERNIAS 388 OTHER VENTRAL HERNIAS 391 Incisional Hernias��������������������������������������������������������� 391 Epigastric and Umbilical Hernias���������������������������������� 393 Spigelian Hernias��������������������������������������������������������� 393 PELVIC AND PERINEAL HERNIAS 394 LUMBAR HERNIAS 395 INTERNAL HERNIAS 395 ��������������������������������������������������������

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A hernia is a protrusion of an organ or structure into an opening or pouch. Abdominal wall hernias protrude through the muscular and fascial walls of the abdomen and have 2 parts: (1) the orifice or defect in the aponeurotic wall of the abdomen, and (2) the hernia sac, which consists of peritoneum and abdominal, contents. Abdominal wall hernias are external if the sac protrudes through the abdominal wall or interparietal if the sac is contained within the abdominal wall. Internal hernias are contained within the abdominal cavity and do not always have a hernia sac. Hernias are reducible when the protruding contents can be returned to the abdomen and irreducible or incarcerated when they cannot. A hernia is strangulated when the vascular supply of the protruding organ is compromised, and as a consequence the organ becomes ischemic or necrotic. An incarcerated hernia is generally repaired because there is danger of strangulation, which can result in the loss of bowel. Because it can be difficult to determine whether a hernia is incarcerated or strangulated, incarcerated hernias are considered urgent and treated with surgical intervention. Another type of hernia is a Richter hernia, where only one side of the bowel (most often the antimesenteric side) protrudes through the hernia orifice. As opposed to other hernias, strangulation may occur in a Richter hernia without intestinal obstruction, making this type of hernia a diagnostic challenge.

hiatal and paraesophageal hernias. Technically, all these hernias are hiatal hernias because they pass through the esophageal hiatus of the diaphragm. These are centrally located hernias.

Etiology and Pathophysiology Sliding hiatal hernias (type I) occur when the gastroesophageal junction and some portion of the stomach are displaced above the diaphragm, but the orientation of the stomach axis is unchanged. The frequency of sliding hiatal hernias increases with age. The phrenoesophageal membrane anchors the gastroesophageal junction to the diaphragm (see Chapters 43 and 46). Hiatal hernias may be caused by age-related deterioration of this membrane, combined with normal positive intra-abdominal pressure and traction of the esophagus on the stomach as the esophagus shortens during swallowing.1 Paraesophageal hernias (type II) occur when the stomach protrudes through the esophageal hiatus alongside the esophagus (Fig. 27.1A). The gastroesophageal junction remains in a normal position at the level of the diaphragm, because there is preservation of the posterior phrenoesophageal ligament and normal anchoring of the gastroesophageal junction, and only the stomach moves proximally.2 The entire stomach can pass into the chest (see Fig. 27.1B). Most paraesophageal hernias contain a sliding hiatal component in addition to the paraesophageal component and are thus mixed diaphragmatic hernias (type III [see Fig. 27.1C]).3 With a paraesophageal hernia, other intra-abdominal structures (e.g., omentum, colon, spleen) may also herniate (type IV). A barium study is often obtained to diagnose these defects. However, cross sectional imaging with CT scan will be the test of choice to document a type IV defect, as the barium study may not reveal adjacent colon or pancreas through the hiatus. When diagnosing a hiatal or paraesophageal hernia, important questions for the radiologist to address include: (1) Does the gastroesophageal junction lie at or above the hiatus? (2) Does the stomach or any other visceral structure lie above the gastroesophageal junction? For example, if the gastroesophageal junction is above the hiatus and there is stomach above it, the patient has a type III (mixed) hernia. 

Epidemiology

There are 3 main types of diaphragmatic hernias: hiatal and paraesophageal hernias (both involve the hiatus), congenital hernias, and traumatic hernias.

Estimates of the prevalence of hiatal hernia vary widely, ranging from 14% to 84% of patients examined, depending on the patient population, method of diagnosis, and symptoms present.4-8 In general, hiatal hernias are more frequent in patients with GERD.8 About 90% to 95% of hiatal hernias found by radiograph are sliding (type I) hernias; the remainder are paraesophageal hernias.3,7 Most sliding hiatal hernias are small and of little clinical significance. Patients with symptomatic paraesophageal hernias are most often middle-aged to older adults. 

Hiatal and Paraesophageal Hernias

Clinical Features, Diagnosis, and Complications

The most common diaphragmatic hernias are sliding hernias of the stomach through the esophageal hiatus, which include

Many patients with small simple sliding hiatal hernias are asymptomatic. The main clinical significance of the sliding hiatal hernia

DIAPHRAGMATIC HERNIAS

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PART IV  Topics Involving Multiple Organs

A

B

C

D

E

 

Fig. 27.1 A, Paraesophageal (type II) hernia. Barium study showing a paraesophageal hernia with a portion of the stomach above the diaphragm. B, This barium study showing a paraesophageal hernia complicated by an organoaxial volvulus of the stomach (see Fig. 27.5). The gastroesophageal junction remains in a relatively normal position below the diaphragm (arrow). C, The retroflexed endoscopic view of the proximal stomach demonstrates the endoscope traversing a sliding hiatal hernia adjacent to a large paraesophageal hernia. D, Cameron lesion. A large hiatal hernia is seen on endoscopic retroflexed view, with a Cameron lesion at the level of the diaphragmatic hiatus at the 5-o’clock position. E, Laparoscopic view of a paraesophageal hernia. (B, Courtesy Dr. Herbert J. Smith, Dallas, Tex.)

is its contribution to gastroesophageal reflux (see Chapter 44). In addition to heartburn and regurgitation, patients with large sliding hiatal hernias may complain of dysphagia or discomfort in the chest or upper abdomen. With chest radiography, a hiatal hernia may be noted as a soft tissue density or an air-fluid level in the retrocardiac area. Hiatal hernias are sometimes diagnosed on UGI barium studies. CT can demonstrate the proximal stomach above the diaphragmatic hiatus. At endoscopy, the gastroesophageal junction is noted to be proximal to the impression of the diaphragm. Patients with paraesophageal or mixed hiatal hernias are rarely completely asymptomatic if closely questioned. Many patients with paraesophageal hernias have gastroesophageal

reflux, particularly those with larger paraesophageal hernias.3,9 Other symptoms include dysphagia, chest pain, vague postprandial discomfort, and shortness of breath, and some patients will have iron deficiency anemia due to chronic GI blood loss.9,10 A paraesophageal or mixed hiatal hernia may be seen on a chest radiograph as an abnormal soft tissue density (often with a gas bubble) in the mediastinum or left chest. UGI radiography is the best diagnostic study (see Fig. 27.1A). CT scanning can demonstrate that part of the stomach is in the chest. Differences between UGI radiography and CT scan can sometimes be seen, as the latter is performed in the supine position where the stomach may migrate further into the chest. Paraesophageal

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CHAPTER 27  Abdominal Hernias and Gastric Volvulus

hernias are usually obvious on upper endoscopy (see Fig. 27.1B), but the paraesophageal component of a large mixed hernia may be missed. Cameron lesions or linear erosions may develop in patients with sliding hiatal hernias, particularly large hernias (see Chapter 20). These mucosal lesions are usually found on the lesser curve of the stomach at the level of the diaphragmatic hiatus (see Fig. 27.1D). This is the location of the rigid anterior margin of the hiatus formed by the central tendon of the diaphragm. Mechanical trauma, ischemia, irritation by pills, and peptic injury have been proposed as the cause of these lesions. The prevalence of Cameron lesions in patients with hiatal hernias who undergo endoscopy has been reported to be about 5%, with the highest prevalence in the largest hernias, with rates of approximately 30% in paraesophageal hernias referred for surgical repair.11-13 Cameron lesions may cause acute or chronic UGI bleeding with a poor response to acid suppression therapy.14 Iron deficiency anemia due to chronic bleeding is seen in 30% to 40% of patients with paraesophageal hernia.9,13 The presence of Cameron lesion(s) and occult GI bleeding is one factor that will influence the surgeon’s decision to repair a paraesophageal hernia that is otherwise apparently asymptomatic. Gastric volvulus is a life-threatening complication of paraesophageal hernia. Symptoms include acute abdominal pain and retching, and it can progress rapidly to a surgical emergency (see “Gastric Volvulus”). With UGI radiography or CT, lack of filling the gastric lumen with contrast or gastric wall thickening with pneumatosis can increase suspicion for a volvulus and associated gastric necrosis.15 The diagnosis of gastric volvulus is mostly clinical and the clinician must have a low threshold to entertain this diagnosis in a patient with a known paraesophageal hernia and new symptoms. Endoscopy may be difficult if the hernia is associated with gastric volvulus, and reaching the pylorus may be a challenge due to positioning of the stomach.16 

Treatment and Prognosis Simple sliding hiatal hernias do not require treatment, unless symptomatic from reflux (see Chapter 46). Patients with symptomatic giant sliding hiatal hernias, paraesophageal, or mixed hernias should be offered surgery. When closely questioned, most patients with type II, III, or IV hernias will have symptoms.9,10 In the past, all paraesophageal hernias were thought to be a surgical emergency, but it is now clear that the risk of progression to gastric necrosis is lower than initially believed.17 Elective repair of paraesophageal hernias is more frequently offered to symptomatic patients, although some experts suggest that surgery should be offered to all patients with paraesophageal hernias because of the risk of future complications.3,9,18,19 In general, a selective approach to patients with large paraesophageal hernias is warranted; those with symptoms that may be due to the hernia should be considered for surgical intervention, depending on other comorbidities. A careful history is essential for determining the presence of symptoms. One should pay careful attention to chest pain and postprandial shortness of breath; these may be symptoms related to the paraesophageal hernia. Indeed, patients with pulmonary issues may benefit from having their paraesophageal hernias repaired to create room in the chest and decrease aspiration events. The extent of the preoperative evaluation needed for paraesophageal hernia repair is controversial. Patients often have already had a barium esophagogram or other esophageal study that characterizes the paraesophageal hernia. Many surgeons recommend routine preoperative evaluation with esophageal manometry and ambulatory esophageal pH monitoring because of the high prevalence of associated gastroesophageal reflux and esophageal motility disorders, while others may forgo pH testing and use reflux symptoms as a guide for the type of repair

383

chosen.20 The idea behind forgoing pH testing is that the result will not change the surgical management of the patient, who will receive hernia reduction and wrap of some kind anyway. Options for assessment of esophageal pH include 24-hour impedance/ pH testing and 48-hour wireless capsule pH monitoring. The object of manometric evaluation is to determine whether the patient has a significant motility disorder (e.g., achalasia, aperistalsis) and what type of fundoplication is needed in patients with reflux symptoms (complete vs. partial wrap). However, esophageal manometry is challenging in these patients, and anatomic distortions can make it difficult to identify the lower esophageal sphincter, making this measurement unreliable.21-24 Patients with dysphagia should be studied to ensure that significantly abnormal motility is not present. Many surgeons routinely add a fundoplication to hernia repairs to prevent postoperative reflux esophagitis and to fix the stomach in the abdomen. However, in patients with motility disorders, the surgeon may elect to perform a loose anterior wrap (Dor fundoplication) or use a gastrostomy tube or gastropexy to fix the stomach intra-abdominally. The authors’ practice is to forgo motility and pH testing, as the preference is to perform an incomplete wrap of some kind and not a 360-degree wrap that is dependent on good motility. Addition of gastropexy may reduce the recurrence rate after hernia repair.25,26 The principles of surgery for repair of hiatal or paraesophageal hernias include 4 main elements: (1) reduction of the hernia from the mediastinum or chest, with excision of the hernia sac; (2) reconstruction of the diaphragmatic hiatus, with simple posterior closure with or without bolstering with prosthetic mesh; (3) providing bulk at the hiatus to prevent prolapse into the chest with a fundoplication, which can lessen postoperative reflux; and (4) addition of a gastropexy or gastrostomy tube to provide an additional tacking mechanism for the stomach intraabdominally. These elements can be accomplished minimally invasively (laparoscopically or robotically), or via open operation performed through the abdomen or chest.3,18,27,28 Most patients are approached minimally invasively through the abdomen, which leads to a shorter hospital stay, less postoperative pain, and an equivalent risk of recurrence (see Fig. 27.1E).27,28 Reduction of chronic paraesophageal hernias from the chest can be difficult and may be approached through a combined thoracoscopic and abdominal procedure. Injury to the lung can occur with vigorous traction; however, as the diaphragmatic defect is central (medial) rather than peripheral (lateral), as in a traumatic defect, intense lung adhesions are usually not present. Resection of the hernia sac can result in violation of the left chest, requiring chest tube placement. Reconstruction of the diaphragm can be performed by placing nonabsorbable sutures posterior to the esophagus.22,23 Use of prosthetic mesh has resulted in fewer recurrences in some studies.29-31 The use of mesh is still controversial as there has been no clear long-term results demonstrating a decreased risk of hernia recurrence. However, most surgeons are wary of using synthetic mesh close to the esophagus, and therefore “biological” products are favored. The shape of the mesh is also an area of controversy. Keyhole mesh can be used, in which the esophagus is completely encircled with mesh, with the concern being dysphagia in this situation.30,32 Alternatively, U-shaped mesh can be used, where the anterior portion is left open, therefore reinforcing only posteriorly (the major area of recurrence). Fixation of the stomach in the abdomen is usually achieved by using a fundoplication, which provides some bolstering effect at the hiatus to keep the stomach in the abdomen and can reduce postoperative gastroesophageal reflux. Additional use of gastropexy, with suturing of the stomach to the abdominal wall or gastrostomy tube placement for 2 weeks to allow the stomach to mature to the abdominal wall, may result in fewer recurrences.25 It is the authors’ preference to perform a Dor fundoplication, close the diaphragm with keyhole biological mesh, and place a temporary

27

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PART IV  Topics Involving Multiple Organs

gastrostomy tube (as a pexy) in all patients with large paraesophageal hernias. Patients with sliding hiatal or paraesophageal hernias may have shortening of the esophagus. This makes it difficult to restore the gastroesophageal junction below the diaphragm without tension, a key factor in decreasing recurrence. In such cases, an extra length of neoesophagus can be constructed from the proximal stomach (Collis-Nissen procedure).33 In this situation, a stapler is fired parallel to the axis of the esophagus along a bougie that is passed into the stomach, creating a lengthened esophagus. Alternatively, transmediastinal dissection of the esophagus for more than 5 cm into the chest will usually result in adequate intra-abdominal length of esophagus without the need for additional stapling.34 In the authors’ experience, if an adequate transmediastinal dissection is undertaken with excision of the hernia sac, esophageal lengthening is rarely needed. Potential surgical complications include esophageal and gastric perforation, pneumothorax, and liver laceration. Potential long-term complications may include dysphagia if the wrap is too tight or gastroesophageal reflux if the fundoplication breaks down or migrates into the chest. When examined closely, radiographic recurrence after paraesophageal hernia repair is 15% to 25%.28,35 However, the clinical impact of a recurrence may be minimal because most of these patients remain symptom free and do not require further treatment.36 The patient who develops both reflux and dysphagia after paraesophageal hernia repair should be evaluated for a symptomatic recurrence. This is best performed by a UGI barium study. Upper endoscopy can also be helpful and provide dynamic information. The retroflex view from the stomach will demonstrate the presence or absence of a paraesophageal hernia. Recurrence is higher in obese patients and many will favor a Roux-en-Y gastric bypass (RYGB) procedure in those that have a BMI greater than 35kg/m2.37,38 

Congenital Diaphragmatic Hernias Congenital diaphragmatic hernias (CDHs) are rare but can have significant complications. Many are diagnosed at birth.

Etiology and Pathophysiology CDHs result from failure of fusion of the multiple developmental components of the diaphragm (Fig. 27.2). Embryologically, the diaphragm is derived from the septum transversum, which separates the peritoneal and pericardial spaces, the mesentery

1

1

2

3

3

Fig. 27.2  Congenital diaphragmatic hernias. Diagram of the diaphragm viewed from below with areas of potential herniation shown. 1, Sternocostal foramina of Morgagni anteriorly. 2, Esophageal hiatus. 3, Lumbocostal foramina of Bochdalek posteriorly. Arrows indicate the direction of herniation.

of the esophagus, the pleuroperitoneal membranes, and muscle of the chest wall. Morgagni hernias form anteriorly at the sternocostal junctions of the diaphragm, and Bochdalek hernias form posterolaterally at the lumbocostal junctions of the diaphragm.39 Bochdalek hernias most commonly manifest immediately after birth and are commonly associated with pulmonary hypoplasia. 

Epidemiology Congenital diaphragmatic hernias occur in about 1/2000 to 1/10,000 births, with some types seen more frequently in males.40-43,44 Hernias manifesting in neonates are most often Bochdalek hernias. With the routine use of prenatal ultrasound, CDHs can be discovered in the prenatal period. The presence of intra-abdominal contents in the chest during fetal development results in significant hypoplasia of the lung. It is the degree of pulmonary dysfunction, not the presence of the hernia per se, that determines the child’s prognosis. Prenatal measures are then taken to prepare for the pulmonary hypoplasia that invariably accompanies a large CDH. Only a few Bochdalek hernias are first discovered in adulthood.45 Bochdalek hernias occur on the left side in about 80% of cases (Fig. 27.3).46-48 Right-sided Bochdalek hernias usually contain liver in the right chest. Morgagni hernias make up about 2% to 3% of surgically treated diaphragmatic hernias (Fig. 27.4).49,50 Although thought to be congenital, they usually manifest in adults and occur on the right side in 80% to 90% of cases.49 

Clinical Features, Diagnosis, and Complications The clinical presentation of congenital diaphragmatic hernias varies greatly, from death in the neonatal period to an asymptomatic serendipitous finding in adults. Newborns with Bochdalek hernia have respiratory distress, absent breath sounds on one side of the chest, and a scaphoid abdomen.51 Serious chromosomal anomalies are found in 30% of cases, but in many cases the exact mutation (or mutations) cannot be identified.52 Pulmonary hypoplasia occurs on the side of the hernia, but some degree of hypoplasia may also occur in the contralateral lung. Pulmonary hypertension is common. The major causes of mortality in infants with Bochdalek hernias are respiratory failure and associated anomalies, which can include cardiac abnormalities and musculoskeletal defects.51 Most of these neonates are diagnosed in utero with routine use of prenatal ultrasound, which visualizes stomach or loops of bowel in the chest. The pregnancy is considered high risk when congenital diaphragmatic hernia is diagnosed in the prenatal period. These babies are delivered electively and preparations are made for immediate extracorporeal membrane oxygenation (ECMO). In older children and adults, a Bochdalek hernia may manifest as an asymptomatic chest mass. The differential diagnosis includes mediastinal or pulmonary cyst or tumor, pleural effusion, or empyema. Symptoms, when present, can include pain, pulmonary symptoms, and obstructive symptoms and are due to herniation of the stomach, omentum, colon, or small bowel.48 About 30% of adult patients present with acute emergencies caused by strangulation, and gastric volvulus can occur.48 Other patients may have chronic intermittent symptoms, including chest discomfort, shortness of breath, dysphagia, nausea, vomiting, and constipation. The diagnosis may be suspected on a chest radiograph, particularly a lateral view. The key finding is a posterior chest mass, as the defect of Bochdalek is posterior. The diagnosis may be confirmed by barium UGI radiography (useful if only the stomach is involved), CT, or MRI.40,48 Morgagni hernias are most likely to manifest in adult life. They may contain omentum, stomach, colon, or liver. Bowel sounds may be heard in the chest if bowel has herniated through the defect. As with Bochdalek hernias, the diagnosis is often

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27

A

B Fig. 27.3  Bochdalek hernia. A, This plain chest film shows a Bochdalek hernia as a small opacity in the posterior chest at the level of the diaphragm, with bowel in the left chest (arrows). B, CT of the same patient showing bowel above the diaphragm and causing a mediastinal shift.

B

A

Fig. 27.4  Morgagni hernia. A, A mass is noted in the right chest on a chest film (posteroanterior view). B, Lateral chest film shows that the mass is in the anterior chest. C, Barium enema shows that a portion of the transverse colon is the hernia (top left). D, CT shows a contrast-filled colon in the right anterior chest (11-o’clock position).

D

C

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PART IV  Topics Involving Multiple Organs

made by chest radiography, particularly the lateral view, because Morgagni hernias are anterior, differentiating this hernia from a Bochdalek defect (see Fig. 27.4). The contents of the hernia can be confirmed with barium radiography or CT (see Fig. 27.3A and B and Fig. 27.4C and D). The differential diagnosis is similar to that of Bochdalek hernias. Many patients have no symptoms or nonspecific symptoms such as chest discomfort, cough, dyspnea, and upper abdominal distress. Gastric, omental, or intestinal incarceration with obstruction and ischemia may cause acute symptoms.49,50 

Treatment and Prognosis For infants with Bochdalek hernias, intubation and mechanical ventilation are often needed at the time of delivery. ECMO is useful in some cases with cardiac dysfunction and pulmonary hypertension.51 Once the infant’s pulmonary issues have stabilized, surgical repair is performed, either open or laparoscopically, using a mesh prosthesis. Despite advances in critical care and surgical techniques, the mortality rate is still around 60%, although higher survival rates have been reported by some centers.51 The abdomen may not be able to tolerate the increased pressure when the intestinal contents are reduced, and therefore a gradual abdominal closure (“Silo” technique) can also be used.53 Laparoscopic and thoracoscopic repair of Bochdalek hernias have been reported.48,54 Morgagni hernias have been repaired through the chest or abdomen, using open, thoracoscopic, and/ or laparoscopic techniques.49,50 An abdominal laparoscopic approach is favored in small diaphragmatic hernias. One must be careful to note the inferior epigastric vessels that are present in the location of the Morgagni hernia. This anterior defect can be bridged with synthetic mesh. Larger Bochdalek defects require open approach with use of prosthetic mesh. 

Traumatic and Posttraumatic Diaphragmatic Hernias Etiology and Pathogenesis Traumatic diaphragmatic hernias are caused by blunt trauma such as motor vehicle accidents in about 75% of cases, and by penetrating trauma such as stab or gunshot wounds in the remainder.55 During blunt trauma, abrupt changes in intraabdominal pressure may lead to large rents in the diaphragm. A huge impact is needed to cause a diaphragmatic injury. As such, associated injuries are commonly life threatening in the circumstance of a blunt diaphragmatic injury. Penetrating injuries often cause only small lacerations. Blunt trauma is more likely than penetrating trauma to eventually lead to herniation of abdominal contents into the chest, because the defect is usually larger. The right hemidiaphragm is somewhat protected by the liver during blunt trauma. Thus, in one series, 68% of diaphragmatic injuries from blunt trauma occurred on the left side, 24% on the right side, 1.5% were bilateral, 1% pericardial, and 5% unclassified.55 Diaphragmatic injury may not result in immediate herniation, but with time, normal relative negative intrathoracic pressure may lead to gradual enlargement of a small diaphragmatic defect and protrusion of abdominal contents through the defect, leading to a delayed diagnosis in about 15% of cases.56 Stomach, omentum, colon, small bowel, spleen, and even kidney may be found in a posttraumatic diaphragmatic hernia. 

Epidemiology The incidence of posttraumatic diaphragmatic hernia is uncertain. Diaphragmatic injury occurs in about 5% of patients with multiple traumatic injuries who undergo laparotomy and was found in approximately 1% of patients in a large trauma database.57,58 

Clinical Features, Diagnosis, and Complications Posttraumatic diaphragmatic hernias may cause respiratory or abdominal symptoms. After serious trauma, rupture of the diaphragm is often masked by other injuries.59 Penetrating injuries between the fourth intercostal space and the umbilicus should raise the level of suspicion of a diaphragmatic injury. Respiratory or abdominal symptoms manifesting several days to weeks after injury should suggest the possibility of a missed diaphragmatic injury. The diaphragm must be closely inspected to detect injury at the time of exploratory laparotomy or laparoscopy, as these injuries can easily be missed. Careful examination of the chest radiograph or CT is important but is diagnostic in only 40% to 80% of cases, depending on the type of CT performed.60 The coronal and sagittal reconstructions can show the defect in the diaphragm. In patients on ventilatory support after trauma, positive intrathoracic pressure may prevent herniation through a diaphragmatic tear. However, on attempted ventilator weaning, herniation may occur, causing respiratory compromise. Symptoms may also manifest long after injury. Delays of more than 10 years have been reported.56 In such cases, the patient may not connect the acute illness with remote trauma. The treating physician should consider a traumatic cause when a diaphragmatic defect is not hiatal and is not located in the usual locations of congenital defects. 

Treatment and Prognosis Acute diaphragmatic ruptures are most commonly approached from the abdomen during exploratory laparotomy or laparoscopy. Associated intra-abdominal injuries that can be life threatening must be ruled out in these cases. However, a chest approach can be undertaken. Diagnostic laparoscopy has been used in patients who are thought to have a high risk of diaphragmatic injury, but appear to have no other visceral injury (e.g., after a stab wound to the lower chest).61 Chronic posttraumatic diaphragmatic hernias are characterized by a lack of a peritoneal lining, or hernia sac. As such, these hernias are commonly associated with extensive adhesions to adjacent lung, reduction of which can cause significant bleeding. In such cases, repair is best performed through the chest or by a combined thoracoscopic-abdominal approach, although laparoscopic or thoracoscopic repair has been reported.61 A combined thoracoscopic-abdominal approach lowers the risk of lacerating the lung if adhesions and absence of a peritoneal hernia sac complicate the abdominal approach. 

GASTRIC VOLVULUS Gastric volvulus results when the stomach twists on itself, but rarely occurs unless there is an associated diaphragmatic hernia. Paré described the first case of gastric volvulus in 1579 in a patient who had a diaphragmatic injury from a sword wound. Gastric volvulus may be transient and produce few symptoms, or it may lead to obstruction and ischemia.

Etiology and Pathophysiology The stomach is normally fixed in position by ligamentous attachments to the spleen, liver, and diaphragm. When there is normal intestinal rotation, the duodenum is fixed to the retroperitoneum, which results in pexy of the distal stomach. Laxity of these ligamentous attachments, elevation of the left hemidiaphragm, or fixation of an otherwise mobile stomach to a specific point can result in volvulus. Focal adhesions, gastric tumor, or masses in adjacent organs may predispose to gastric volvulus. In two thirds of cases, the volvulus occurs above the diaphragm in association with a paraesophageal or mixed diaphragmatic hernia. In the other third of cases, volvulus occurs below the diaphragm.

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CHAPTER 27  Abdominal Hernias and Gastric Volvulus

Gastric volvulus may be mesenteroaxial or organoaxial (Fig. 27.5).62 In mesenteroaxial volvulus, the stomach folds on its short axis, which runs across the stomach from the lesser curvature to the greater curvature (see Fig. 27.5, 1A and 1B), with the antrum twisting anteriorly and superiorly. In rare cases, the antrum and pylorus rotate posteriorly. Mesenteroaxial volvulus is often incomplete and intermittent, manifesting chronic symptoms. In organoaxial volvulus, the stomach twists along its long axis, which passes through the esophagastric junction region to the pylorus. In most cases, the antrum rotates anteriorly and superiorly and the fundus posteriorly and inferiorly, twisting the greater curvature at some point along its length (see Fig. 27.5, 3A and 3B). Less commonly, the long axis passes through the body of the stomach itself, in which case the greater curvature of the antrum and fundus rotate anteriorly and superiorly (see Fig. 27.5, 2A and 2B). This type of volvulus is commonly associated with a diaphragmatic hernia. Organoaxial volvulus is usually an acute event. Mixed mesenteroaxial and organoaxial volvulus has also been reported.63

Epidemiology The incidence and prevalence of gastric volvulus are unknown. It is difficult to estimate how many cases are intermittent and

1

A

B

387

undiagnosed. About 15% to 20% of cases occur in children younger than 1 year of age, most often in association with a congenital diaphragmatic defect. The peak incidence in adults is in the fifth decade. Men and women are equally affected.64,65 

27

Clinical Features, Diagnosis, and Complications Acute gastric volvulus causes sudden severe pain in the upper abdomen or lower chest, associated with the inability to swallow. Persistent unproductive retching is common. In cases of complete volvulus, it is impossible to pass a nasogastric tube into the stomach. Hematemesis is rare but may be due to an esophageal tear or gastric mucosal ischemia.65 Vascular compromise and gastric infarction may occur. The combination of pain, unproductive retching, and inability to pass a nasogastric tube is called Borchardt triad.66 If the volvulus is associated with a diaphragmatic hernia, plain chest or abdominal films will show a large gas-filled structure in the chest.15 CT is often obtained in the emergency department and will show the stomach in the chest. A barium UGI radiograph will confirm the diagnosis but is often unnecessary in the case of the classic triad and diagnostic CT. Upper endoscopy may show twisting of the gastric folds (Fig. 27.6C). Acute gastric volvulus is a surgical emergency. The surgeon must have a low threshold for making this diagnosis in a patient that presents with this symptom complex. Delay in surgery can result in gastric necrosis, which has a high mortality. Chronic gastric volvulus is associated with mild and nonspecific symptoms like dysphagia, epigastric discomfort or fullness, bloating, and heartburn, particularly after meals. Symptoms may be intermittent and present for months to years.65 A substantial number of cases likely go unrecognized. The diagnosis should be suspected in the proper clinical setting if a UGI radiograph or CT shows a large diaphragmatic hernia, even if the stomach is not twisted at the time of the radiograph.15 

Treatment and Prognosis 2

A

B

A

B

3

Fig. 27.5  Pathogenesis of gastric volvulus. 1A, Axis for potential mesenteroaxial volvulus bisecting the lesser and greater curvatures. 1B, Mesenteroaxial volvulus resulting from anterior rotation of the antrum along this axis. 2A, Axis for potential organoaxial volvulus passing through the body of the stomach. 2B, Organoaxial volvulus resulting from anterior-superior rotation of the antrum along this axis. 3A, Axis for potential organoaxial volvulus passing through the gastroesophageal junction and the pylorus. 3B, Organoaxial volvulus resulting from anterior-superior rotation of the antrum and posterior-inferior rotation of the fundus along this axis. (Adapted from Carter R, Brewer LA 3rd, Hinshaw DB. Acute gastric volvulus. A study of 25 cases. Am J Surg 1980; 140:101–6.)

Acute gastric volvulus is an emergency, with a mortality rate in the vicinity of 30%.62 Nasogastric decompression should be performed if possible. If signs of gastric infarction are not present, acute endoscopic detorsion may be considered. Using fluoroscopy, the endoscope is advanced to form an alpha loop in the proximal stomach.67 The tip is passed through the area of torsion into the antrum or duodenum if possible, avoiding excess pressure. Torque may then reduce the gastric volvulus. This technique is most often used in chronic gastric volvulus without signs of ischemia.67,68 Definitive surgical intervention should not be delayed for endoscopy. Surgery for gastric volvulus may be performed by open or minimally invasive techniques. In recent years, minimally invasive repair has become the gold standard for repair of chronic volvulus. Insufflation of the abdomen may not be hemodynamically tolerated in a critically ill patient. In this circumstance, acute torsion should be repaired open.64,65 After the torsion is reduced, the stomach is fixed by gastropexy or tube gastrostomy. Associated diaphragmatic hernia must be repaired.65,69 However, in the circumstance of a critically ill patient, the surgeon may elect to place a gastrostomy tube and later return to the operating room to complete the other components of the repair, as noted earlier. Combined endoscopic and laparoscopic repair or simple endoscopic gastropexy by placement of a percutaneous gastrostomy tube has been reported.69-71,72 Chronic gastric volvulus is treated in the same manner as acute volvulus. If the patient is clinically stable, the surgeon may elect to treat the underlying cause of the volvulus (e.g., associated paraesophageal hernia) in the usual manner, with repair of the diaphragm and fundoplication. It is unusual to have a gastric volvulus in the absence of an associated paraesophageal hernia. 

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PART IV  Topics Involving Multiple Organs

INGUINAL AND FEMORAL HERNIAS Etiology and Pathophysiology

A

GE

B

C Fig. 27.6  Gastric volvulus with paraesophageal hernia. A, Chest film showing a gas-filled mediastinal mass. B, Barium examination showing that the greater curvature and lesser curvature of the stomach are reversed in position (upside-down stomach). C, Twisting of the gastric folds at the point of torsion is noted in this endoscopic view of a gastric volvulus. (A, Courtesy Dr. Mark Feldman, Dallas, Tex.)

The abdominal wall is protected from hernia formation by several mechanisms. In the lateral abdominal wall, there are layers of muscles that together with intervening fascia provide support. These muscles travel at oblique angles to each other and therefore handle forces in various planes, affording greater support than if they were parallel to each other. In the central abdomen, the bulky rectus abdominis muscles provide a barrier to herniation. Abdominal wall hernias occur in areas where these muscles and fascial layers are attenuated, and the hernias can be congenital or acquired. In the groin, an area prone to herniation is bounded by the rectus abdominis muscle medially, the inguinal ligament laterally, and the pubic ramus inferiorly; the aponeurosis of the transversus abdominis muscle provides the deep layer. In this area, the external and internal oblique muscles thin to a fascial aponeurosis only, so there is no muscular support of the transverse abdominal fascia and the peritoneum. Upright posture causes intra-abdominal pressure to be constantly directed to this area. During transient increases in abdominal pressure (e.g., coughing, straining, heavy lifting), reflex abdominal muscle wall contraction narrows the myopectineal orifice and tenses the overlying fascia (shutter mechanism).73 Chronic cough, smoking, increasing age, and male gender are thus associated with an increased risk of hernia.74,75 During embryologic development, the spermatic cord and testis in men (the round ligament in women) migrate from the retroperitoneum through the anterior abdominal wall to the inguinal canal, along with a projection of peritoneum (processus vaginalis). The defect in the abdominal wall (internal inguinal ring) associated with this process represents an area of potential weakness through which an indirect inguinal hernia may form (Fig. 27.7). The processus vaginalis may persist in 12% to 20% of adults, further predisposing to hernia formation.76 Direct inguinal hernias do not pass through the internal inguinal ring but rather protrude through defects in an area called Hesselbach triangle, bounded medially by the rectus abdominis muscle, laterally by the inferior epigastric artery, and inferiorly by the inguinal ligament (see Fig. 27.7). Therefore, indirect inguinal hernias travel with the spermatic cord (or round ligament) and are found lateral to the inferior epigastric vessels, whereas direct hernias are found in the floor of the inguinal canal—an area supported only by the weak transversalis fascia—and are medial to the inferior epigastric vessels. Femoral hernias pass through the opening associated with the femoral artery and vein. They manifest inferior to the inguinal ligament and medial to the femoral artery (see Fig. 27.7).73 Clinical examination cannot easily differentiate indirect from direct inguinal hernias. The importance of distinguishing these 2 entities preoperatively is not critical, because the operative approach and repair are identical. However, it is important to accurately diagnose femoral hernias because they can be mistaken for lymph nodes in the groin. Misinterpreting an incarcerated loop of bowel in a femoral defect as a lymph node can lead to fine-needle aspiration of the mass and bowel injury. Any mass that is medial to the femoral arterial pulsation and inferior to the inguinal ligament should be evaluated for a femoral hernia. The omentum, colon, small bowel, and bladder are the most common contents of groin hernias, although the appendix, Meckel diverticulum, fallopian tube, and ovary have been reported to herniate.77-82 In a Richter hernia, only the antimesenteric side of the bowel protrudes. In this situation, the patient can have strangulation of the bowel without evidence of bowel obstruction, which is typically present when bowel is incarcerated in a hernia. The surgeon must be wary of the Richter hernia, as

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CHAPTER 27  Abdominal Hernias and Gastric Volvulus Spigelian hernia External oblique

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Indirect inguinal hernia

27

Spermatic cord

Inguinal ligament

Direct inguinal hernia

Internal inguinal ring

Femoral hernia

Femoral artery Femoral vein

Fig. 27.7  Anatomic diagram of Spigelian hernia, indirect and direct inguinal hernias, and femoral hernia. The external oblique muscle has been omitted, and the spermatic cord (the round ligament in women) is retracted. Spigelian hernia occurs through defects in the fused aponeurosis of the internal oblique and transverse abdominal muscles. Indirect inguinal hernia occurs through the internal inguinal ring. Direct inguinal hernia occurs through defects in the transversalis fascia in Hesselbach triangle. Femoral hernia occurs inferior to the inguinal ligament and medial to the femoral vein and femoral artery.

this can result in intestinal necrosis, despite the lack of the typical association with a bowel obstruction.

Epidemiology The lifetime risk of groin hernia requiring repair is 27% for men and 3% for women, with repair seen most often in children under age 5 and adults older than 70.83,84 The incidence increases with age, from 1% in men younger than age 45 to 3% to 5% in those older than 45. About 800,000 groin hernia repairs are performed annually in the USA.85 Of these, 80% to 90% are performed in men.83,86 Indirect inguinal hernias account for about 65% to 70% of groin hernias in men and women. In men, direct inguinal hernias account for about 30% and femoral hernias for about 1%. In women, about 25% of groin hernias requiring repair are femoral, and the occurrence increases with age.83,86 Groin hernias are somewhat more common on the right than on the left side. Congenital hernias are more common in males because they represent a patent processus vaginalis. These pediatric hernias are commonly bilateral, and pediatric surgeons are taught to always evaluate the contralateral side. 

Clinical Features, Diagnosis, and Complications Many groin hernias are asymptomatic. The most common symptom is a mass in the inguinal or femoral area that enlarges when the patient stands or strains. An incarcerated hernia may produce constant discomfort. Strangulation causes increasing pain. Symptoms of bowel obstruction or ischemia may occur. In a Richter-type hernia, pain from bowel strangulation may occur

Fig. 27.8  Plain film in a 28-year-old man with a giant incarcerated inguinal hernia. (Courtesy Dr. Michael J. Smerud, Dallas, Tex.)

without symptoms of obstruction, as only 1 wall of the intestine is involved in the hernia. The patient should be questioned about risk factors for hernia formation (e.g., smokers with a chronic cough, prostatism, constipation). These factors, if not corrected prior to herniorrhaphy, can lead to recurrence.87,88 On physical examination, inguinal hernias present as a soft mass in the groin. The mass may be larger on standing or straining. It may be slightly tender. It may be possible to palpate the fascial defect associated with the hernia. The patient should be examined upright, the examiner’s finger should be inserted into the inguinal canal, and a prolonged Valsalva maneuver should be initiated; it is normal to feel a small impulse against the examining finger with coughing. However, when a hernia is present, a prolonged Valsalva maneuver will result in protrusion of the sac, which is tender against the examiner’s finger. Direct and indirect hernias may be difficult to distinguish. Groin hernias may also be noted on a plain abdominal radiograph (Fig. 27.8), barium radiograph, sonogram, or CT, and MRI may be helpful for identifying other causes of groin pain.89 Femoral hernias are more difficult to diagnose than other groin hernias, and 30% to 40% manifest as surgical emergencies due to strangulation.74,86 The correct diagnosis is often not made before surgery. The neck of femoral hernias is usually small. Even a small femoral hernia that is difficult to palpate may cause obstruction or strangulation. Richter hernias are most common in the femoral area, further complicating the diagnosis. Femoral hernias are most common in women, in whom clinicians may have a lower level of suspicion for hernia than in men. Femoral hernias also occur in children.90 Delay in diagnosis, strangulation, and need for emergency surgery are common.86,91 Any mass below the inguinal ligament and medial to the femoral artery should raise the suspicion of femoral hernia. Femoral hernias are commonly mistaken for femoral adenopathy or groin abscess.91 Obviously, bedside incision and drainage of an incarcerated femoral hernia must be avoided, and therefore liberal use of sonography or CT is useful for distinguishing a hernia from adenopathy,

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PART IV  Topics Involving Multiple Organs

abscess, or other masses.89 The radiologist should perform these examinations with and without a prolonged Valsalva maneuver to demonstrate small defects. 

Treatment and Prognosis Many surgeons recommend repair of direct and indirect inguinal hernias even if they are asymptomatic, but this is controversial. A study by the American College of Surgeons has shown that males with minimally symptomatic groin hernias can be safely watched.92 This study randomized 720 male patients to elective hernia repair or watchful waiting. Only 2 of the 364 patients in the watchful waiting arm of the study developed complications related to their hernia in 4.5 years. This suggests that minimally symptomatic patients can be watched safely and have their hernia repaired when symptoms increase.93 Femoral hernias must be repaired promptly because the risk of strangulation is higher.79,84 When a patient presents with an incarcerated hernia and does not have clear signs and symptoms of ischemic bowel, it is reasonable to try to reduce the hernia manually. This will convert an emergent surgery into a semi-elective one. The patient can be sedated and placed in Trendelenburg position. Two hands must be used to coax the hernia back through the hernia defect. The patient must be watched closely to ensure dead bowel has not been reduced into the peritoneal cavity, a situation that can cause peritonitis and death. It is the authors’ experience that ischemic bowel is so edematous that manual reduction is usually not possible. Repair of the hernia should occur within that same hospitalization, unless there are medical issues that justify a delay (e.g., recent acute myocardial infarction). Groin hernias can be repaired using various techniques, including open or minimally invasively, with or without mesh, and are a source of ongoing debate for surgeons. Historically, tissue repairs have been performed. However, several studies have shown a decreased recurrence rate with the use of mesh resulting in tension-free repairs, both for open and laparoscopic repairs.94-97 Use of mesh is considered standard of care in the current era of hernia repair. The traditional tissue-based repairs were performed exclusively until the 1990s. There are 2 key components to successful hernia repair: (1) high ligation of the hernia sac, which treats the direct defect, and (2) repair of the floor of the canal, which treats the indirect defect. Even if there is no direct component, a repair of the floor is routinely undertaken. These repairs involve approach to the inguinal canal through a small incision parallel to the inguinal ligament and centered over the internal inguinal ring. Dissection is continued through the external oblique muscle, exposing the internal inguinal ring. The cord structures are then isolated and explored thoroughly to identify an indirect hernia sac, which is ligated and transected. The floor of Hesselbach triangle is then reinforced and strengthened by apposing the lateral border of the rectus abdominis aponeurosis to the inguinal ligament (Bassini or Shouldice repair) or to Cooper ligament (McVay repair).98-100 Tissue repairs inherently are not tensionfree and pose a greater risk of recurrence than tension-free mesh repairs. Use of mesh is considered the gold standard in elective hernia repair.85 However, in cases where there is probable contamination (e.g., in a strangulated hernia), it is important to perform a primary tissue repair and not a mesh repair, because there is a high risk of mesh infection. Open mesh repairs are most commonly performed as described by Lichtenstein.97,101 These can be performed under local, regional, or general anesthetic.102,103 The major components of successful repair begin with high ligation of the sac, but the floor is repaired using synthetic mesh to bridge the gap between the conjoint tendon (edge of the rectus aponeurosis) and inguinal ligament, thus reconstructing the floor of the canal. The mesh can be sutured or stapled in place. Mesh plug

repairs have also been developed and appear to have outcomes similar to other repairs.104 In these cases, minimal dissection is undertaken, and the mesh plug, which looks like a badminton shuttlecock, is laid into the defect and tacked in place with a few sutures. The mesh causes fibroblast ingrowth and scarring that leads to strengthening of the floor of the inguinal canal. Mesh repairs have the advantage of being somewhat simpler to perform than tissue repairs and have less tension, less acute pain, and a decreased rate of recurrence.94,95,96 Bilateral, very large, or complex abdominal hernias can be repaired with a large mesh that reinforces the entire ventral abdominal wall. This is called giant prosthetic reinforcement of the visceral sac (GPRVS), or the Stoppa procedure.105 Several series have compared open hernia repair with laparoscopic repair. The largest and most recent study was performed by the Veterans Cooperative group.106 Almost 1700 patients were followed for 2 years after being randomized to open versus laparoscopic repair of inguinal hernias. Patients who had their hernias repaired laparoscopically had less pain initially and returned to work 1 day sooner than those who had open repair. However, the recurrence rate was higher in the laparoscopic group (10% vs. 4% in the open group), and complication rates were higher and more serious in the laparoscopic group than in the open repair group. Meta-analyses of open versus laparoscopic repair have suggested that laparoscopic repair causes less pain, but recurrence rate is higher, as is the risk of complications.107,108,109 Results of the Veterans Cooperative group trial and other studies have changed the face of hernia repair in the USA. Patients with primary groin hernias are treated with open mesh repair unless they have a strong preference for a laparoscopic approach. Those with recurrent or bilateral hernias can be considered for laparoscopic repair, which can be performed effectively in experienced hands. Minimally invasive hernia repair can be performed via a totally extraperitoneal (TEP) approach or transabdominal preperitoneal approach (TAPP).110-112 In the former case, the dissection is performed just above the peritoneum using a balloon for dissection. The mesh is then placed in this plane. In the TAPP procedure, the abdomen is entered and a peritoneal flap is raised. The mesh is placed and the flap is reattached to prevent the mesh from being in contact with bowel. The TAPP approach can cause intra-abdominal adhesions and future risk for adhesive bowel obstruction, a down side to this approach. The robotic approach utilizes the TAPP technique. 

Post-Surgery Complications and Recurrence Elective groin hernia repair is safe, and serious complications are unusual.106-108 Lacerations of the bowel, bladder, or blood vessels may occur, particularly during a TAPP repair, and may cause serious consequences if not detected early. Damage to the bowel may also occur during reduction of an incarcerated hernia. Minor acute complications include acute urinary retention, seroma, hematoma, and infection.92,104,113 Serious infection occurs in less than 1% of cases. Damage to the spermatic cord may lead to ischemic orchitis.92 Tissue dissection predisposes to thrombosis of the venous drainage of the testis. Symptoms are swelling and pain of the cord and testis. The condition persists for 6 to 12 weeks and may result in testicular atrophy. Fortunately, this is a rare complication, occurring after about 0.04% of tissue repairs.114,115 Hydrocele or vas deferens injury occurs in less than 1% of cases.115 Damage to sensory nerves is not uncommon during inguinal hernia surgery, and can be related to the division or preservation of the ilioinguinal nerve as it traverses the inguinal canal.116-118 Chronic paresthesias and pain of the medial aspect of the scrotum are reported by about 10% of patients, either caused by damage to the sensory nerves or neuroma. This can be treated by local nerve block, desensitization therapy, and neurectomy.118-120

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CHAPTER 27  Abdominal Hernias and Gastric Volvulus

Some recurrent hernias are actually indirect hernias missed during the first hernia repair. The risk of recurrence is related to conditions that lead to tissue deterioration, such as malnutrition, liver or renal failure, glucocorticoid therapy, and malignancies.121 Patients with scrotal hernias and recurrent hernias are at higher risk for recurrence or re-recurrence, respectively.88 Recurrent hernias are also more common among smokers than nonsmokers.75 In patients with cirrhosis and no ascites or moderate ascites, inguinal hernia repair is reported to be safe, although the recurrence rate is increased in some series.122,123 Ideally, the ascites is aggressively controlled prior to elective herniorrhaphy, and a TIPS or liver transplantation should be considered. As mentioned, recurrence rates are higher with laparoscopic hernia repair than with open herniorrhaphy.106-108 Routine use of mesh has reduced recurrences, because the learning curve for open mesh repair is quicker than for laparoscopic or tissue repair. Overall, recurrence rates are higher after tissue repairs than after tension-free mesh repairs.95,108 For inguinal hernias, the most favorable reported recurrence rates for Canadian and Cooper ligament repairs have been about 1.5% to 2% for primary repairs and about 3% for repair of recurrent hernia.98,100 Reported recurrence rates for mesh repairs vary from 0% to 4% for primary repairs, and use of mesh appears to reduce recurrence.94,106,108 

Inguinal Hernias and Colorectal Cancer Screening Some practitioners recommend that patients aged 50 years or older with inguinal hernias be screened for colorectal neoplasms before hernia repair. One older prospective study using flexible sigmoidoscopy to screen primarily middle-aged or elderly men with inguinal hernias reported the prevalence of colorectal polyps to be 26% and the prevalence of colorectal cancers to be 3.6%.124 However, more recent data have clearly shown that there is no increased risk of colorectal cancer in patients who have groin hernias. In a prospective study of colonoscopy for screening of asymptomatic U.S. veterans, the prevalence of polyps was 37.5% and of colorectal cancer 1%.125 Thus, the prevalence of colorectal neoplasms is substantial in middle-aged or older men with or without inguinal hernias. In several more recent studies, the risk of colorectal cancer was found to be similar in patients with hernias (5%) compared with a control group that did not have hernias (4%).126 Large inguinal hernias, particularly incarcerated hernias, may cause difficulty during sigmoidoscopy or colonoscopy. In such patients, it may be advisable to defer the examination until after hernia repair. Incarceration of colonoscopes within hernias has been reported.127 

Inguinal Hernias and Benign Prostatic Hyperplasia Inguinal hernia and symptomatic benign prostatic hyperplasia commonly occur in older men.128 Straining to void may cause worsening of inguinal hernia. Conversely, the risk of postoperative urinary retention after hernia repair is increased by prostatic hyperplasia, and older male patients with any symptoms of prostate disease should be counseled on the risk of urinary retention after hernia repair.128 With the advent of improved medical therapy for benign prostatic hyperplasia, most patients can be managed with medical therapy prior to herniorrhaphy. It is important that the prostatism is dealt with medically prior to elective hernia repair. This will avoid urinary retention postoperatively that can be painful and extend length of stay. If elective inguinal hernia repair and transurethral prostatic resection are required, some surgeons would consider performing these procedures concurrently,129,130 but more frequently, concerns about infection of mesh lead to sequential surgery. 

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OTHER VENTRAL HERNIAS True ventral hernias include incisional, epigastric, umbilical, and spigelian hernias. Patients often mistake diastasis recti for ventral hernia. Diastasis recti is a separation of the rectus abdominis muscles without a defect in the abdominal fascia and can be demonstrated as a midline defect exaggerated by a Valsalva maneuver. No fascial ring can be palpated, and the defect is often very wide and long. This condition does not require repair and is cosmetic only.

27

Incisional Hernias Incisional hernias, as the name implies, are hernias that occur after a prior operation. Incisional hernias include postlaparotomy hernias, parastomal hernias, and trocar-site hernias.

Etiology and Pathophysiology Incisional hernias are caused by patient- and surgery-related factors. The former includes conditions that may increase intraabdominal pressure (e.g., obesity, collagen vascular diseases, a history of surgically repaired aorta, nutritional factors, ascites).123,131-133 Conditions that impair healing, such as collagen vascular disease in patients receiving glucocorticoid therapy and smoking, can also increase postoperative hernia formation.134 Surgery-related factors include the type and location of the incision. It is more common for hernias to develop after a vertical midline incision than after a transverse incision.135 This has led some surgeons to use transverse incisions in patients who are predisposed to hernias, such as patients with Crohn disease who are receiving glucocorticoids or other immunosuppressants. Development of a postoperative wound infection can lead to a higher incidence of hernia formation.135 Placement of a stoma results in an intentional creation of a hernia through which the intestine runs. By placing these intentional hernias within the rectus muscle rather than lateral to the rectus, or by using mesh to reinforce the area, the risk of parastomal hernia can be decreased.136 Trocar-site hernias have become a more common occurrence with the increased use of minimally invasive surgery. The rate of hernia formation is related to the size of the trocar used (trocars > 10 mm in diameter are more commonly associated with hernia formation), length of surgery, obesity, and advancing age.137 Lateral trocar placement has a lower chance of hernia formation than midline placement. 

Epidemiology Incisional hernias are common after laparotomy. When followed carefully over a long period, up to 20% of patients can be found to develop a hernia. This incidence increases to 35% to 50% of cases when there is wound infection or dehiscence.138,139 Up to 50% of such hernias manifest more than 1 year after surgery.138 Vertical incisions (as compared with transverse incisions), obesity, advanced age, diabetes, sepsis, postoperative pulmonary complications, immunosuppression, and glucocorticoid use increase the risk.135 Parastomal hernias are reported to occur in as many as 50% of cases after stoma placement.136 Specific measures are taken at the time of surgery to decrease the incidence of hernia formation. For example, the smallest fascial defect is created within the rectus sheath, rather than lateral to it. The use of biological mesh in primary stoma placement may reduce the incidence of subsequent hernia formation, but this routine use of mesh is controversial, and a multicenter randomized controlled trial is planned to address this.136,140 Conditions that lead to bowel dilation prior to stoma placement (e.g., obstruction) can result in subsequent

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bowel shrinkage after stoma placement. This shrinkage can increase the space between the bowel wall and fascia, facilitating hernia formation. Trocar-site hernias are estimated to occur after 0.5% of laparoscopic cholecystectomies.137 They usually occur at the site of the largest trocar, which is typically larger than 10 mm in diameter and is at the umbilical location. 

Clinical Features, Diagnosis, and Complications Incisional hernias can cause chronic abdominal discomfort. Because the fascial defect of incisional hernias is usually large, strangulation is unusual even with incarceration. Reduced ability to voluntarily increase intra-abdominal pressure interferes with defecation and urination. Lordosis and back pain may occur, due to decrease in a balanced “core.”139 Large incisional hernias may lead to “eventration disease.” With the loss of integrity of the abdominal wall, the diaphragm cannot contract against the abdominal viscera during inspiration, but rather forces the viscera into the hernia. The diaphragm thus becomes inefficient, and the hernia tends to enlarge. The viscera may lose the so-called right of domain in the abdominal cavity. Surgeons need to be careful about reducing and repairing these large hernias, because the acute increase in abdominal pressure can lead to pulmonary failure and reduced venous return, resulting in an effective abdominal compartment syndrome.141 Parastomal hernias often interfere with ostomy function and the fit of appliances. This can lead to leakage of stool that can be incapacitating. Prolapse of the bowel through the stoma can occur. This results in the stoma protruding as a proboscis at times. The patient may bring in pictures of an exgorged and protruding stoma that is the prolapsed bowel. Incarceration and strangulation of bowel may occur within the parastomal defect, presenting as a bowel obstruction.136 Trocar site hernias usually cause pain and a bulge at the trocar site. Because of the small opening, it is more likely intra-abdominal contents could become strangulated in the defect. Richter hernia has been reported, and other organs (e.g., stomach) can herniate into trocar hernias.142,143 Diagnosis of an incisional hernia can be difficult if the defect is small, tender, or in an obese patient. A useful adjunct to diagnosis can be ultrasound or CT. The physician requesting the ultrasound or CT should carefully communicate his or her suspicions to the radiologist, because specific maneuvers can be performed by the radiologist to demonstrate the defect. For example, ultrasound can be performed with the patient in an upright position or CT in the prone position.144 Parastomal hernias can also be identified with intrastomal ultrasound,145 although CT is the diagnostic modality of choice. Trocar site hernias are especially challenging to diagnose, as the site of fascial entry can be tangential to the skin incision site. This is because the abdomen is insufflated with carbon dioxide at the time of trocar placement, leading to different fascial entry point than when the abdomen is desufflated. The finding of localized pain at a site that is close to a trocar site should trigger evaluation with CT scan. 

Treatment and Prognosis Incisional hernias are best repaired with prosthetic mesh; the recurrence rate is substantially lower than after traditional tissue repair.135 Synthetic mesh and biologic mesh (which provides a tissue matrix into which ingrowth occurs with remolding) are available for use. The key element in hernia repair is to achieve a tension-free repair. In general, every attempt should be made to bring the fascia together with an underlay of mesh underneath the fascia to reinforce the repair. In fact, the term “abdominal wall reconstruction” has been coined as a better description for this type of surgery. This term emphasizes the attempt to restore

anatomy, with medialization of the components of the abdominal wall. The trend has been toward restoring anatomy whenever possible. Every attempt is made to place a layer of peritoneum or hernia sac between the abdominal contents and the mesh. However, if this cannot be done, special double-sided mesh is available with a barrier of some kind on one side, to prevent adhesions to viscera. This material does not stick to bowel and is therefore unlikely to erode into the intestine.141 There has been a trend toward using biological mesh in patients who are high risk for poor wound healing, such as patients with obesity, diabetes, or a smoking history. If diaphragmatic dysfunction (eventration disease) is suspected, the abdominal wall may have to be stretched by repeated progressive pneumoperitoneum before repair.146 Recurrences of incisional hernia are reported in 2% to 60% of cases, depending on the method used for repair and the duration of follow-up.139,147,148 Minimally invasive repair of ventral defects can be performed. There is some suggestion that minimally invasive repair results in fewer recurrences and lower morbidity.135,147 Minimally invasive hernia repair is performed by insufflating the abdomen and gradually creating a working space by carefully lysing adhesions. Double-sided mesh is then placed in the retroperitoneal position and fixed by tacks and sutures. This approach effectively bridges the gap rather than medializing the hernia edges. This can result in the sensation of a residual hernia, caused by retention of fluid in the hernia sac between the mesh and the skin, which can be frustrating for the clinician and patient. In contrast to open repairs, the fascia is not brought together in minimally invasive hernia repair, and therefore the patient will have a persistent bulge in the area of the hernia. This is due to the lack of abdominal musculature within the hernia defect itself, which contains only mesh. Some surgeons perform a minimally invasive components separation, where the lateral components are incised and slide to meet at the midline. This can be performed minimally invasively and can result in no bridging with mesh, and hence no bulge. Chronic pain at suture or tack sites appears to be a greater issue with laparoscopic hernia repair than with open repair.149,150 Small and minimally symptomatic parastomal hernias may be treated with a modified ostomy belt. If surgery is necessary, there are several modes of treatment. The best treatment is to eliminate the stoma completely. This requires the ability to reconstruct the patient, an option not possible in the patient who has undergone abdominoperineal resection. The stoma can be relocated to the other side or another quadrant of the abdomen. Primary repair of the parastomal defect is no longer considered adequate treatment; mesh placement is advocated. A piece of mesh shaped with a keyhole defect through which the stoma can be exteriorized can be used.136 Alternatively, the “Sugarbaker technique” can be performed, where a flat piece of mesh is placed over the piece of bowel as it exits for the stoma. This changes the angle of the bowel to parallel to the abdominal wall and creates a physiologic effect preventing future hernia formation. Important for the gastroenterologist to know in this case is that the scope will travel parallel to the abdominal wall before diving into the abdomen. These repairs can all be performed minimally invasively.151,152 To decrease the incidence of trocar site hernias, it is recommended that trocar ports be removed under direct vision and the defects sutured closed, particularly those defects related to trocars larger than 10 mm in diameter. Newer prosthetic materials with biological components are now available. These biological meshes can be used in place of mesh in patients in whom there has been contamination, such as when bowel resection is necessary. The mesh substrates are thought to be degradable over time. After implantation, it is thought that they cause an influx of fibroblasts, resulting in a vigorous scar that can provide strength similar to mesh. With time, biological mesh degrades, leaving only autologous tissue. This is called tissue ingrowth and remolding. However, hernia

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CHAPTER 27  Abdominal Hernias and Gastric Volvulus

recurrence is still a significant issue and can occur in up to 21% of patients.153 Because of the significant recurrence rate, bridging of defects should be avoided when using biological mesh. 

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strangulation of umbilical hernias may occasionally be precipitated by rapid removal of ascites.159,167 

27

Treatment and Prognosis Epigastric and Umbilical Hernias Etiology and Pathophysiology Epigastric hernias occur through midline defects in the aponeurosis of the rectus sheath (linea alba) between the xiphoid and umbilicus. These defects are usually small and frequently multiple. Because of the location in the upper part of the abdominal wall, it is unusual for bowel to become incarcerated in epigastric hernias. The falciform ligament lies in this location, providing protection for bowel incarceration. More commonly, preperitoneal fat or omentum protrude through these hernias.154 Umbilical hernias in infants are congenital (see Chapter 98). They often close spontaneously. There is an increased incidence of congenital umbilical hernias in children of African descent.155 In general, these defects will close spontaneously by 4 years of age.156 If they are still evident after this age, surgical repair is indicated. In adults, umbilical hernias may develop consequent to increased intra-abdominal pressure due to ascites, pregnancy, or obesity. 

Epidemiology Epigastric hernias are found in 0.5% to 10% of autopsies.154 Many are asymptomatic or undiagnosed during life. They generally occur in the third through fifth decades. Risk factors for epigastric hernia include obesity, smoking, and heavy lifting.154 Epigastric hernia has also been reported after deep inferior epigastric perforator (DIEP) flap breast reconstruction.157 Umbilical hernias occur in about 30% of African American infants and 4% of white infants at birth, and are present in 13% and 2%, respectively, by 1 year of age.158 Umbilical hernias are more common in low birth weight infants than in those of normal weight. Other risk factors include obesity and pregnancy. Umbilical hernias occur in roughly 20% of patients with cirrhosis and ascites.159 

Clinical Features, Diagnosis, and Complications The main symptom of epigastric hernia is upper abdominal pain, usually localized to the abdominal wall, rather than the deep visceral pain that accompanies intestinal pathology. A specific tender nodule or point of tenderness can be palpated in the nonobese patient. Diagnosis may be difficult, particularly in obese patients. However, symptoms are sometimes mistaken for those of a peptic ulcer or biliary disease. Determining that the discomfort is in the abdominal wall, rather than deep within the peritoneum, can help distinguish incarcerated bowel from fat in the hernia. Sonography and CT may be helpful in the diagnosis.160,161 Complications of epigastric hernia are very rare, with reports of acute pancreatitis from incarceration of the head of the pancreas, perforation of a gastroduodenal ulcer incarcerated in the hernia, and strangulation of bowel in the hernia.162-164 Umbilical hernias in children are usually asymptomatic. Adults may be asymptomatic or report some discomfort with palpation of the hernia. Incarceration and strangulation may occur in children and adults. Spontaneous rupture of umbilical hernias may occur in patients with ascites and, rarely, in pregnant women.165,166 Skin changes with maceration and ulceration generally occur prior to frank rupture. Therefore, the findings of skin changes in a patient with an umbilical hernia should warrant urgent repair. Care must be taken when performing a therapeutic paracentesis in patients with umbilical hernias; the hernia must be reduced and kept reduced during the paracentesis, because

If surgery is performed for epigastric hernia, the linea alba should be widely exposed because multiple defects called Swiss cheese defects may be found. A minimally invasive approach is preferred in this circumstance, where excellent visualization of the midline can be achieved with just a few 5-mm ports. A single defect can be fixed easily, and a Swiss cheese–type scenario can also be fixed minimally invasively without opening the whole midline of the abdomen. Mesh is laid within the abdomen to cover all of these defects. Surgical repair is typically successful, with a low recurrence rate. Umbilical hernias are most often left untreated in children; complications are unusual, and they usually close spontaneously if smaller than 1.5 cm in diameter. Repair should be considered if they are larger than 2 cm or if they are still present after 4 years of age.158 Repair of umbilical hernias should be recommended for adults if they are difficult to reduce or symptomatic. Techniques for repair of all abdominal wall defects rely on a tension-free repair to decrease the risk of recurrence. Open or minimally invasive techniques can be used to achieve this end.168 Data support routine use of mesh in repair of these defects, because this results in a decrease in recurrences.169 Mesh is always used in minimally invasive repair. When complications develop in patients with umbilical hernias, the prognosis worsens significantly. Those patients requiring bowel resection at the time of umbilical herniorrhaphy or who have ascites and cirrhosis have increased mortality.167,170 Repair of umbilical hernias in patients with cirrhosis and ascites is a difficult clinical problem. In general, ascites should be aggressively controlled. If this is not possible, consideration should be given to TIPS or liver transplantation (see Chapters 93 and 97). Spontaneous rupture of umbilical defects in patients with ascites portends a poor prognosis, with reported mortality rates of up to 60%.159,165,171 Minimally invasive techniques and earlier repair of hernias in patients with cirrhosis should be considered, although ascitic leak from even a trocar site can be fatal. The morbidity of elective repair appears not to be as high as once thought, with a recent trial reporting a mortality rate of 3.7% for elective repair, with even lower rates (1.3%) for patients with a MELD score less than 15.172 Outcome after surgical repair is directly dependent on nutritional status and control of ascites. Control of ascites may require frequent paracentesis to keep the abdomen flat to allow healing. Topical fibrin sealant has been used to successfully treat a leaking umbilical hernia in a patient with ascites.173 In general, one should undertake umbilical hernia repair with caution in cirrhotic patients with ascites. This would be a circumstance where liver transplantation evaluation prior to hernia repair would be prudent. 

Spigelian Hernias Etiology and Pathophysiology Spigelian hernias occur through defects in the fused aponeurosis of the transversus abdominis muscle and internal oblique muscle, lateral to the rectus sheath; they most commonly occur just below the level of the umbilicus (see Fig. 27.7). This area is called the spigelian fascia, named after the Belgian anatomist Adriaan van den Spiegel. This fascia is where the linea semilunaris, the level at which the transversus abdominis muscle becomes aponeurosis rather than muscle, meets the semicircular line of Douglas. The epigastric vessels penetrate the rectus sheath in this area. The combination of all these anatomic features can lead to a potential defect and a spigelian hernia. The spigelian fascia is covered by the external oblique muscle, and therefore, spigelian hernias do

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not penetrate through all layers of the abdominal wall, making the diagnosis of a hernia challenging.156 

Epidemiology Spigelian hernias are very rare. Only about 1000 cases have been reported.174 The largest series of patients included 81 patients.175 They are twice as common in females as in males and are somewhat more common on the left side of the abdomen.176,177 They generally occur in patients around age 60 years.175-177 

Clinical Features, Diagnosis, and Complications Spigelian hernias can be difficult to diagnose because the external oblique muscle overlies the defect in the deeper fascia. Only 75% to 80% of patients with a Spigelian hernia are correctly diagnosed before surgery.175,177 The examiner must have a high degree of suspicion when a patient complains of pain at the lateral edge of the rectus, inferior to the umbilicus. Careful examination will suggest that the pain originates in the abdominal wall and not in the peritoneal cavity. This determination is critical because a Spigelian hernia can be mistaken for conditions like acute appendicitis and diverticulitis.178-180 Frequently, only omentum is present in the hernia, but large or small bowel, ovary, appendix, or fallopian tube may herniate.175,179,181 A Richter hernia or a bowel obstruction caused by incarcerated small intestine may occur.182 The differential diagnosis includes rectus sheath hematoma, lipoma, or sarcoma. Sonography and CT are the most useful adjuncts for diagnosing a Spigelian hernia.175,177,183 An astute radiologist will perform these studies using various techniques (e.g., Valsalva maneuver) to increase detection of even a small spigelian hernia. The finding of a viscera structure penetrating through the 2 inner layers of the abdominal wall at the correct location will lead to the diagnosis of a spigelian hernia. 

Treatment and Prognosis Spigelian hernias may be approached by open or minimally invasive techniques.184,185 Laparoscopy can be helpful as a diagnostic tool in patients suspected of having a Spigelian hernia, even if open repair is anticipated.186 The hernia can be best identified from within the peritoneal cavity. Preperitoneal laparoscopic techniques can be used, with the advantage of staying outside the peritoneal cavity, thereby avoiding adhesions.185 Intraperitoneal laparoscopic repair can be performed using mesh that is coated on 1 side so as not to stick to the underlying bowel.185,187 Minimally invasive approaches result in decreased pain and decreased length of hospital stay compared with open techniques.188 However, these hernias are so rare, the surgeon’s choice of technique should be based on personal experience. It is the authors’ preference to at least start with a laparoscopic approach, as this can confirm the diagnosis and help locate the hernia itself. As with other hernias, most spigelian hernias are closed using mesh repairs, a technique that appears to have a lower recurrence rate than primary repair.175,185 

PELVIC AND PERINEAL HERNIAS The 3 main types of pelvic and perineal hernias are obturator, sciatic, and perineal hernias.

Etiology and Pathogenesis Obturator hernias are rare and occur in older women, and thus are sometimes called “little old lady’s hernia.”189 Obturator hernias occur through the greater and lesser obturator foramina. The obturator foramen is larger in women than in men and is ordinarily filled with fat. Marked weight loss predisposes to herniation.190

Sciatic hernias occur through the foramina formed by the sciatic notch and the sacrospinous or sacrotuberous ligaments. Abnormal development or atrophy of the piriform muscle may predispose to sciatic hernia. Sciatic hernias may contain ovary, ureter, bladder, or large or small bowel.191 Perineal hernias occur in the soft tissues of the perineum and are very rare. They may be primary or postoperative. Primary perineal hernias occur anteriorly through the urogenital diaphragm or posteriorly through the levator ani muscle or between the levator ani and coccygeus muscles. Secondary perineal hernias occur most often after surgery, such as abdominal-perineal resection, pelvic exenteration, or hysterectomy.192-194 Radiation therapy, wound infection, and obesity predispose to the development of secondary perineal hernias.195,196

Epidemiology Obturator hernias typically occur in older, cachectic, multiparous women. About 800 cases have been reported.197 In Asia, obturator hernias account for about 1% of all hernia repairs, but in the West, they account for 0.07% of all hernias.198,199 Sciatic hernias are even less common than obturator hernias, with fewer than 100 cases reported.191 They are most common in older women, although are occasionally seen in children.200 Perineal hernias are also rare. Primary perineal hernias are most common in middle-aged women. Secondary perineal hernias occur after less than 3% of pelvic exenterations and less than 1% of abdominal-perineal resections for rectosigmoid cancer.196,201 

Clinical Features, Diagnosis, and Complications Obturator hernias occur almost exclusively in older women and are more common on the right side.197,202 They commonly cause cramping lower abdominal pain, nausea, and vomiting. Almost all patients present with symptoms of small bowel obstruction.202 Because the hernia orifice is small, Richter hernia and strangulation are common, and bowel necrosis is not uncommon.202,203 There are 3 signs specific for an incarcerated obturator hernia.202 The first is obturator neuralgia, manifesting as paresthesia that extends along the medial aspect of the thigh. Second is the Howship-Romberg sign, caused by pressure on the obturator nerve and resulting in paresthesias and pain in the hip and inner thigh. The pain is diminished by hip flexion and increased by hip extension, adduction, or medial rotation. This sign is seen in 25% to 50% of patients with obturator hernia and is considered pathognomonic. Third is the Hannington-Kiff sign, elicited by percussing the adductor muscle above the knee. Absence of the normal adductor reflex contraction is a strong indicator of obturator nerve impingement caused by an obturator hernia. Occasionally a mass may be palpable in the upper medial thigh or in the pelvis on pelvic or rectal examination. The diagnosis is difficult, often delayed, and usually not made preoperatively. The treating physician must have a low threshold for entertaining this diagnosis in an elderly cachectic female patient with a bowel obstruction in the pelvis. Preoperative diagnosis is sometimes evident on ultrasound or CT.202,204,205 Sciatic foramen hernias may manifest as a mass or swelling in the gluteal or infragluteal area, but are generally difficult to palpate because they occur deep to the gluteal muscles. Chronic pelvic pain caused by incarceration of a fallopian tube and/or ovary may occur.206 Impingement on the sciatic nerve may also produce pain deep in the buttock or radiating to the thigh.207 Intestinal or ureteral obstruction may occur. The differential diagnosis includes lipoma or other soft tissue tumor, cyst, abscess, and aneurysm.208 The diagnosis is often difficult, with only 37% of patients diagnosed by physical exam findings.191 CT and MRI

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may be helpful, but many patients are diagnosed at laparotomy or laparoscopy. In women, primary perineal hernias manifest anteriorly in the labia majora (pudendal hernia) or posteriorly in the vagina.195 In men, they manifest in the ischiorectal fossa. Primary and postoperative perineal hernias are usually soft and reducible. Most patients complain of a mass that produces discomfort on sitting. Because the orifice of the hernia is usually wide, incarceration is rare. If the bladder is involved, urinary symptoms may occur.209 Postoperative perineal hernias may be complicated by cutaneous ulceration. The differential diagnosis includes sciatic hernia, tumor, hematoma, cyst, abscess, and rectal or bladder prolapse.210 

Treatment and Prognosis The treatment of pelvic hernias is surgical. Laparoscopic repair of obturator, sciatic, and perineal hernias has been reported.192,211,212 However, most patients with pelvic hernias present with an acute surgical condition, often bowel obstruction, and it is often necessary to perform an open procedure to manage the problem. Repair of perineal hernias can be complex. When bowel resection is required, mesh placement is usually not used because of the high risk of infection. The advent of biologic products has allowed these materials to be used in contaminated fields.191 Peritoneal flaps or muscle advancement flaps can be used to perform tissue repairs of these defects.213 The prognosis is poor when patients present with an acute illness, and is more related to the underlying medical conditions rather than the hernia itself. Nutritional depletion, advanced age, and poor medical health are all confounding variables. 

LUMBAR HERNIAS Etiology and Pathophysiology Lumbar hernias can occur in 2 separate triangular areas of the flank. The superior triangle (Grynfeltt lumbar triangle) is bounded by the 12th rib superiorly, the internal oblique muscle inferiorly, and the sacrospinous muscles medially. The inferior triangle (Petit lumbar triangle) is bounded by the latissimus dorsi muscle posteriorly, the external oblique muscle anteriorly, and the iliac crest inferiorly (Fig. 27.9).214 Grynfeltt hernias are more common than Petit hernias. Lumbar hernias are more common on the left than on the right side. This may be because the liver pushes the right kidney inferiorly in development, leading to protection of the lumbar triangles. Pseudohernia may occur in the lumbar area as the result of paresis of the thoracodorsal nerves.215,216 This is caused by loss of muscle control and tone, but there is no associated fascial defect. Causes of pseudohernia include diabetic neuropathy, herpes zoster infection, nerve injury, and syringomyelia.217 Of the acquired lumbar hernias, about half are spontaneous and the rest are incisional or posttraumatic hernias. Flank incisions are used to access the retroperitoneum for procedures such as nephrectomy, and hernias can result, which may be true hernias or pseudohernias caused by postoperative muscle paralysis.218,219 Lumbar hernias have also been reported after harvest of bone from the iliac crest.220 Motor vehicle accidents are the most common cause of posttraumatic lumbar hernias. If a lumbar hernia is found after a motor vehicle accident, it is critical to assume that the patient has other intra-abdominal injuries. Most of these patients will undergo urgent laparotomy; more than 60% of them will have major intra-abdominal injuries.221,222

Epidemiology Lumbar hernias are rare, with about 300 cases reported.215 Some 20% are congenital, and they are rarely bilateral.223,224 

27 Latissimus dorsi 12th rib

External oblique Internal oblique Iliac crest Sacrospinalis

Fig. 27.9  Anatomic diagram of lumbar hernias.The inferior triangle hernia, Petit hernia (thick arrow), is bounded by the latissimus dorsi muscle, the external oblique muscle, and the iliac crest. The superior triangle hernia, Grynfeltt hernia (thin arrow), is bounded by the 12th rib, the internal oblique muscle, and the sacrospinalis muscle.

Clinical Features, Diagnosis, and Complications Lumbar incisional hernias generally present as a large bulge that may produce discomfort. These are especially evident when the patient strains or is in the upright position. Because of the large size of the defect, incarceration is not common. Moreover, the location, in the retroperitoneum, makes incarceration of intraabdominal structures rare. Superior and inferior lumbar triangle hernias may occur through small defects and can manifest with incarceration (24%) and strangulation (18%).225 The differential diagnosis includes lipoma, renal tumor, abscess, and hematoma. Bowel, mesentery, spleen, ovary, and kidney have been reported to herniate.223 Occasionally a small lumbar hernia may impinge on a cutaneous branch of a lumbosacral nerve, causing pain referred to the groin or thigh. CT may aid in the diagnosis.226 

Treatment and Prognosis Closure of large lumbar hernias, as well as superior and inferior lumbar triangle hernias, often requires the use of prosthetic mesh or an aponeurotic flap. These can be challenging cases. Identifying fascia with good tensile strength and repairing the defect with mesh in a tension-free manner is critical to preventing recurrence.223,227 Fixation of mesh to bony structures (e.g., rib, iliac crest) may be required. Preperitoneal as well as transperitoneal laparoscopic repair has been reported and can result in less pain and quicker return to activity.215,219,228,229 Large and symptomatic lumbar pseudohernias should be treated by managing the underlying condition. Resolution has been reported following treatment of herpes zoster.217 

INTERNAL HERNIAS Internal hernias are protrusions into pouches or openings within the abdominal cavity, rather than through the abdominal wall. Internal hernias may be the result of developmental anomalies or may be acquired.230 Commonly, internal hernias develop after earlier abdominal surgery, such as after an RYGB procedure.

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Etiology and Pathophysiology Internal hernias caused by developmental anomalies include paraduodenal, foramen of Winslow, mesenteric, and supravesical hernias. During gestation, the intestines are extra-abdominal. During fetal development, the mesentery of the duodenum, ascending colon, and descending colon becomes fixed to the posterior peritoneum. These segments of the bowel become reperitonealized and attach to the retroperitoneum. Anomalies of mesenteric fixation may lead to abnormal openings through which internal hernias may occur. The extreme example of this is a complete intestinal malrotation, in which the ligament of Treitz does not assume its appropriate location to the left of the spine. This condition predisposes to midgut volvulus and can lead to extensive mesenteric ischemia (see Chapter 98).231,232 Lesser anomalies of fixation lead to defects such as paraduodenal and supravesical hernias. Abnormal mesenteric fixation may lead to abnormal mobility of the small bowel and right colon, which facilitates herniation. During fetal development, abnormal openings may occur in the pericecal, small bowel, transverse colon, or sigmoid mesentery, as well as the omentum, leading to mesenteric hernias.230 Unusual hernias can occur on structures like the broad ligament.233 Abnormal fixation of the mesentery of the descending or ascending colon may lead to paraduodenal hernias. Paraduodenal hernias occur on the left side in 75% of cases and have a 3 : 1 male predominance.234,235-237 Patients most commonly present in the fourth decade. In cases of left paraduodenal hernia, an abnormal foramen, the fossa of Landzert, occurs through the mesentery close to the ligament of Treitz, leading under the distal transverse and descending colon, posterior to the superior mesenteric artery. Small bowel may protrude through this fossa and become fixed in the left upper quadrant of the abdomen. The mesentery of the colon thus forms the anterior wall of a sac that encloses a portion of the small intestine. Right paraduodenal hernia occurs in the same fashion through another abnormal foramen, the fossa of Waldeyer, leading under the ascending colon.230,238 Foramen of Winslow hernias may occur when this foramen is abnormally large, particularly if there is abnormal mesenteric fixation of the small bowel and right colon. Most commonly, the right colon is abnormally fixed to the retroperitoneum, resulting in a patulous foramen of Winslow. Abnormally mobile small bowel and colon may herniate through the foramen of Winslow into the lesser sac. Symptoms of small bowel or colonic obstruction may occur, and these may be intermittent as the hernia reduces spontaneously. Impingement on the portal structures can occur but rarely results in biliary obstruction or compression of the portal vein.239,240 Gastric symptoms may also occur if the herniated bowel becomes distended, because the herniated bowel loops are located in the lesser sac, behind the stomach. Mesenteric hernias occur when a loop of intestine protrudes through an abnormal opening in the mesentery of the small bowel or colon. These mesenteric defects are thought to be developmental in origin, although they may also be acquired as a result of surgery, trauma, or infection. The most common area for such an opening is in the mesentery of the small intestine, most often near the ileocolic junction. Defects have been reported in the mesentery of the appendix, sigmoid colon, and a Meckel diverticulum.241-243 The intestine finds its way through the defects through normal peristaltic activity. Various lengths of intestine may herniate posteriorly to the right colon into the right paracolic gutter (Fig. 27.10). Compression of the loops may lead to obstruction of the herniated intestine. Strangulation may occur by compression or by torsion of the herniated segment. Obstruction may be acute, chronic, or intermittent. The herniated bowel may also compress arteries in the margins of the mesenteric defect, causing ischemia of nonherniated intestine. Similar defects may occur in the mesentery of the small bowel, transverse mesocolon, omentum, and sigmoid mesocolon.

Fig. 27.10  CT of an internal (pericecal) hernia with strangulation. A mass of infarcted small intestine is seen in the right side of the abdomen (white arrow). The area of herniation (open arrow to right of spine) shows twisting of the small bowel as it passes through the mesentery. (Courtesy Dr. Michael J. Smerud, Dallas, Tex.)

There are 3 types of mesenteric hernias involving the sigmoid colon. Transmesosigmoid hernias have no true sac. They occur through both layers of the mesocolon. Generally, the bowel becomes trapped in the left gutter, lateral to the sigmoid colon. Intermesosigmoid hernias are hernias that occur within the leaves of the sigmoid colon. This results in the hernia contents being contained within the mesentery of the sigmoid colon, generally posterior to the sigmoid colon. Intersigmoid hernias occur between the retroperitoneal fusion plane, between the sigmoid colon mesentery and the retroperitoneum. These hernias are contained in the retroperitoneum and generally lift and dissect the sigmoid colon on its mesentery out of the left gutter.236 Supravesical hernias protrude into abnormal fossae around the bladder. They are classified as internal or external supravesical hernias. Internal supravesical hernias occur within the abdomen and thus are internal hernias. They may extend anterior, lateral, or posterior to the bladder. External supravesical hernias occur outside the abdominal wall and appear much like indirect inguinal hernias. They usually contain small bowel but may contain omentum, colon, ovary, or fallopian tube.244-246 Acquired internal hernias may occur as a complication of surgery or trauma if abnormal spaces or mesenteric defects are created. Adhesions can create spaces into which bowel may herniate. Division of mesentery to create conduits, such as Rouxen-Y limbs, can lead to defects within the mesentery or around the reconstruction, which can result in herniation. With the increased popularity of the RYGB procedure for morbid obesity, there has been an increased incidence of unusual hernias related specifically to this surgery (discussed later).247,248,249 Retroanastomotic hernias may occur after gastrojejunostomy, colostomy or ileostomy, ileal bypass, or vascular bypass when an abnormal space may be created into which small bowel, colon, or omentum may herniate. Retroanastomotic hernia can occur after gastrojejunostomy, usually after gastric resection with Billroth II reconstruction. The afferent loop, efferent loop, or both, protrude into the space posterior to the anastomosis. Efferent loop hernias are about 3 times as common as afferent loop hernias, likely caused by the limited length of the afferent loop and the tethering effect of fixed structures involved in the afferent loop. For example, after a Billroth II anastomosis, the afferent loop is connected to the duodenum, which is fixed, and the efferent loop is connected to the remainder of the small intestine. The efferent loop is therefore more mobile and can herniate into potential spaces.236,250 Colostomy, ileostomy, ileal bypass, and vascular bypass procedures may also lead to the creation of a space into

These proofs may contain color figures. Those figures may print black and white in the final printed book if a color print product has not been planned. The color figures will appear in color in all electronic versions of this book. For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.

CHAPTER 27  Abdominal Hernias and Gastric Volvulus

which organs can protrude. Obstruction secondary to retroanastomotic hernia has been reported after liver transplantation.251 Renal transplant procedures are extraperitoneal, but an unrecognized inadvertent rent in the peritoneum can lead to pararenal intestinal herniation.252 Hernias after RYGB procedures have become more common with the increasing demand for this operation. These can be internal or external hernias through the incision or port sites. Small bowel obstruction related to internal hernias after RYGB occurs in 2% to 3% of patients.247,248,253 There are 3 potential spaces created during the RYGB that can result in internal herniation. The Peterson defect occurs to the right of the jejunum as it traverses the mesentery of the transverse colon to reach the pouch of the stapled stomach. By definition, the Roux limb has to travel in the retrocolic location for this to occur. The endoscopist encounters this as a narrowing that occurs in the Roux limb at around 40 to 60 cm distal to the pouch-jejunum anastomosis. The jejunojejunostomy mesenteric defect occurs between the divided leaves of the small intestinal mesentery. The mesentery is divided to create the Roux limb, which is brought up to the gastric pouch. The 2 edges of the transected mesentery are then sewn together to prevent this defect. However, despite these measures, a defect can develop resulting in herniation of intra-abdominal contents. The transverse mesocolic defect occurs through the defect in the transverse mesocolon through which the jejunal limb is brought to reach the stomach pouch. The Peterson and transverse mesocolic defects can be avoided by placing the jejunal limb in an antecolic position. In this case, the jejunum is not placed through a rent in the transverse mesocolon, but rather is brought anterior to the transverse colon. Although this makes intuitive sense, it is not always possible to achieve enough length of small intestinal mesentery to ensure an antecolic anastomosis without tension. With the majority of RYGB being performed laparoscopically, there are fewer adhesions being formed after surgery; this in fact allows for greater mobility of the small intestine and a greater ability to prolapse through hernia defects. Adhesions with open surgery can actually reduce the risk for this type of internal hernia. However, adhesive causes for bowel obstruction occur more frequently in the open gastric bypass cases. Hernias can occur in the mesentery of the colon very rarely after colonoscopy.254,255 This likely occurs as a rent develops in the sigmoid mesocolon with insufflation of the colon. Hernias may occur through the broad ligament of the uterus, most commonly through tears occurring during pregnancy, because the majority of these hernias occur in parous women. Other cases may be developmental or caused by surgery.233,256

Epidemiology Internal hernias are rare and occur most often in adults. They are found in 0.2% to 0.9% of autopsies, but a substantial proportion of these remain asymptomatic.236 About 5% of bowel obstructions are caused by internal hernias. Although half of developmental internal hernias are paraduodenal hernias, 1% or fewer of all cases of intestinal obstruction are caused by paraduodenal hernias.230,237,257 They are more common in males than in females. They may occur in children or adults but typically manifest between the third and sixth decades of life; most (75%) paraduodenal hernias occur on the left side.234-237 Foramen of Winslow hernias are very rare, accounting for 8% of internal hernias.230,257 Mesenteric hernias are rare and can occur at any age.236,250 Supravesical hernias are extremely rare, with limited case reports. They are more common in men than in women. Almost all reported cases have occurred in adults, most commonly in the sixth or seventh decade.246 Similarly, broad ligament hernias are exceedingly rare.233 Postgastroenterostomy internal hernias have become less common because the frequency of surgery for peptic ulcer disease has declined. Other

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postanastomotic internal hernias are also rare.236 Internal hernias related to RYGB procedures have become more common because surgeries for morbid obesity have become more widely performed. Small bowel obstruction related to internal hernias in most patients occurs with an incidence of 2% to 3% after RYGB.247,248,253 

27

Clinical Features and Diagnosis Any of the various forms of internal hernias may manifest with symptoms of acute or chronic intermittent intestinal obstruction. The diagnosis is difficult in patients with chronic symptoms and is rarely made preoperatively in patients who present with acute obstruction and strangulation.230,236,250 Intestinal obstruction, which may be low-grade, chronic, and recurrent or high-grade and acute, develops in about half of patients with paraduodenal hernias.236,237 UGI tract contrast radiography has been shown to have excellent accuracy. Barium radiographs may show the small bowel to be bunched up or agglomerated as if it were contained in a bag, and displaced to the left or right side of the colon. Small bowel is often absent from the pelvis, and appears to be present in the lesser sac, posterior to the stomach. The colon may be deviated by the internal hernia sac. Bowel proximal to the hernia may be dilated.236,258 However, barium radiographs may be normal if the hernia has reduced at the time of the study. Endoscopy is not reliable for the diagnosis of paraduodenal hernias. Displacement of the mesenteric vessels can be noted if CT with intravenous contrast or arteriography is performed.234,236 However, CT may miss a paraduodenal hernia unless specific attention is paid to the relationship of the small intestine to the colon and mesenteric vessels. In hernias of the foramen of Winslow, small bowel herniates behind the portal structures in about two thirds of cases; in the remaining cases, the right colon herniates into the lesser sac. Herniation of the gallbladder has been reported.239 Patients may have symptoms of gastric or proximal intestinal obstruction, even in the case of colon herniation, because of pressure of the herniated bowel on the stomach. Occasionally, an epigastric mass is palpable. Plain abdominal radiographs may show the stomach displaced anteriorly and to the left. Bowel, most commonly right colon, will be seen posterior to the stomach in the lesser sac. Contrast enema may show displacement of the cecum into the epigastrium. CT is accurate for the diagnosis of foramen of Winslow hernias. The herniated bowel is posterior to the stomach within the lesser sac. There may be associated dilation of the biliary tree or portal vein narrowing caused by compression of the portal structures. Rarely is there any physiologic consequence to this finding.236,240 Mesenteric hernias are difficult to diagnose preoperatively. Symptoms and signs are those of acute or chronic intermittent bowel obstruction or acute strangulation.250 Plain abdominal radiographs may show evidence of bowel obstruction or displacement of the normal gas pattern. For example, with hernias through the sigmoid mesentery, the small intestine gas pattern lies laterally to the sigmoid gas pattern.236 This finding, in association with bowel obstruction, may increase the suspicion for an internal hernia. Internal supravesical hernias produce symptoms of bowel obstruction. Associated symptoms of bladder compression occur in about 30% of cases. Anterior supravesical hernias may result in a suprapubic mass or tenderness. Patients with supravesical hernia may also have an inguinal hernia. Barium radiography or abdominal CT with oral contrast may be helpful in the diagnosis.244,246 Hernias of the broad ligament of the uterus cause symptoms of bowel obstruction in about half of cases and can cause chronic pelvic pain.256 Other cases are discovered incidentally at surgery. Small bowel, sigmoid colon, appendix, omentum, and ureter have been reported to herniate. CT scanning may show dilation of small bowel and deviation of the uterus.

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A

B Fig. 27.11  CT on an internal hernia showing the “whirl sign.” A, Whirl sign is seen in a patient with an internal hernia after Roux-en-Y gastric bypass (arrow). B, Upright view of same patient shows the point of twisting of the bowel and mesentery (arrow).

Retroanastomotic hernias cause symptoms and signs similar to those of other internal hernias. Postgastrojejunostomy hernias cause symptoms of gastric outlet obstruction. The efferent loop herniates most often. Afferent loop hernias are a cause of the afferent loop syndrome (see Chapter 53). About 50% of postgastrojejunostomy hernias occur within the first month after surgery, 25% occur during the first year, and the rest occur later.257 The physical examination is not specific. The serum amylase and lipase level is often elevated with afferent limb obstruction. Plain abdominal radiographs may show gastric distention and a fluid-filled loop. Barium UGI radiographs are most useful for documenting efferent limb obstruction versus afferent limb obstruction. Sonography or CT may show dilation of the afferent limb, or the “whirl sign,” where the mesenteric vessels and small bowel appear to twist around a point259 (Fig. 27.11). Biliary scintigraphy will show excretion of radionuclide into the biliary tree but retention of the tracer in an obstructed afferent limb.236 The clinical presentation of post-RYGB hernias is similar to that of other internal hernias. Most commonly, bowel obstruction is present. Herniation of the afferent limb of the jejunojejunostomy (the limb that carries pancreaticobiliary secretions) can present an interesting diagnostic dilemma because this loop does not carry food material. Therefore, vomiting may not occur. As a consequence, herniation of the afferent limb may present with biliary obstruction and pancreatitis rather than classic bowel obstruction. CT and plain films will show evidence of duodenal distention, and on biliary scintigraphy there is lack of progression of radionuclide from the dilated duodenum into the distal small intestine. Herniation of the distal small intestine manifests with signs and symptoms of a bowel obstruction. The finding of a “whirl sign” after RYGB in a patient with symptoms should lead to immediate surgical evaluation. Delay in treatment can result in bowel loss and death. Strictures at the base of the Roux limb can present with a similar obstructive syndrome. However, findings of a more distal bowel obstruction should increase suspicion for an internal hernia. 

Treatment and Prognosis Symptomatic internal hernias require surgery.230,236,250,257 Laparoscopic repair is preferred if the hernia is detected prior to complications.240,246,256 Once the patient has developed signs and symptoms of bowel obstruction, it is reasonable to explore the patient, reduce the hernia, ensure the bowel is viable, and repair the defect. Acute obstruction leads to strangulation, bowel ischemia, and death if not promptly treated.243 Paraduodenal hernias are usually corrected by incising the enclosing mesentery. Care must be taken to avoid injuring the superior or inferior mesenteric arteries, because they follow an abnormal course within the border of the hernia. Sometimes the small bowel can be reduced through the opening of the hernia without incising the mesentery.234,237 Thereafter, the paraduodenal defect must be closed. This may involve performing a formal Ladd procedure if the hernia is associated with a true malrotation (see Chapter 98).231,232 If there is a patulous paraduodenal space, a simple resection of the hernia sac and plication of the defect can afford adequate repair. Once incarceration has occurred, mortality can be higher than 20%,237 so it is recommended that all paraduodenal hernias be repaired electively if possible. Broad ligament hernias and supravesical hernias can all be successfully repaired laparoscopically.233,246,256 Post-RYGB hernias are a common event in the current era, and the gastroenterologist must have a working knowledge of the anatomy and the possible defects that can occur. The post-RYGB patient who is unable to eat may have an internal hernia if there is no obstruction of the pouch-jejunal anastomosis. CT will usually show the “whirl sign” that should alert the treating physician to a possible internal hernia.259 The surgeon should have a low threshold to operate on these patients, as missing an internal hernia can lead to bowel necrosis and short gut syndrome. Full references for this chapter can be found on www.expertconsult.com

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These proofs may contain color figures. Those figures may print black and white in the final printed book if a color print product has not been planned. The color figures will appear in color in all electronic versions of this book. For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.

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28

Foreign Bodies, Bezoars, and Caustic Ingestions Patrick R. Pfau, Mark Benson

CHAPTER OUTLINE GASTROINTESTINAL FOREIGN BODIES���������������������������� 399 Epidemiology����������������������������������������������������������������� 399 Pathophysiology������������������������������������������������������������� 400 History and Physical Examination����������������������������������� 400 Diagnosis����������������������������������������������������������������������� 401 Treatment���������������������������������������������������������������������� 402 Specific Foreign Bodies�������������������������������������������������� 403 Procedure-Related Complications����������������������������������� 406 BEZOARS�������������������������������������������������������������������������� 406 Epidemiology����������������������������������������������������������������� 407 Clinical Features������������������������������������������������������������� 407 Diagnosis����������������������������������������������������������������������� 407 Treatment���������������������������������������������������������������������� 407 CAUSTIC INGESTIONS������������������������������������������������������� 408 Epidemiology����������������������������������������������������������������� 408 Pathophysiology������������������������������������������������������������� 408 Clinical Features������������������������������������������������������������� 408 Diagnosis ����������������������������������������������������������������������� 408 Treatment���������������������������������������������������������������������� 409 Late Complications��������������������������������������������������������� 410

Gastrointestinal foreign bodies (GIFBs) are composed of food bolus impactions and intentionally and unintentionally ingested or inserted foreign objects. Bezoars are ingested materials (food or other materials) that accumulate in a normal or abnormal stomach. Caustic ingestions present following ingestion of acid or alkaline materials, which may result in acute and/or chronic injury to the esophagus and stomach. These topics are discussed in detail in this chapter.

GASTROINTESTINAL FOREIGN BODIES GIFBs are a common problem encountered by gastroenterologists. Most resolve without serious clinical sequelae.1 Older studies have suggested that between 1500 and 2750 deaths occurred in the US secondary to GIFBs.2-4 More recent studies have suggested the mortality from GIFBs to be significantly lower, with no deaths reported in over 850 adults and only one death in some 2200 children with reported GIFBs.5-11 Regardless of imprecise morbidity and mortality rates, serious complications and deaths result from foreign body ingestions.12-14 Because of their frequent occurrence and potential for negative consequences, it is important to understand which patients are at risk and know how to diagnose and treat GIFBs and deal with their complications.

body ingestions.15 Children’s natural oral curiosity leads to placing objects in their mouth and occasionally swallowing them. Coins are the most common objects swallowed by children, but other frequently swallowed objects include marbles, small toys, crayons, nails, and pins.6,10,16,17 Accidental ingestion due to loss of tactile sensation during swallowing may also occur in adults with dental covers or dentures18; mistakenly ingesting one’s own dentures is not uncommon.19 Patients with altered mental status or sensorium, including the very old, demented, or intoxicated, are at risk for accidental foreign body ingestions (Fig. 28.1). Accidental coin ingestion has been noted in college-aged adults during a tavern beer drinking game called “Quarters,” in which the coin becomes lodged in the esophagus.20 Finally, those in certain occupations (e.g., roofers, carpenters, seamstresses, tailors) are at risk of accidental ingestion when nails or pins are held in the mouth during work. The most common groups that intentionally ingest foreign bodies are psychiatric patients and prisoners,21 in whom ingestion is often done for secondary gain; they often ingest multiple objects multiple times and often the most complex foreign bodies. Iatrogenic foreign bodies are increasing in prevalence because of complications from capsule endoscopy, migrated stents (esophageal, enteral, and biliary), and migrated enteral access tubes and bolsters.22,23 Esophageal food impaction is the most common GIFB requiring medical attention in the US, with an incidence of 16/100,000.24 The vast majority (75% to 100%) of patients with an esophageal food impaction have an underlying predisposing esophageal pathology,25,26 most often peptic strictures, Schatzki rings, and increasingly eosinophilic esophagitis (EoE).27 Esophageal cancer rarely presents with acute food bolus impaction.28 Other causes that contribute to esophageal food impactions include altered surgical anatomy following esophagectomy, fundoplication, or bariatric surgery and motility disorders such as achalasia and distal esophageal spasm.29 Food impactions most commonly occur in adults in their fourth or fifth decade of life but are becoming more prevalent in young adults because of the rising incidence of eosinophilic esophagitis. Cultural and regional dietary habits influence GIFBs.

Epidemiology GIFBs may result from unintentional or intentional ingestion. The most common patient group that unintentionally ingests foreign bodies is children, particularly those between ages 6 months and 3 years. Children account for 80% of true foreign

Fig. 28.1  Endoscopic image of a bottle opener (in the stomach) ingested by an intoxicated patient.

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PART IV  Topics Involving Multiple Organs

Hypopharynx Upper esophageal sphincter Level of aortic arch Gastroesophageal junction Pylorus Duodenum

Fig. 28.2  Endoscopic image of bratwurst with sauerkraut impacted in the esophagus while the patient was tailgating at a football game.

Fish bone injury is common in Asian countries and the Pacific rim, whereas impactions due to meats (e.g., hot dogs, pork, beef, chicken) are common in the US (Fig. 28.2).30,31 Symptomatic rectal foreign bodies are more often the result of insertion through the anus rather than oral ingestion and transit. This is reported most commonly in young adult males.32 Rectal foreign bodies that come to medical attention are most commonly inserted with the intention of autoeroticism but may present following consensual sexual acts or sexual assault.33 Less common but still prevalent causes of rectal foreign bodies include concealment of illegal drugs during smuggling efforts, loss of objects during attempts by the patient to relieve constipation, and even reports of falling on objects.34 

Pathophysiology The majority (≈ 80% to 90%) of GIFBs pass through the GI tract without any clinical sequelae and cause no harm to the patient.1,35 The remaining 10% to 20% of GIFBs will require endoscopic intervention, and 1% of GIFBs may require operative therapy.5,36 Recent data suggest that in the setting of intentional ingestions, the need for endoscopic and surgical intervention is higher with endoscopy being performed in two thirds of cases and surgery needed in greater than 10% of patients.37 True foreign bodies and food impactions can cause significant morbidity, with the most serious complications being bowel perforation or obstruction and rarely ensuing death.3 To help stratify therapeutic interventions, it is important to understand the conditions, patients, and anatomic locations in which complications associated with GIFBs are apt to occur. Perforation and obstruction from GIFBs can occur in any part of the digestive tract, but they are more apt to occur in areas of narrowing, angulation, anatomic sphincters, or previous surgery (Fig. 28.3).38 The pharynx is the first area where foreign bodies may become entrapped and cause complications. In the hypopharynx, short sharp objects like fish bones and toothpicks may lacerate the mucosa or become lodged.39,40 Once in the esophagus, there are 4 areas of narrowing where food boluses and foreign bodies become lodged: upper esophageal sphincter, level of the aortic arch, level of the mainstem bronchus, and esophagogastric junction. These areas all have luminal narrowing to 23 mm or less.41 However, food and foreign bodies more commonly lodge in the esophagus at areas of pathology, including rings, webs, or strictures. Multiple esophageal rings associated with eosinophilic esophagitis (see Chapter 30) contribute to esophageal food impaction at an increasing prevalence in young adults.27,42,43 Similarly, esophageal motor abnormalities (see Chapter 44) such as distal esophageal spasm

Ileocecal valve

Rectum and anus Fig. 28.3  Gastrointestinal areas of luminal narrowing and angulation that predispose to foreign body impaction and obstruction.

or achalasia may lead to food or foreign body impaction in the esophagus.44-47 Foreign body and food impaction in the esophagus have the highest incidence of overall adverse events, with the complication rate directly proportional to how long the object is lodged in the esophagus. Esophageal foreign bodies in children have a significantly lower spontaneous passage rate, as low as 12% compared with other GIFBs.48 Serious complications of esophageal foreign bodies include perforation, abscess, mediastinitis, pneumothorax, fistula formation, and cardiac tamponade.49,50 If a GIFB passes through the esophagus, the vast majority will pass through the entire GI tract without further difficulty or complication. Exceptions are sharp, long, and large objects. Sharp or pointed objects may have a perforation rate as high as 35%. Large objects (>2.5 cm [1 inch] in diameter) may not be able to pass through the pylorus. Long objects (>5 cm [2 inches]) such as pens, pencils, and eating utensils may not negotiate around the duodenal sweep or through the pylorus. Objects may become impacted in the small intestine at the ligament of Treitz or ileocecal valve. Adhesions, postinflammatory strictures, and surgical anastomoses within the small intestine may also be sites where foreign bodies lodge and obstruct. However, most objects, even sharp ones, rarely cause damage once in the small intestine and colon, because the bowel naturally protects itself through peristalsis and axial flow. These factors tend to keep the foreign body concentrated in the center of fecal residue, with the blunt end leading and the sharp end trailing.51,52 Inserted rectal objects are often tenaciously retained because of anal sphincter spasm and edema, making spontaneous passage of the object difficult. The angulation and valves of Houston may also impede passage of objects through the rectum. 

History and Physical Examination The history from children or noncommunicative adults is often unreliable. Most gastric and up to 20% to 30% of esophageal

CHAPTER 28  Foreign Bodies, Bezoars, and Caustic Ingestions

foreign bodies in children are asymptomatic.53 Most of these present after having been witnessed or suspected by a parent, caregiver, or older sibling, but in up to 40% of cases, there is no history of a witnessed ingestion.54 Thus, symptoms are often subtle in children, presenting as drooling, not wanting to eat, and failure to thrive. For communicative adults, history of the timing and type of ingestion is usually reliable. Patients are able to relate exactly what they ingested, when they ingested it, and symptoms of pain and/or obstruction. Patients with esophageal food bolus impactions are symptomatic with complete or intermittent obstruction. They are unable to drink liquids or retain their own oral secretions. Sialorrhea is common. Ingestion of an unappreciated small, sharp object, including obscured fish or animal bones, may cause odynophagia or a persistent foreign body sensation because of mucosal laceration. The type of symptoms can aid in determining whether an esophageal foreign object is still present. If the patient presents with dysphagia, odynophagia, or dysphonia, there is an 80% likelihood a foreign body is present, causing at least partial obstruction. Symptoms of drooling and inability to handle secretions are indicative of a near-total esophageal obstruction. If symptoms are restricted to retrosternal chest pain or pharyngeal discomfort, less than 50% of patients will still have a foreign body present.55 Patient localization of where an ingested foreign object is lodged is not accurate, with only a 30% to 40% correct localization in the esophagus and essentially a 0% accuracy for foreign bodies in the stomach.53,56 Once the object reaches the stomach, small intestine, or colon, the patient will not report symptoms unless a complication occurs (e.g., obstruction, perforation, bleeding). Patients with rectal foreign bodies are frequently asymptomatic,33 but embarrassment may interfere with obtaining an accurate history. Presentation is often after the patient or another person has made multiple attempts to remove the object.39 Symptoms may include anorectal pain, bleeding, and pruritus, with a small number of patients presenting with more serious complications, including obstruction, perforation, and peritonitis. Past medical history is useful to identify previous foreign body ingestion; repeat offenders are likely to ingest multiple and more complex foreign objects. A history of dysphagia in a person with a food impaction or esophageal foreign body suggests a high likelihood of underlying esophageal pathology. Previous food impaction or need for esophageal dilation makes recurrent episodes more likely. A history of allergies (e.g., asthma, allergic rhinitis, food allergy) may be a clue that a patient may have eosinophilic esophagitis.57 Physical examination does little to secure the diagnosis or location of a retained foreign body, but it is crucial to identifying already developed complications related to foreign body ingestion. Assessment of the patient’s airway, ventilatory status, and risk for aspiration are crucial prior to initiating therapy to remove a GIFB. A neck and chest examination looking for crepitus, erythema, and swelling can suggest a proximal perforation. Lung examination should be performed to detect the presence of aspiration or wheezing. An abdominal examination should be performed to evaluate for signs of perforation or obstruction. 

Diagnosis Imaging Plain films of the chest and abdomen are recommended for patients presenting with suspected foreign body ingestion to determine the presence, type, number, and location of foreign objects present. Radiologic evaluation is not routinely needed for patients with non-bony food impactions who have no complications.58 Both anteroposterior and lateral chest films are needed because lateral films will aid in determining if a foreign body is

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Fig. 28.4  Chest film demonstrating pneumomediastinum and bilateral pneumothoraces in a patient who developed esophageal perforation secondary to a food impaction left untreated for longer than 24 hours.

in the esophagus or the trachea59 and may detail foreign bodies obscured by the overlying spine in an anteroposterior film. Biplanar neck films are recommended if there is a suspected object or complication in the hypopharynx or cervical esophagus. Plain films are also useful in identifying complications like free air, aspirations, or subcutaneous emphysema (Fig. 28.4).60 Unfortunately, radiography cannot image nonradiopaque objects (e.g., plastic, glass, wood) and may miss small bones or metal objects. The false-negative rate for plain film investigation of foreign bodies is as high as 47%, with false-positive rates up to 20%. False-negative rates for food impactions have been reported as high as 87%.61 If continued clinical suspicion or symptoms warrant, the individual should undergo further clinical investigation.62 Use of plain films in children is more controversial because of the inability of the child to give a history and the associated radiation exposure. Some have suggested mouth-to-anus screening films to detect the presence of foreign bodies in children. Bedside US has been effective in identifying esophageal foreign bodies in children without the need of radiation.63,64 Also to limit radiation, hand-held metal detectors have been used, with a sensitivity ranging from 89% to 95% for detection and localization of metallic foreign bodies.65,66 Barium studies are generally not recommended for evaluating GIFBs. Aspiration of hypertonic contrast agents in patients with complete or near-complete esophageal obstruction may lead to aspiration pneumonitis.67 Barium may also delay or impair the performance of a therapeutic endoscopic intervention by interfering with endoscopic visualization.68 Even if a barium study is considered normal, an endoscopy is still recommended if symptoms persist or suspicion of a foreign body is high.39 CT or MRI are rarely necessary for the diagnosis of GIFBs. However, CT has been found to detect foreign bodies missed by other modalities69 and may aid in detecting complications of foreign body ingestion, such as perforation or abscess, prior to the use of endoscopy.70 CT of the cervical esophagus or hypopharynx prior to endoscopic investigation may benefit diagnosis.71 

Endoscopy Endoscopy provides the most precise means to diagnose suspected foreign bodies or food impactions. This ensures an almost 100% diagnostic accuracy for objects within the reach of the endoscope, including nonradiopaque objects and objects obscured by overlying bony structures that are not visualized by radiography.

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Endoscopy allows the most accurate diagnosis of the underlying pathology, such as esophageal strictures, which may have led to a food impaction or impacted esophageal foreign body. Endoscopy also allows visualization of mucosal defects, abrasions, or ulcerations that may have resulted from the foreign body. Diagnostic endoscopy is also linked to the most efficacious therapy for GIFBs, the use of therapeutic endoscopy to remove or treat the object. Diagnostic upper endoscopy for foreign bodies is relatively contraindicated when there are clinical or radiographic signs of perforation. Once an ingested foreign object has passed the ligament of Treitz, endoscopy is generally not indicated, because these objects will typically pass unimpeded with notable exceptions (see later). Similarly, most small (2 cm) more likely to remain in the esophagus and cause complications.125 Grasping forceps and snares are generally ineffective for disc battery removal, but use of a retrieval net permits successful removal in almost 100% of cases.126 Protection of the airway with an overtube or, in pediatric patients, endotracheal intubation is crucial in retrieval of disc batteries. Half of patients with disc batteries in the stomach have mucosal damage and thus gastric batteries should also be removed via the endoscope.127 Once in the small intestine, disc batteries rarely cause clinical problems and can be observed radiographically, with 85% passing through the GI tract within 72 hours.128 Cylindrical batteries appear to cause symptoms less frequently, with no reports of major life-threatening injuries and only 20% having some minor symptoms after ingestion including mucosal ulceration and rarely bowel obstruction.128 Cylindrical batteries should be removed from the esophagus and, if in the stomach, ones larger than 20 mm or batteries that have not progressed in 48 hours should be removed by endoscope (Fig 28.10). Small coupling magnets have become popular as children’s toys. Ingested magnets within the reach of the endoscope should also be removed on an urgent basis. Although a single magnet will rarely be a cause of symptoms, concern exists if multiple magnets are ingested or if magnets were ingested with other metal objects. This can result in magnetic attraction and coupling between interposed loops of bowel, with subsequent pressure necrosis, fistula formation, and bowel perforation.129,130 Removal should be performed urgently when the magnets are likely to be within reach of a standard endoscope; this can be achieved with grasping forceps, retrieval net, or basket. Magnetic attraction to metallic retrieval devices may ease the task of removal. 

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52.13mm

229.20mm Fig. 28.10  Multiple cylindrical batteries greater than 2 cm found in stomach and subsequently removed with the endoscope.

SUPINE

Narcotic Packets Ingested packets of illicit narcotics in the GI tract present in 2 general groups: body stuffers and body packers. Body stuffers are drug users or traffickers who quickly ingest small amounts of drugs, but in poorly wrapped or contained packages that are prone to leakage. Body packers are “mules” used by drug smugglers for drug transport; they ingest large quantities of carefully prepared packages intended to withstand GI transit.131,132 These patients may present with intestinal obstruction due to the packages or with symptoms related to the drug ingested. The latter may result in serious toxicity and death in 5% of individuals.133 Suspected patients are typically uncooperative and accompanied by law enforcement agents. Diagnosis is initiated with plain film radiology or CT scan, with multiple round or tube-shaped packets seen. Endoscopic removal is contraindicated because of the high risk of package perforation, with resultant drug overdose.1 Observation on a clear liquid diet is recommended with serial radiographs. Operative intervention is indicated when bowel obstruction, failure to progress, or drug leakage/toxicity is suspected. In a large study, up to 45% may require surgery with gastrotomy, enterotomy, or colotomy performed based upon the location of the packages.134 Other data has suggested that conservative therapy of narcotic packers with just observation led to surgery in less than 3% of cases.135,136 

Colorectal Foreign Bodies Ingested objects uncommonly become lodged in the colorectum. More commonly, colorectal foreign bodies were inserted into the rectum intentionally or unintentionally. Radiographs should be obtained prior to attempting removal of colorectal foreign bodies for better visualization of the location, orientation, and configuration of the object (Fig. 28.11). To avoid health care provider injury, attempts at manual removal or digital rectal examination should be deferred until the presence of a sharp or pointed object has been excluded. Manual digital extraction may be successful for the removal of small, blunt, palpable objects in the distal rectum. Conscious sedation may be adequate for manual removal in some patients, but examination and extraction under general anesthesia may be required in others to allow greater anal sphincter relaxation and successful object extraction.

Fig. 28.11  Plain film showing a self-introduced rectal foreign body in a 73-year-old man presenting with lower abdominal pain. (Courtesy Dr. William Beaujohn, Plano, Tex.)

Nonpalpable and sharp or pointed objects should be removed under direct visualization with the use of a rigid proctoscope or flexible sigmoidoscope.137 Standard retrieval devices can be used as described earlier for the upper digestive tract. A latex hood or overtube can be particularly useful in removing long, sharp, pointed objects to protect the rectal mucosa from laceration and to overcome the tendency of the anal sphincter to contract on attempted removal of objects. Although conscious sedation will often facilitate removal, general anesthesia can allow maximum dilation of the anal sphincter to help remove larger and more complex objects.138 Operative intervention is indicated for any suspected complications secondary to a rectal or colon foreign body, including perforation, abscess, and obstruction. Complications are more common when the object is proximal to the rectum. 139 

Procedure-Related Complications Although the reported complication rate associated with endoscopic removal of GIFBs and food impactions is low (0% to 1.8%), it is thought to be much higher in practice.5,9,24,25,36,68 Perforation is the most feared complication, although aspiration and sedation-related cardiopulmonary complications may also occur (see Chapter 41). Factors that increase the risk for complications include removal of sharp and pointed objects, an uncooperative patient, multiple and/or deliberate ingestion, and extended duration of time from food impaction or foreign body ingestion.12 

BEZOARS Bezoars are collections of indigestible material that accumulate in the GI tract, most frequently in the stomach. The 3 most common types of bezoars encountered are phytobezoars, composed of vegetable matter; trichobezoars, made up of hair or hair-like fibers; and medication bezoars (pharmacobezoars) (Fig. 28.11 and Box 28.2).

CHAPTER 28  Foreign Bodies, Bezoars, and Caustic Ingestions

407

BOX 28.2 Oral Pharmacologic Agents Associated with Medication Bezoar Formation Nonabsorbable antacids Bulk laxatives Cardiovascular medications Nifedipine Verapamil Procainamide Vitamins and minerals Vitamin C Vitamin B12 Ferrous sulfate Miscellaneous agents Sucralfate Guar gum Cholestyramine Enteral feeding formulations Theophylline Sodium polystyrene sulfonate (Kayexalate) resin

Epidemiology Phytobezoars are the most common type of bezoar. Offending fruits and vegetables include celery, pumpkin, prunes, raisins, leeks, beets, and persimmon.5 All these foods contain large amounts of insoluble and indigestible fibers such as cellulose, hemicellulose, lignin, and fruit tannin.140 A phytobezoar develops when large quantities are ingested and accumulate. Trichobezoars occur most commonly in young women and children from ingestion of large amounts of hair, carpet fiber, or clothing fiber. Trichobezoars are more often associated with psychiatric disorders, mental retardation, or pica.141 Medication bezoars occur with fiber-containing medications, resin-water products, or extended-release medications designed to resist digestion.142 Medication bezoars can result in decreased pharmacologic efficacy when the active agent is trapped in the bezoar and cannot be absorbed or, alternatively, toxicity when the contents of a large gastric medication bezoar are released all at once into the small intestine. The clear majority of patients with bezoars (other than trichobezoars) have a predisposing factor that decreases emptying of gastric contents. Prior gastric surgery is evident in as many as 70% to 94% of patients with bezoars. Retained gastric contents may be observed in up to 65% to 80% of patients who have undergone a vagotomy with pyloroplasty.56 Bezoar formation after gastric surgery results from delayed gastric emptying, decreased gastric accommodation, and reduced acid-peptic activity.143 Gastroparesis is commonly seen in patients with gastric bezoars. Patients with diabetes or end-stage renal disease and patients on mechanical ventilation are at greater risk for bezoar formation.144 

Clinical Features Patients with gastric bezoars may be asymptomatic, but most (80%) have vague symptoms of epigastric discomfort.144 Associated anorexia, nausea, vomiting, weight loss, and early satiety may also be present. Bezoars can cause gastric ulceration secondary to pressure necrosis. Bezoar-induced gastric ulcers can cause bleeding and gastric outlet obstruction.145 Bezoars may also accumulate in the small bowel and usually present with mechanical obstruction. Rapunzel syndrome is a term used to describe trichobezoars located primarily in the stomach that extend past the pylorus and into the duodenum, causing bowel obstruction or even jaundice or pancreatitis because of obstruction at the level of the ampulla of Vater.146,147 

28

Fig. 28.12  Endoscopic image of a pharmacobezoar in a patient with a history of a pancreaticoduodenectomy who had obstructive symptoms. The pills were removed with an endoscopic net, with subsequent relief of the patient’s symptoms.

Diagnosis The history is helpful in the diagnosis of bezoar, with a focus on the amount and types of food or medications consumed. A history of previous bezoar, gastric surgery, or gastric dysmotility should be considered. Physical examination usually assists little in the diagnosis, although occasionally a palpable abdominal mass may be appreciated. Halitosis due to the putrefying materials of the bezoar residing in the stomach may be present. Baldness and a patchy hair pattern may be present in patients who suffer from trichotillomania; they are consistently ingesting their own hair. A plain abdominal radiograph may demonstrate the outline of the bezoar. On contrast radiography, a gastric bezoar classically presents as filling defects within the stomach.140 Plain films and contrast studies will detect only 25% of bezoars detected at upper endoscopy. CT scan may aid in identifying small bowel bezoars and predict, based on size and degree of vegetable matter the bezoar is made of, whether an obstruction will occur.148 Gastric bezoars are more definitively diagnosed with upper endoscopy; phytobezoars are seen as a dark brown, green, or black mass of amorphous vegetable material in the stomach. Trichobezoars tend to have a hard, blackened, and almost concrete appearance. Medication bezoars will be seen as whole pills or pill fragments in the midst of the material (Fig. 28.12). 

Treatment Smaller bezoars may be treated with conservative medical management; usually this consists of a liquid diet for a short period of time and a prokinetic agent to promote gastric emptying.140 Chemical dissolution, most commonly with cellulase, has been reported successful in up to 85% of patients with small bezoars.145 Cellulase can be taken as a tablet or instilled into the stomach as a liquid via an endoscope or nasogastric tube. Nasogastric lavage may aid in the physical dissolution of small bezoars. Carbonated soda (e.g., Coca-Cola) may be effective in the dissolution of over 50% of cases of phytobezoars and over 90% when combined with endoscopic methods.148 Additional medications that have been shown to effectively treat gastric bezoars include pancreatin and ursodeoxycholic acid, alone or in combination with cellulase and carbonated beverages.149 For larger bezoars and bezoars resistant to medical therapy, endoscopic therapy may be effective. The endoscope is used to fragment the bezoar into smaller pieces. Fragmentation can be performed with the endoscope itself, with accessory devices like forceps or snares, or with instillation of saline or water flushes

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through the endoscope. The fragments of the bezoar can be pushed into the small bowel or removed by mouth. If most of the bezoar is to be removed, an overtube is recommended to facilitate frequent passes of the endoscope and to protect the airway. Mechanical disruption and endoscopic removal will be successful in 85% to 90% of gastric bezoars. Resistant gastric bezoars may be treated with mechanical lithotripsy, electrohydraulic lithotripsy, Nd : YAG laser, or a needle-knife sphinctertome.150-152 Operative intervention may be needed if endoscopic therapy fails or if there is a complication related to the bezoar (e.g., perforation, obstruction, bleeding). Trichobezoars more often require surgery than phytobezoars. Gastric bezoars are usually removed via a small gastrostomy.145,147 Small bowel bezoars are removed via an enterotomy or can be transmurally milked to the cecum, where they rarely cause a problem in the larger-diameter colon. Laparoscopic removal can first be attempted in bezoar removal but conversion to an open surgery may occur in just over half of patients.153 When operative intervention is contemplated, care must be made to exclude multiple bezoars in more than one location. Preventing bezoar recurrence is as important as active treatment. If the underlying causes of bezoar formation are not corrected, recurrence is likely. Avoidance of high-fiber and other non-digestible foods should be followed. A starting dose of cellulase, an enzymatic dissolution medication, can be taken prophylactically by patients who have frequently recurring bezoars. Prokinetic drugs may be useful for patients with underlying motility disorders. In particularly refractory patients with recurring gastric bezoars, repeated periodic endoscopy with physical disruption of food material may prevent larger and clinically significant bezoar formation. 

CAUSTIC INGESTIONS Epidemiology Some 5000 caustic ingestions are reported annually in the US.154 Most occur as accidental ingestions by children younger than 6 years.155 Caustic ingestions in adults occur as suicide attempts, in patients with mental health problems, and in the intoxicated person as a result of alcohol or recreational drug ingestion. Adults can ingest larger amounts of caustic substances, so they tend to have more serious injuries than children, who will typically spit out or throw up the caustic agent they swallowed. Broadly, 2 types of caustic agents are most commonly ingested: alkali agents or acidic agents. Alkali agents are most commonly in household cleaners like drain, toilet bowl, and oven cleaners. Lye is an alkali ingestion that contains sodium or potassium hydroxide. Alkali solutions are often odorless and tasteless, which can result in large amounts being swallowed accidentally. Finally, as noted, disc batteries may also cause alkali-induced damage. Acid ingestion usually comes from swallowing toilet bowl cleaner, swimming pool cleaner, or battery acid. Acid ingestion often causes immediate pain, which results in the agent being rapidly expelled. Household bleach may contain both acid and alkali products but rarely causes severe injury because of their diluted concentration. 

Pathophysiology Alkali Alkaline ingestion causes a liquefactive necrosis that very rapidly extends through the mucosa, submucosa, muscularis of the esophagus, and stomach.156 Vascular thrombosis occurs following the necrosis. The initial alkali injury can be transmural and result in perforation, mediastinitis, and peritonitis.157 External sloughing and ulceration occur a few days after ingestion. Finally,

Fig. 28.13  Barium esophagogram showing a stricture in the upper esophagus, with narrowing of the midesophagus, several weeks after a caustic ingestion. (Courtesy Dr. Robert N. Berk, University of California, San Diego, Calif.)

extensive granulation tissue, fibroblastic activity, and collagen deposition occur over weeks, leading to chronic stricture formation (Fig. 28.13). With alkali ingestion, the esophagus is most affected; neutralization by gastric acid limits damage in the stomach. A minority of patients have damage in the small intestine as well.158 The degree of injury is also dependent on the agent ingested, its quantity, and how long the GI tract was exposed.159 

Acid Acidic agents cause a coagulative necrosis, with thromboses of mucosal blood vessels and a more limited superficial necrosis. Acidic agents are more apt to damage the stomach, particularly the antrum, more than the esophagus (Fig. 28.14). Acidic agents tend to be ingested in smaller quantities because of their offensive taste and immediate pain, so they are associated with less overall damage than alkali agents. 

Clinical Features Patients may present with oropharyngeal pain, epigastric pain, chest pain, dysphagia, or odynophagia. Oropharyngeal involvement can cause sialorrhea and drooling. Hoarseness, stridor, and dyspnea suggest injury to the epiglottis, larynx, and upper airway. Persistent chest or back pain may suggest esophageal perforation and mediastinitis, whereas severe abdominal pain can be related to gastric perforation and peritonitis. Of importance is that early signs and symptoms do not always correlate with the amount of caustic injury and likelihood for late complications.160 On physical examination, patients may have evidence of burns to the oral cavity, with edema, ulceration, and exudate, but as many as 20% to 45% of patients will have normal physical examinations.161 

Diagnosis Radiologic images such as chest x-ray and abdominal films will not aid in the direct diagnosis or grading of severity of injury

CHAPTER 28  Foreign Bodies, Bezoars, and Caustic Ingestions

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A

B Fig. 28.14  Caustic injury to the esophagus and stomach by acid.  A, After the ingestion of acid, the squamous mucosa of the esophagus has sloughed in a linear pattern. The esophageal mucosa is edematous and has a bluish discoloration. B, The gastric mucosa in this patient is hemorrhagic and edematous. (From Wilcox MC. Atlas of clinical gastrointestinal endoscopy. Philadelphia: WB Saunders; 1995. p 85.)

TABLE 28.1  Endoscopic Grades of Caustic Injury

Acute caustic ingestion

Airway management and resuscitation

Chest and abdominal radiographs Perforation EGD Grade of I or IIA injury No therapy

IIB or Ill Observe for perforation and stricture formation, with appropriate therapy

IV Surgery

Fig 28.15  Algorithm for the approach to acute caustic injury.  For the definitions of endoscopic grades of injury, see Table 28.1.

Grade

Endoscopic Findings

I

Edema and erythema

IIA

Hemorrhage, erosions, blisters, ulcers with exudate

IIB

Circumferential ulceration

III

Multiple deep ulcers with brown, black, or gray discoloration

IV

Perforation

caustic ingestion will have no evidence of injury on endoscopic examination.164 Emergency CT scan can also be used to grade esophageal injury at time of caustic ingestion and predict stricturing.165 The degree of injury seen on endoscopic examination can be graded and provides prognostic information (Table 28.1). Grades I and IIA burns, which correspond to first- and second-degree burns, will usually heal without sequelae.158 However, strictures will develop in 70% to 100% of patients with grade IIB injury, which causes circumferential ulceration, and grade III injury with associated necrosis.166 Grade IV injury with perforation carries a mortality rate of up to 65% and requires urgent surgery. 

Treatment but will indicate the presence of perforation by showing a pneumomediastinum, pneumothorax, or pneumoperitoneum. CT of the neck, chest, and/or abdomen should be considered when a high degree of suspicion remains for perforation, despite negative plain films. If perforation is present, surgery rather than endoscopy should be performed emergently (Fig. 28.15). Symptoms and the physical examination may not match the degree of injury after a caustic ingestion, so an upper endoscopy examination should be performed in the first 24 to 48 hours after ingestion in patients without perforation.162 An upper endoscopy allows diagnosis of injury to the GI tract, permits grading of the degree of injury, establishes a prognosis, and can guide therapy (see Fig. 28.15). A re-look endoscopy at 5 days post-ingestion may be performed as well, as it can better predict esophageal and gastric complications than an endoscopy performed in the first 24 hours.163 It is important to note that 40% to 80% of patients with a reported

Initial management should address the ABCs of resuscitative management: airway, breathing, and circulation. Regional poison control should be contacted at 1-800-222-1222. Once initially stabilized, management is based on the clinical status of the patient and grade of injury seen on endoscopy. Asymptomatic patients who have a normal endoscopic examination or only grade I or IIA injury can be started on oral intake in the first 24 to 48 hours and usually discharged within that same time frame. Clinically ill patients with hypotension, respiratory distress, and grade IIB (circumferential ulceration) or III necrosis on endoscopy should be admitted to an intensive care unit and managed with intravenous fluid resuscitation and close monitoring for evidence of perforation. Laryngoscopy should be performed in patients with respiratory distress. A patient with an edematous, necrotic laryngopharynx should not undergo endotracheal intubation and will need a tracheotomy to maintain an airway.

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Emergency surgery with esophagectomy or gastrectomy is required for perforation. Colonic interposition is sometimes required. Operator and institutional experience affects mortality and morbidity of emergent esophagogastrectomy and is best undertaken at referral centers when circumstances allow.167 The need for and timing of operative intervention in patients with severe ulceration or necrosis without clear evidence of perforation remains controversial. Comparative analyses are difficult in this patient population. Some authorities have suggested that early operative exploration decreases mortality,168,169 but others cite lower mortality rates and complete healing in patients with nonoperative supportive care.159 Advanced age, tracheobronchial injuries, extended resections, and emergent esophagectomy are negative predictors for survival in those undergoing early surgical management.169 As such, management must be considered on an individualized basis. Inducing emesis or placing a nasogastric tube to clear or dilute the GI tract of the caustic agent is contraindicated because it may re-expose the esophagus, oropharynx, and airway to the caustic agent. Induced retching and vomiting may increase the risk of perforation. The use of neutralizing agents is not recommended because they have not been shown to be efficacious, may lead to increased thermal injury, and may also promote retching and emesis.170 The routine use of glucocorticoids156 and systemic antibiotics154 is not recommended, but use of a PPI may reduce complications.171 

Fig 28.16  Barium study of a chronic antral stricture caused by a caustic ingestion. (Courtesy Dr. Robert N. Berk, San Diego, Calif.)

Caustic exposure

Late Complications Up to one third of caustic ingestion patients will develop esophageal stricture after initial recovery (see Fig. 28.13). Stricture formation presents most commonly at 2 months after injury but can occur at any time from 2 weeks to many years after the initial injury.158 Stricture formation occurs more commonly following more severe (grade IIB or III) injuries (see Table 28.1). The primary treatment of esophageal strictures secondary to caustic ingestion is frequent dilation. Endoscopic management of caustic strictures must be deliberate, with gradual and incremental progressive dilation to 15 mm or until symptom relief is obtained.172 Endoscopic injection of triamcinolone into the stricture or use of topical mitomycin has been reported to be beneficial in treating caustic strictures.173,174 The perforation rate is 0.5% for endoscopic dilation of chronic caustic strictures, and as many as 10% to 50% of patients will eventually require operative intervention. Those requiring surgical intervention for late complications have better functional outcome and survival than those requiring early surgery for the management of caustic ingestions.169 Esophageal resection with an esophagogastric anastomosis, esophagojejunostomy, or colonic interposition may be considered.175 Case reports have described successful treatment with the use of temporary esophageal stents soon after caustic ingestion, but there is insufficient evidence to support recommendations for routine prophylactic stenting or for prophylactic early endoscopic dilation to prevent caustic-related strictures.170 Antral and pyloric strictures may also occur after caustic injury (Fig. 28.16). Antral and pyloric stenoses will usually develop 1 to 6 weeks after caustic ingestion but can also occur years later.154 The risk of antral stenosis is also related to the degree of injury. Endoscopic dilation with the addition of acid suppression is successful in many patients, but many others will require antrectomy.

Seconds Necrosis Perforation

24-72 hours Ulceration 14-21 days Fibrosis Weeks-years Stricture Decades Carcinoma

Fig. 28.17  Sequence of the consequences of caustic injury to the gastrointestinal tract as a function of time after ingestion.

Alkaline caustic ingestion, in particular, is associated with an increased risk for squamous cell cancer of the esophagus. Patients with a history of lye ingestion have a 1000-fold increased risk of developing esophageal cancer, with a lag time from injury of approximately 40 years.176 Periodic endoscopic surveillance is advocated every 1 to 3 years, beginning 20 years after the caustic ingestion. Fig. 28.17 summarizes the time course of complications from caustic ingestions reviewed in this section. Full references for this chapter can be found on www.expertconsult.com

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29

Abdominal Abscesses and Gastrointestinal Fistulas Gregory de Prisco, Scott Celinski, Cedric W. Spak

CHAPTER OUTLINE ABDOMINAL ABSCESS 411 Pathophysiology����������������������������������������������������������� 411 Bacteriology����������������������������������������������������������������� 412 Diagnosis��������������������������������������������������������������������� 412 Management���������������������������������������������������������������� 414 Outcomes�������������������������������������������������������������������� 418 GASTROINTESTINAL FISTULAS 419 Classification���������������������������������������������������������������� 419 Pathophysiology����������������������������������������������������������� 419 Diagnosis��������������������������������������������������������������������� 419 Management���������������������������������������������������������������� 419 Outcomes�������������������������������������������������������������������� 422 ���������������������������������������������������

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ABDOMINAL ABSCESS An intra-abdominal abscess (IAA) is a localized abdominal infection arising in the background of infectious peritonitis. Primary peritonitis (spontaneous bacterial peritonitis, discussed in Chapter 93) is not usually associated with development of abscesses, whereas secondary peritonitis, peritoneal infection due to an inflammatory process in the GI tract, is commonly associated with abscess formation (see Chapter 39). Most cases of IAA arise in the setting of secondary peritonitis due to bowel perforation (Box 29.1). Tertiary peritonitis, a persistent or recurrent infection arising 48 hours after treatment of secondary peritonitis, often arises in the setting of preexisting comorbidities and may be associated with IAA (see Chapter 39).1, 2 Abscesses in solid organs are discussed in Chapters 58, 61, and 84.

Pathophysiology Sterility in the peritoneal cavity is maintained when host defense mechanisms designed to clear bacterial contamination outweigh bacterial factors fostering microbial primacy. Bacteria commonly gain access to the peritoneal cavity through perforation of the intestinal wall. The bulk of these bacteria are delivered to the reticuloendothelial system for destruction via the continuous lymphatic drainage caused by function of the diaphragm.2 Lymphatic clearance is so efficient that abscess formation occurs when adjuvant substances such as hemoglobin, barium, or necrotic tissue are present.3 These adjuvant substances may block lymphatic vessels (barium, fecal particulate matter), provide bacterial nutrients (iron from hemoglobin), or impair bacterial killing, all fostering bacterial infection. Shortly after bacterial contamination, the predominant phagocytic cell types are peritoneal macrophages, which are also cleared by the lymphatic system. As bacteria proliferate, polymorphonuclear leukocytes invade the contaminated area and become more numerous. The resultant peritoneal inflammation leads to an increase in splanchnic blood flow, with protein and fluid exudation into the peritoneal cavity. The delivery of fibrinogen combined with the procoagulatory effects of the inflammatory process and reduced levels of plasminogen activator activity enhance fibrin deposition, leading to entrapment of

bacteria and localization of infection.4 The peritoneal cavity contains numerous recesses, pouches, and potential spaces that allow for compartmentalization of abdominal infection to prevent further spread of infection and the dreaded occurrence of sepsis.5,6 Thus, abscess formation ultimately may be regarded as a means of controlling severe intra-abdominal infection. Although peritoneal defense mechanisms can prevent the spread of bacterial infection, they can have adverse effects as well. Lymphatic clearance of bacteria may be so effective that it results in sepsis. Exudation of fluid into the peritoneal cavity can lead to hypovolemia and shock; it can also dilute the opsonins that target bacteria for phagocytosis. In addition, fibrin entrapment of bacteria can impair antimicrobial drug penetration and phagocytic migration.1 A number of host factors interact with bacterial contamination to increase the risk of IAA (Box 29.2). Diabetes, malnutrition, advancing age, preexisting organ dysfunction, underlying malignancy, and transfusion are all factors that predispose to abscess formation.7–9 In all these conditions, the immune system’s ability to combat bacterial contamination is weakened, whether it is in the setting of secondary or tertiary peritonitis. Iatrogenic immunosuppression in the setting of IBD offers insights into the pathogenesis of IAA. Chronic glucocorticoid administration is associated with an increased risk of IAA.10 Similarly, preoperative use of azathioprine for IBD increases the risk of intra-abdominal septic complications.11 In contrast, 2 recent large studies showed that anti-TNF-α therapy for IBD within the 12 weeks before surgery did not increase the incidence of IAA.12–14 The relationship between IAA and retained surgical sponges, so-called gossypiboma (textiloma), is well recognized.15 Although not commonly encountered, such causes of IAA remain an important preventable source of morbidity. Similarly, the use of interventional radiology techniques in the management of traumatic solid visceral injury has improved the care of trauma patients but may be associated with delayed IAA formation.16 

BOX 29.1 Causes of Intra-abdominal Abscesses Abdominal trauma Appendicitis Cholecystectomy and other operations or invasive procedures Crohn disease Diverticulitis Neoplastic disease Pancreatitis Perforated hollow viscus (e.g., duodenal or gastric ulcer)

BOX 29.2 Clinical Risk Factors for Intra-abdominal Abscess Chronic glucocorticoid use Increasing age Malnutrition Preexisting organ dysfunction Transfusion Underlying malignancy

411

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PART IV  Topics Involving Multiple Organs

Fig. 29.1 A, Axial CT image shows a large rim-enhancing structure containing an air-fluid level in the right lower quadrant (arrow) and a smaller similar structure in the left lower quadrant (arrowheads). B, Coronal image in the same patient shows that the 2 collections constitute a single large C-shaped collection that crosses the midline in the low pelvis (arrowheads) and demonstrates thrombosis of the superior mesenteric vein (arrow), one of the potential complications of abscess.  

A

B

Bacteriology The microbiology of IAA depends on the stage of presentation, as well as the host in which the infection has occurred. Animal studies have shown that the composition of an intra-abdominal infection changes over time. In classic studies by Onderdonk et al., Escherichia coli was shown to initially predominate in a rat model of abdominal sepsis.17 As peritonitis developed, many animals developed E. coli bacteremia and died. Of those animals who survived, IAAs developed with Bacteroides fragilis as the predominant microbe. Thus, there is a fluid interplay between the bacterial species responsible for abdominal infection. Formation of an IAA can be viewed as beneficial because it contains infection and prevents fatal sepsis and death. Bacteroides species are important microbes in the formation of IAA, so they have been studied extensively to better understand the process of abscess formation. B. fragilis is known to have 8 forms of capsular polysaccharides,18 some of which have a zwitterionic structure. Polysaccharide A (PSA) of B. fragilis can stimulate either a proinflammatory or anti-inflammatory response in the digestive tract, dependent upon their location.19,20 This has been termed a “love-hate” relationship19 or the “yin-yang” of bacterial polysaccharides.20 On one side, PSA from B. fragilis appears to have a vital role in induction of normal T cell–mediated immunity arising from normal commensal bacterial colonization in the gut, whereas on the other side, PSA introduced into the peritoneal cavity, in conjunction with lymphatic obstruction, induces abscess formation. The effect of PSA on abscess formation is through regulation of the T-helper 17 cells, which are needed for secretion of interleukin (IL)-17 and abscess formation,21 as well as Forkhead Box (FOX) transcription factor regulatory T cells and CD4+ CD45RBlow cells, both of which secrete IL-10, which promotes abscess formation.22,23 Interestingly, another source of IL-10 has been shown to be peritoneal macrophages, also vital to abscess formation.23 Recent research suggests the direct binding of B. fragilis to fibrinogen and the activity of fibrinogenolytic proteases may circumvent abscess formation, giving rise to bacteremia and potentially sepsis.24 It is apparent there are extremely complex interactions that occur between bacteria and cells of the immune system to promote or prevent spread of bacteria. Indeed, the theory has been put forth by numerous authors that abscess formation may be considered a form of “bacteria apoptosis,” a means whereby extraintestinal commensals are sacrificed to circumvent sepsis and prevent death of the host organism, thereby ensuring the continued growth of the larger intraintestinal bacterial cohort. Classic studies have shown that the polymicrobial nature of the abdominal infection may in fact be from synergy between the various bacterial subspecies. Facultative anaerobic organisms

such as E. coli can provide the ideal anaerobic environment for B. fragilis to multiply.25 Consequently, the increased number of anaerobic organisms such as B. fragilis will make it more difficult for host defenses to engage against the E. coli, because local effects will reduce efficacy of phagocytosis. The bacteria associated with intra-abdominal infections and abscesses in ICU patients subjected to broad-spectrum antimicrobial selection pressure are different from those in patients with abscesses due to secondary bacterial peritonitis.26 The organisms that cause tertiary peritonitis are no longer dominated by E. coli and B. fragilis. Rather, nosocomial infections with resistant gramnegative organisms, Enterococcus species, and/or yeast are more common.27,28 A microbiological analysis of abscesses in severely ill patients (Acute Physiology and Chronic Health Evaluation II score >15) revealed that 38% had monomicrobial infections. The most common organisms were Candida (41%), Enterococcus (31%), and Enterobacter (21%) species and Staphylococcus epidermidis (21%); E. coli and Bacteroides species accounted for only 17% and 7%, respectively.29 

Diagnosis The classic presentation of IAA is abdominal pain, fever, shaking chills, and palpable abdominal mass, but this tetrad of symptoms is not commonly seen in practice. The presence of additional symptoms and signs may be observed, depending on the location of the abscess. Subphrenic abscesses may cause pleurisy; lesser sac or perigastric abscesses may result in nausea and early satiety. Interloop abscesses may present with ileus or obstructive symptoms and signs including vomiting and distension. Pelvic abscesses may cause tenesmus or rectal urgency. In older adults and patients with underlying comorbidities, the signs and symptoms of IAA may be more varied and subtle, mandating a high clinical suspicion.30 Imaging is at the forefront of IAA diagnosis, be it in the patient presenting to the emergency department or in the hospitalized patient experiencing a clinical downturn.

CT CT is the gold standard for the diagnosis of IAA. Detection of abscess is optimized following oral and intravenous contrast. The classic CT appearance of IAA is a rim-enhancing fluid collection containing gas.31 Multidetector CT with helical acquisition allows for rapid scanning and affords creation of coronal and sagittal images that optimally characterize complex-appearing and insinuating collections (Fig. 29.1).32 CT exams following proper protocols afford diagnosis of associated bowel obstruction, pylephlebitis, and may suggest or confirm the presence of a fistula.33

CHAPTER 29  Abdominal Abscesses and Gastrointestinal Fistulas

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*

A

B

Fig. 29.2 A, Axial CT image shows an apparently rim-enhancing structure containing gas (asterisk) in the deep pelvis adjacent to tethered bowel loops in a patient with prior pelvic irradiation. The structure could represent an abscess or a dilated loop of small bowel. The presacral inflammation (arrows) is related to radiation change. B, CT image obtained 2 hours later shows ingested oral contrast in this structure (arrows), confirming that this is a bowel loop rather than an abscess.  

Despite the sensitivity of CT for detecting intraperitoneal collections, the a priori correct diagnosis of infection in an intraabdominal collection has been reported recently to be 83%, with a specificity of only 39%.34 Detection of extraluminal gas remains the most specific indicator of infection using CT but is observed in fewer than 40% of patients.35 Presence of a fluid collection with attenuation greater than 20 Hounsfield units is also predictive of an abscess.34 Hematomas, seromas, pseudocysts, and necrotic tumors may all confound diagnostic accuracy of CT for IAA. Thus, fluid aspiration followed by Gram stain and culture of the aspirate remain requisite for definitive diagnosis of abscess. An important pitfall in detection of IAA is confusing fluidfilled bowel loops for an abscess. This diagnostic dilemma is best prevented by administration of oral contrast 90 minutes (or more) before the CT. Occasionally, despite oral contrast administration, slow bowel transit time will leave some bowel nonopacified. These cases require a longer delay and repeat scanning to allow more time for oral contrast migration distally (Fig. 29.2). Importantly, there is a growing trend in emergency departments to perform abdominal CT without oral contrast to increase patient throughput.36,37 As a result, some patients presenting to the emergency department may need oral contrast administration and repeat scanning to confirm a questioned diagnosis of abscess. 

US US is a commonly used screening exam that is readily available, rapid, and does not expose the patient to radiation, making it especially useful in young and gravid patients. The appearance of an abscess may vary from a relatively simple anechoic fluid collection to a more complex fluid with heterogeneous echogenicity, a reflection of the amount of debris and gas present (Fig. 29.3).38 US is an excellent modality for evaluation of suspected solid abdominal visceral IAA and for pelvic collections. Fluid in the urinary bladder serves as an ultrasonographic window for localization of IAA. Transvaginal imaging affords US detection of most pelvic abscesses. Gas prevents US beam penetration, and gas-containing bowel in the midabdomen hampers abscess detection, with detection rates of 43% in a recent report.39 Furthermore, surgical wounds, dressings, and drains may preclude or limit the use of US in the postoperative period. These limitations are to some degree offset by the portability of the machine, allowing US to be performed at bedside in critically ill patients for whom transport to the radiology department is unsafe. 

MRI Improvement in MRI protocols and scanners in conjunction with increasing awareness of the radiation dose associated with CT have resulted in increased utilization of MRI for acute and

Fig. 29.3  Abdominal US of a typical abscess (arrowheads) demonstrating central decreased echogenicity, thickened wall, and debris arising anterior to the descending colon (arrow) in a patient with diverticulosis, compatible with a diverticular abscess.

subacute indications. The use of MRI initially was spawned by advances in MRI that allow for the accurate diagnosis of appendicitis in pregnancy.40 Now, MRI is more commonly being performed in patients presenting to the emergency department with acute intra-abdominal pain.41,42 Moreover, a recent multicenter study demonstrated that in experienced hands, MRI compares favorably with CT in the diagnosis of appendicitis, which will likely increase the role for MRI use in these patients.43 One advance that has become standard in the evaluation of Crohn disease is magnetic resonance enterography.44 This technique combines intravenous administration of a gadolinium-based contrast agent with high-resolution coronal MRI to detect abnormalities in the bowel wall, a common finding in Crohn disease. On contrast-enhanced MRI enterography, abscesses are extraluminal, rim-enhancing collections with heterogeneous signal elevation on fluid-sensitive sequences (Fig. 29.4).44,45 Diffusion-weighted imaging may increase the ability to discriminate abscesses from cysts.46 Barriers to mainstream use of MRI in the diagnosis of IAA are limited to the availability of MRI in the acute setting, radiologist/clinician comfort with CT, and time and cost of the exam compared with CT.41 

Radiographic Studies Radiographs may demonstrate large abscesses that have significant mass effect. Supine and upright films may reveal an air-fluid level in a large abscess cavity, localized ileus, or bowel obstruction that may support the diagnosis. Overall, however, radiographs are

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Matted inflamed loops of small bowel Small rim-enhancing abscess demarcated with arrowheads

insensitive to the detection of the majority of IAA, and sizeable abscesses may be overlooked. CT is far superior to radiography in sensitivity, specificity, and accuracy of diagnosing acute nontraumatic abdominal pathology, with rates of 96%, 95%, and 96% for CT versus 30%, 88%, and 56% for radiography, respectively.47 

Nuclear Medicine Studies Nuclear medicine studies that can be used to diagnose IAA include the gallium scan, labeled leukocyte scan, and PET/CT scan, among others.48 Historically, the gallium scan has been used most frequently for diagnosis of IAA, but normal uptake in bowel and tumors may give rise to false-positive results. Radiolabeled leukocyte scans afford whole-body imaging with high sensitivity and specificity. Still, these scans have drawbacks; they are not readily available owing to the time required for synthesis of the radiolabel, and they typically require 18 and possibly up to 72 hours to perform.49 Furthermore, upper quadrant abscess detection may be confounded by tracer uptake, both in the liver and spleen, which may require addition of a sulfur colloid scan to distinguish physiologic uptake from infection.50 PET/CT scans have great potential for an important role in diagnosis of IAA. Cells involved in the inflammatory process take up great quantities of glucose, making the use of 18F-FDG PET scans extremely useful.18 F-FDG uptake, combined with the CT component of the scan, allows for accurate anatomic localization of abnormalities, a problem that has long plagued nuclear medicine studies. In the persistently bacteremic patient, whole-body images obtained using PET/CT may uncover unsuspected IAA.51 PET/CT is the test of choice in the setting of fever of unknown origin; it can detect infectious, inflammatory, and neoplastic sources for fever.52 The greatest disadvantage of PET/CT and gallium scanning is their inability to differentiate between sterile inflammation and infection.48 Although CT will remain the first-line test of choice for IAA in the foreseeable future, PET/CT scans and other nuclear medicine studies can be of utility in diagnosing challenging cases. 

Management Stabilization Initial management entails fluid and electrolyte resuscitation and support of vital organ function, especially important if there

Fig. 29.4  Coronal MRI with gadolinium contrast of a patient with Crohn disease showing a small rimenhancing collection (arrowheads) interposed between several loops of inflamed bowel (arrows), compatible with an interloop abscess. Interloop abscesses are not amenable to percutaneous drain placement.

is presentation with sepsis. Fluid resuscitation in septic shock entails aggressive crystalloid infusion per the Surviving Sepsis Campaign.33,53 

Antibiotic Therapy Empirical therapy should be started once the presumptive diagnosis of IAA is made, optimally after obtaining blood cultures. Although an important component of early management, antibiotics may not be fully effective prior to drainage of an abscess, owing to inability to penetrate the area of infection. This is due to both host factors (e.g., tissue necrosis, an acidic environment, lack of adequate perfusion) and pathogenic factors (e.g., high colony count, slow growth rate of bacteria and their byproducts). Such factors can present specific obstacles for certain antibiotics: as examples, β-lactams are less effective in dense bacterial populations, and aminoglycosides have reduced activity at a lower pH. Initial choice of antibiotics should be based on the clinical scenario of each individual patient. In IAA associated with secondary peritonitis, antibiotics should target usual bowel flora such as E. coli and other coliforms, including B. fragilis. These cases are usually less complicated and do not have extraintestinal manifestations like bacteremia. Unfortunately, there are no randomized controlled trials showing that one agent is superior to another. Multiple noninferiority trials have been published, however, providing a variety of options (Box 29.3). Antibiotic selection will follow patient factors such as renal function and prior allergies. Hospital antibiograms are also helpful; for example, some institutions have high rates of E. coli resistance to fluoroquinolones. Guidelines issued by the Infectious Diseases Society of America and Surgical Infection Society recommend that single agents (e.g., β-lactams with β-lactamase inhibitors, carbapenems, the second-generation cephalosporin cefoxitin, the fluoroquinolone moxifloxacin, the glycylcycline tigecycline) are considered appropriate for mild to moderate disease (see Box 29.3).26 Gram stain and cultures can be useful, but the updated guidelines point out that there have been no studies to validate this practice. Combination choices can also be selected by the clinician. Most experts recommend reserving antipseudomonal coverage for those cases with a more severe illness or with high-risk comorbid conditions. Important points to consider in the selection of empirical antibiotics come from more recent published reports. Certain pathogens are less likely to play a role in those patients that present

CHAPTER 29  Abdominal Abscesses and Gastrointestinal Fistulas

BOX 29.3 Antibiotic Choices in the Treatment of Intraabdominal Infections Second-Generation Cephalosporin Cefoxitin*  Third and Fourth-Generation Cephalosporins Ceftriaxone* † Ceftazidime† Cefepime†   

Carbapenems Imipenem-cilastatin Meropenem Ertapenem*  Combination Antibiotics with Broad-spectrum Activity for Drug-resistant Pathogens Piperacillin/tazobactam Ceftolazone/tazobactam† Ceftazidime/avibactam† Meropenem/vaborbactam Imipenem-cilastatin/relebactam  Tetracycline Derivatives Tigecycline* Eravacycline* Omadacycline*  Fluoroquinolones Ciprofloxacin† Levofloxacin† Moxifloxacin*   

*Provides no coverage for Pseudomonas spp. †Add metronidazole IV or PO for anaerobic activity.

with community-associated abdominal abscesses. Methicillinresistant Staphylococcus aureus (MRSA) is unusual in these cases, so vancomycin or other anti-MRSA antibiotics are not usually recommended at the time of initial presentation. Enterococci are not usually pathogenic at this stage of infection, so antibiotic choices do not typically require good enterococcal coverage.26 The traditional practice of adding an aminoglycoside or clindamycin can no longer be routinely recommended; more recent studies have shown that aminoglycosides are associated with higher rates of nephrotoxicity without additional benefit54 and that rates of resistance to clindamycin, especially with B. fragilis, have been on the increase in the past decade. Cefotetan has been shown to have diminished efficacy against anaerobes such as B. fragilis, and ampicillin/sulbactam is no longer routinely recommended owing to increasing rates of E. coli resistance to ampicillin. IAA associated with tertiary peritonitis includes those cases at later or more aggressive stages of abdominal infection as well as “health care–associated infections” with more resistant nosocomial pathogens (see Chapter 39). Empirical choices in these patients will have to provide broader coverage, considering the possibility of Pseudomonas aeruginosa, enterococci, MRSA, drugresistant gram-negative bacilli, and even Candida species. Antipseudomonal β-lactams, carbapenems, or combination therapy with an antipseudomonal cephalosporin or antipseudomonal quinolone added to metronidazole are considered equally good choices. Of the β-lactams, piperacillin/tazobactam is the most widely used. Carbapenems can be imipenem-cilastin, doripenem, or meropenem; however, ertapenem has no antipseudomonal activity. Cefepime and ceftazidime are both active against Pseudomonas species, but anaerobic coverage should be added with

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metronidazole. Ciprofloxacin or levofloxacin can be used with metronidazole in patient populations where quinolone resistance is uncommon (defined as 500 mL/day) Low output (500 mL/day; see Box 29.4). Output greater than 1000 mL/day is not uncommon if the fistula originates in the proximal small bowel. To prevent intravascular volume depletion and electrolyte imbalance, fluid and electrolyte replacement must be a priority and should be addressed before more detailed diagnostic studies of the fistula are undertaken. Administration of replacement fluids should take into account the volume and electrolyte content lost through the fistula. In general, fistula output is isosmotic and rich in potassium. Initially, fistula output should be replaced milliliter for milliliter with a balanced salt solution that contains added potassium. If difficulties are encountered when managing electrolyte imbalances, a sample of fistula fluid can be sent to the laboratory for electrolyte determination, and subsequent electrolyte replacement can then be formulated on the basis of laboratory results. 

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A

Fig. 29.9  Abdominal films showing a rectovesical fistula in a patient with Crohn disease, pneumaturia, and urinary tract infection. A, Catheter in the bladder, with contrast beginning to fill the bowel. B, Contrast has filled the sigmoid colon and rectum through the fistulous tract. (Courtesy Dr. Mark Feldman, Dallas, TX.)

B

A

B

Fig. 29.10 A, Fluoroscopic image of a patient with Crohn disease with 2 draining abdominal wounds in whom guidewires have been placed within each tract, one within the transverse colon (large arrow) and the other within a loop of jejunum (small arrow). Note an additional thin enterocolonic fistula connecting the jejunum and transverse colon (arrowheads). B, Same patient after placement of drainage catheters into the transverse colonic (large arrow) and jejunal (small arrow) components of this complex fistula.  

Several hyperenhancing small bowel loops with stellate configuration representing enteroenteric fistulas

Fig. 29.11  Axial MRI after gadolinium contrast of a patient with Crohn disease, showing matted loops of small bowel (circle) in a tethered stellate configuration typical of enteroenteric fistulas (arrow).

CHAPTER 29  Abdominal Abscesses and Gastrointestinal Fistulas

Establishment of Adequate Drainage A cornerstone of the early management strategy in the treatment of enterocutaneous fistulas is establishing adequate drainage. This issue requires immediate attention because if drainage is not facilitated, pooling of fistula contents within the abdominal cavity can lead to infection, abscess formation, and sepsis. Minor surgical maneuvers, such as opening a recent surgical incision to allow adequate drainage, are often required. Placement of percutaneous catheters may be needed to drain collections and control the fistula effluent. Some patients present with diffuse peritonitis that cannot be managed with percutaneous drainage alone. In these situations, patients may require abdominal exploration and washout. Definitive repair of such fistulas at the time of operation for peritonitis is rarely successful. In these circumstances, the goal of surgery is to remove contamination and establish drainage, often with placement of drains during surgery. Diverting enterostomies and surgical feeding tubes are placed when appropriate.115 Once ongoing peritoneal contamination is resolved and external drainage is established, the effluent from the fistula must be controlled. Because most enterocutaneous fistulas occur postoperatively, some ingenuity may be required when trying to protect the skin from the caustic effects of the fistula output. Most acute postoperative enterocutaneous fistulas decompress through the surgical incision. Because the incision shows signs of infection and drainage, it must be opened. A reopened incision that is draining intestinal contents is not amenable to simple placement of an ostomy bag to collect the drainage. There are multiple options for containment, but an experienced enterostomal therapist should be consulted when dealing with this difficult problem.116 A recent adjunct in the management of enterocutaneous fistulas has been local wound care with the VAC system described earlier. The VAC device has simplified management of these difficult wounds, because control of the effluent and the open wound can be managed simultaneously.108,117–119 With the increasing popularity of DCL and OA, enteroatmospheric fistulas have become more common.120–122 These “exposed fistulas” are often very difficult to manage and give rise to drainage challenges. Many inventive strategies have been used to care for these complex fistulas.123–126 

Nutritional Support Well-nourished patients without infectious complications are more likely to experience spontaneous fistula closure and are at lower risk for operative complications if surgical repair is required.103,127–130 Thus, nutritional evaluation and support must be aggressively pursued (see Chapters 5 and 6). The causes of malnutrition in the patient with a GI fistula are multifactorial, including underlying disease states, lack of protein intake, protein losses through the fistula, and underlying sepsis with hypercatabolism.114 Soon after diagnosis of a GI fistula, aggressive caloric support must be given. Once the anatomic origin of the fistula is determined, the route of feeding is considered. TPN seems to be the natural first choice for a patient with an enterocutaneous fistula, but not all patients must be placed on TPN. In a study of 335 patients with external fistulas, 85% were managed solely with enteral feedings.131 In a subgroup of patients with uncomplicated fistulas in this study, 50% healed spontaneously with this mode of nutritional therapy alone. In another study, initiation of enteral feeding within 2 weeks of admission in patients with GI fistulas complicated with severe sepsis resulted in more rapid abdominal wound closure and decreased mortality compared with later initiation.132 Enteral feeding enhances mucosal proliferation and villous growth through direct and indirect mechanisms. Nutrients in contact with the bowel mucosa provide direct stimulation to the

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enterocyte, and feedings high in glutamine may be particularly beneficial because glutamine is the main source of energy for the enterocyte.133 Furthermore, nutrients within the gut lumen cause the release of gut-derived hormones that have an indirect trophic effect on the intestinal mucosa (see Chapter 4). TPN, in contrast, has been shown to lead to gut mucosal atrophy. This may in part be because standard TPN solutions do not contain glutamine, which crystallizes out of solution. In a small study of patients on TPN, spontaneous resolution of fistula drainage was more likely in patients supplemented with oral glutamine.134 Despite recent advances in enteral feeding of patients with GI fistulas, TPN remains the mainstay of nutritional support for most patients because they are unable to absorb sufficient calories enterally.135 Consequently, aggressive nutritional support is vital to improving outcomes in patients with GI fistulas.136 The decision to support the patient with a GI fistula with enteral nutrition or TPN is based on anatomic and physiologic considerations. In most patients, a trial of enteral feeding should be initiated after stabilization. Often, fistula output is not increased significantly despite feeding. If the output does increase significantly, decreasing or stopping enteral feeding should be considered. If the fistula is in the proximal intestine and distal access to the intestine has been established, as in many postoperative fistulas in which a feeding jejunostomy has been placed at the time of surgery, enteral feeding into the distal bowel should be started. Along with the commencement of enteral feeding, infusion of the proximal fistula drainage into the distal bowel has been shown to make fluid and electrolyte management easier, as well as decrease the output of the proximal fistula.106,137 In addition, fistuloclysis or tube feeding directly into the efferent limb of a fistula has been shown to be effective in selected patients.138 It is not mandatory to provide full nutritional support via the enteral route to obtain the benefits of enteral feeding; protein and caloric requirements can be supplemented by TPN. 

Medical Therapy Somatostatin Analogs Somatostatin analogs such as octreotide or lantreotide may be adjunctive to TPN in the management of the patient with a GI fistula. Octreotide has been shown to decrease fistula output by several mechanisms. First, it inhibits the release of gastrin, cholecystokinin, secretin, and many other GI hormones. This inhibition decreases secretion of electrolytes, water, and pancreatic enzymes into the intestine, subsequently decreasing intestinal volume. Second, octreotide relaxes intestinal smooth muscle, thereby allowing for a greater intestinal capacity. Third, octreotide increases intestinal water and electrolyte absorption.139 Meta-analyses of the randomized studies evaluating som­ atostain analogs in the treatment of enterocutaneous fistulas show an increased closure rate, with decreased fistula output, time to closure, and hospital stay, without an effect on mortality.140,141 Octreotide results in an increased fistula closure rate by converting a high-output fistula to a low-output fistula.142 We advocate a time-limited trial to evaluate whether addition of octreotide reduces fistula output. If the output does not decrease within 72 hours of initiation of treatment, octreotide should be discontinued. 

Management of Crohn Disease Historically, conservative management of fistulas associated with Crohn disease had been uniformly unrewarding because most abdominal and perianal fistulas required surgical correction. The observation that TNF-α production in the intestinal mucosa is

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increased in patients with Crohn disease143 has led to development of chimeric monoclonal antibodies against TNF-α (infliximab), as well as other anti-inflammatory monoclonal antibodies (ustekinumab and vedolizumab) for the treatment of Crohn disease (see Chapter 116). For the initial management of fistulas in Crohn disease, a trial of an anti-TNF-α antibody regimen should be considered and has been supported by a Cochrane Database review.144 A number of small series advocate for the use of aggressive immunosuppression of fistulizing Crohn patients with methotrexate or tacrolimus when other nonoperative therapy has failed.145,146 The data for medical treatment of fistulizing Crohn disease are heavily weighted toward the treatment of perianal disease, with little data specifically for enterocutaneous fistulas. Metaanalysis suggests variable quality evidence for the role of TNF antagonists, mesenchymal stem cell therapy, immunosuppressive agents, and therapy with TNF antagonists in combination with antibiotics in the treatment of fistulizing Crohn disease.147,148 In the setting of failed medical management, surgical intervention should be pursued. 

Nonsurgical Intervention Nonsurgical interventions in the management of refractory fistulas include the use of covered stents, clips, endoluminal vacuum (E-vac) therapy, endoscopic suturing, occlusive plugs, and fibrin glue placed endoscopically or percutaneously. Although reports are limited to case series at this time, a variety of nonsurgical techniques, including fistuloscopy, fluoroscopy, and endoscopy, have been reported.149–152 Success with endoscopic clipping of the internal fistula opening has also been seen, and over the scope, clips now available may allow for endoscopic closure of larger defects.153–158 E-vac therapy is very promising in the management of upper and lower GI fistulas and leaks. It has theoretical advantages over other techniques, with improved drainage of infection and enteric effluents through the negative pressure suction applied. This additionally can improve blood flow to the healing defect. This technique involves endoscopic evaluation of the luminal defect, irrigation, and aspiration of any associated abscess cavity or fistulous track, followed by insertion of an open pore polyurethane sponge cut to the appropriate size and attached to the end of a nasogastric tube (there is currently no available commercial E-vac product in the US). Once the sponge is in place, it is placed to continuous negative pressure of 100 to 125 mm Hg. Sponge changes are performed every 3 to 5 days until closure of the cavity and defect. Data from case series are quite encouraging.159–162 Endoscopic and nonoperative techniques may serve as a useful adjunct for fistulas refractory to conservative management or increasingly as front line treatment options. Initial attempts of nonsurgical interventions do not preclude surgery and may spare some patients having to undergo highly morbid procedures. 

Surgical Intervention Surgical therapy remains the mainstay of management of enterocutaneous fistula in which conservative and endoscopic management has failed in the resolution of fistulous output.103,106 Indications for early surgery include inability to control the fistula without surgical drainage, sepsis, abscess formation, intestinal obstruction distal to the fistula, and bleeding. Early surgical intervention often involves temporizing measures to eliminate the source of sepsis and establish fistula control, such as washout

and drainage and/or stoma formation. More complex fistulas may require surgery to remove mesh or other foreign bodies before spontaneous closure can occur or definitive surgery is undertaken. The goal of surgical therapy is to resolve infection and restore intestinal continuity—usually requiring resection.163 Attempts at direct fistula closure are rarely successful and generally should be avoided. Minimally invasive surgery is an option in selected patients.149,164 There are no firm data to dictate the timing of a definitive operation, but timing of surgery should take into account the clinical scenario for the case at hand. In the case of the postoperative enterocutaneous fistula, further surgery should occur either in the favorable “window period,” 7 to 12 days after laparotomy or deferred at least 6 weeks thereafter to allow improvement of intra-abdominal inflammation and adhesions.165 The rationale to waiting is to avoid an operation until the severe inflammatory response in the abdomen has resolved and the associated dense vascular adhesions have diminished. If operative intervention is performed beyond the window period, it is often doomed to fail. Moreover, these patients have an increased likelihood of developing additional enterotomies. In the setting of sepsis, the general consensus in the literature is to wait at least 6 weeks after stabilization and resolution of sepsis, with many advocating for longer waiting periods.165,166 The mainstay of surgical treatment is resection of the involved segment of bowel, with anastomosis. Different techniques have been used in the surgical treatment of fistulas, and some success has been seen with innovative techniques such as pedicled flaps.167 

Outcomes Early morbidity and mortality in the management of external fistulas result from initial fluid and electrolyte derangements that go unchecked. However, the major cause of mortality in patients with GI fistulas is sepsis with multiple organ failure. The typical setting for septic complications is provided by complex fistulas for which there is inadequate or uncontrolled drainage. In this setting, pooling of enteric contents occurs within the abdominal cavity and acts as a nidus of infection. Therefore, as noted, aggressive attempts must be made to ensure that fistulous drainage is well controlled. The mortality rate from all causes in patients with fistulas ranges from

TABLE 29.1  Prognostic Indicators of Spontaneous Fistula Closure with Nonoperative Management Favorable

Unfavorable

Surgical etiology

Ileal, jejunal, nonsurgical etiology

Appendicitis, diverticulitis

IBD, cancer, radiation

Transferrin >200 mg/dL

Transferrin 2 cm, end fistula

Length 6 wk: surgery

Yes Distal enteral feeding, reinfuse fistula output

Spontaneous closure

Fig. 29.12  Algorithm for the management of GI fistulas. See text for details. PAD, percutaneous abscess drainage; VAC, vacuum-assisted closure.

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10% to 30%.100,101,103,106,108,128,129,165,168* Higher mortality rates are seen in those with comorbidities, age older than 55, who are septic, are malnourished, have had previous radiation therapy, or have complex fistulas associated with a postoperative abdominal wall dehiscence.109,129,165 Another major risk of mortality in patients with GI fistulas is severe underlying disease, most frequently cancer. Often, patients who are terminally ill secondary to malignancy forgo further operative procedures.169 Fistula recurrence after surgery has been noted in 5% to 38% of postoperative patients. Factors associated with fistula recurrence after surgery include IBD, poor nutritional status, complex fistula, delayed fascial closure, mesh implantation, infection, advanced underlying disease states, and oversewing the fistula instead of resection and reanastomosis.100–102,108,128,163,165 It has been reported that patients with high-output fistulas had a 4-times greater chance of recurrence than patients with low-output fistulas.167 In a univariate analysis, factors associated with the greatest chance of recurrence after surgery for fistula closure included high output, enteroatmospheric fistula, and/or a history of OA. The authors’ recommendation was to treat any recurrence as a “new” fistula and to follow standard treatments.167 Beyond prevention of morbidity and mortality, the ultimate goal in fistula management is closure. Often this is accomplished spontaneously with supportive measures. The rate of spontaneous closure of fistulas varies in the literature from 15% to 71%. Of those fistulas that close spontaneously, about 90% will do so within 30 days of stabilization and control of sepsis. Important factors for resolution are control of sepsis, control of fistula output, and nutritional support. Table 29.1 lists some prognostic factors important in determining rate of spontaneous fistula closure.170 Fistulas that ultimately require surgical closure are more often associated with high output, short tract, and ongoing sepsis. Although innovative therapy and supportive care have resulted in improving spontaneous closure rates, management of these difficult problems requires a multidisciplinary approach that includes a nutritional support service, an enterostomal therapist, a surgeon, an interventional radiologist, and a gastroenterologist.171 An algorithm to manage GI fistulas is presented in Fig. 29.12. Full references for this chapter can be found on www.expertconsult.com. *See references 100, 101, 103, 106, 108, 128, 129, 165, 168.

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Eosinophilic Disorders of the Gastrointestinal Tract Marc E. Rothenberg, Vidhya Kunnathur

CHAPTER OUTLINE EOSINOPHIL BIOLOGY AND POTENTIAL DIAGNOSTIC AND THERAPEUTIC TARGETS����������������������������������������� 424 GASTROINTESTINAL EOSINOPHILS IN HEALTHY STATES���425 EOSINOPHIL-ASSOCIATED GASTROINTESTINAL DISORDERS��������������������������������������������������������������������� 426 Eosinophilic Esophagitis����������������������������������������������� 427 Eosinophilic Gastritis, Enteritis, and Gastroenteritis������� 431 Eosinophilic Colitis������������������������������������������������������� 433 RESOURCES�������������������������������������������������������������������� 434

Eosinophilic GI disorders (EGIDs) are defined by selective eosinophil-rich inflammation along the GI tract in the absence of known causes for eosinophilia (e.g., drug reactions, parasitic infections, malignancy) and in association with GI-related symptoms. EGIDs include a spectrum of conditions, named by the anatomic location of the associated eosinophil infiltration; eosinophilic esophagitis (EoE), eosinophilic gastritis (EG), eosinophilic enteritis, and eosinophilic colitis (EC). We reserve the term eosinophilic gastroenteritis for when more than one segment of the GI tract is involved. An increasing body of evidence indicates that eosinophils have a key role in the pathogenesis of a number of GI diseases. Our understanding of gut eosinophil pathophysiology primarily arises from the more prevalent and studied entity of EoE, for which there is also an accepted consensus regarding to clinical diagnosis and management. Accumulating data support the concept that EGIDs arise from the interplay between genetic (higher prevalence in families1,2 and EoE genetic risk factors including common single nucleotide polymorphisms3) and rare damaging variants,4 environmental (e.g., diet5–7), and host immune system factors. The immune system signature of EGIDs falls between immunoglobulin E (IgE)-mediated and delayed T-helper type 2 (Th2) responses.8–11 Studies have identified contributory roles for allergens,5–7 cytokines (e.g., interleukin [IL]-5, IL-13), microRNAs (e.g., miR-21),12 chemokines (e.g., eotaxins12), polarization of Th2 immunity (e.g., thymic stromal lymphopoietin [TSLP]),12 loss of barrier function,13 and a protease/protease inhibitor imbalance, favoring protease activation in the disease pathophysiology.14 These factors can hence serve as potential future disease biomarkers as well as therapeutic targets for EGID.

EOSINOPHIL BIOLOGY AND POTENTIAL DIAGNOSTIC AND THERAPEUTIC TARGETS Eosinophils contain a full complement of mediators (cytokines and chemokines) necessary to regulate both innate and adaptive immune responses. They can function as antigen-presenting cells, and they express Th2 cytokines (IL-4, IL-5, IL-13), Th1 cytokines (interferon-γ), proinflammatory cytokines (TNF, IL-6, and IL-8), and inhibitory cytokines (transforming growth factor [TGF]-β and IL-10), as well as receptors for many of these cytokines.15 Eosinophils are produced in the bone marrow from

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pluripotent stem cells under the regulation of the transcription factor globin transcription factor 116 the cytokines IL-3, IL-5, and granulocyte-macrophage colony-stimulating factor.17 Eosinophils contain specialized secondary granules whose protein content is toxic to a variety of tissues, including intestinal epithelium.18 Eosinophil granules contain a crystalloid core composed of major basic protein (MBP)-1 and MBP-2 and a matrix composed of eosinophil cationic protein (ECP), eosinophil-derived neurotoxin, and eosinophil peroxidase.19 Clinical investigations have demonstrated extracellular deposition of MBP and ECP in the small bowel of patients with eosinophilic gastroenteritis.20–24 Circulating levels of eosinophil-derived neurotoxin are also elevated in patients with EoE and can distinguish patients with active and inactive disease.25 IL-5 is the most specific to the eosinophil lineage and is responsible for the selective differentiation of eosinophils,26 their release from the bone marrow into the peripheral circulation,27 and their survival.28 Studies in mice have implicated that the level of IL-5 expression positively correlates with blood eosinophilia, with reduced IL-5 levels causing a marked reduction of eosinophils in the blood, lungs, and GI tract after allergen challenge.29–32 These results have led to development of IL-5 modulators such as reslizumab and mepolizumab.33,34 Reslizumab, a neutralizing antibody against IL-5, significantly reduced intraepithelial esophageal eosinophil counts in children and adolescents with EoE in a double-blind, randomized, placebo-controlled trial.34 However, improvements in symptoms were observed in all treatment groups and were not associated with changes in esophageal eosinophil counts.34 These two anti–IL-5 drugs, as well as an eosinophil-depleting monoclonal antibody directed against the IL-5 receptor, are now FDA approved for eosinophilic asthma and are likely to have additional applications.35 These results also may suggest the importance of other molecules involved in the tissue eosinophil-related inflammatory changes that are characteristic of EoE pathogenesis. Indeed, other products of Th2 cells (e.g., IL-4, IL-13) can affect eosinophils.36 IL-4 and IL-13 induce indirect eosinophil recruitment and survival via several cooperative mechanisms. They mediate their function by inducing endothelial expression of critical adhesion molecules that bind to the β1 and β2 integrins on eosinophils (e.g., intercellular adhesion molecule-1, vascular cell adhesion molecule-1), as well as of eosinophil active chemokines (e.g., eotaxins) and other molecules that influence eosinophils (e.g., chitinases).36,37 IL-4 and IL-13 signal through a common receptor subunit IL-4Rα that utilizes the Janus kinase/signal transducer and activator of transcription (STAT)-6 pathway38 and eosinophils express the predominant IL-4 receptor composed of IL-4Rα and the common gamma chain. Mice with targeted deletion of Stat6 have impaired development of Th2-associated responses in the GI tract.39,40 In addition, activated STAT-6 dimers bind to specific promoter motifs located in a series of inflammatory genes, such as the eotaxin-1, eotaxin-2, and eotaxin-3 promoters.41–45 Indeed, IL-13 was found in several studies to have a positive correlation with disease activity in esophageal tissue and with IL5 and eotaxin-3 messenger RNA expression.46 In addition, IL-13 overexpression in mice induces EoE-like changes, including an esophageal transcriptome that partly overlaps with the EoE transcriptome.47 Early clinical trials with anti-IL-13, as well as anti-IL-4 receptor antibodies, have demonstrated reduction in

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TABLE 30.1  Eosinophilic Esophagitis Diagnostic Panel: 6 Major Categories with 5 Representative Genes in Each Category Cell Adhesion

Epithelial

Inflammation

Remodeling

Eosinophils/Mast cells

Chemokines/Cytokines

CDH26

FLG

TNFAIP6

POSTN

CLC

CCL26

DSG1

UPK1A

ALOX15

KRT23

CCR3

CXCL1

CLDN10

SPINK7

ARG1

COL8A2

TPSB2/AB1

IL4

CTNNAL1

CRISP3

MMP12

CTSC

CPA3

IL5

CHL1

MUC4

IGJ

ACTG2

CMA1

IL13

  

Modified from Rothenberg ME, Stucke EM, Grotjan TM, et al. Molecular diagnosis of eosinophilic esophagitis by gene expression profiling. Gastroenterology 2013; 145(6):1289–99.   

TABLE 30.2  Gastrointestinal Eosinophil Levels in Normal Pediatric Endoscopic Mucosal Biopsy Specimens Villous Lamina Propria

Surface Epithelium

Crypt/Glandular Epithelium

GI segment

Mean

Lamina Propria Max

Mean

Max

Mean

Max

Mean

Max

Esophagus

N/A

N/A

N/A

N/A

0.03 ± 0.10

1

N/A

N/A

Antrum

1.9 ± 1.3

8

N/A

N/A

0

0

0.02 ± 0.04

1

Fundus

2.1 ± 2.4

11

N/A

N/A

0

0

0.008 ± 0.03

1

Duodenum

9.6 ± 5.3

26

2.1 ± 1.4

9

0.06 ± 0.09

2

0.26 ± 0.36

6

Ileum

12.4 ± 5.4

28

4.8 ± 2.8

15

0.47 ± 0.25

4

0.80 ± 0.51

4

Ascending colon

20.3 ± 8.2

50

N/A

N/A

0.29 ± 0.25

3

1.4 ± 1.2

11

Transverse colon

16.3 ± 5.6

42

N/A

N/A

0.22 ± 0.39

4

0.77 ± 0.61

4

Rectum

8.3 ± 5.9

32

N/A

N/A

0.15 ± 0.13

2

1.2 ± 1.1

9

  

The mean number of eosinophils/HPF ± the standard deviation of the mean for the indicated anatomic region of the GI tract and region of the mucosa. HPF, High-power field; Max, maximum; N/A, not applicable. Reproduced from Debrosse CW, Case JW, Putnam PE, et al. Quantity and distribution of eosinophils in the gastrointestinal tract of children. Pediatr Dev Pathol 2006; 9:210–8.   

esophageal eosinophilia and improvement of histology, endoscopic, and clinical symptoms; further studies will hopefully establish the positioning of these mechanism-based therapies for EoE and likely other EGIDs.48,49 Eosinophil localization to the lamina propria in the GI tract is regulated by eotaxins, chemokines constitutively expressed throughout the GI tract.50 The eotaxin receptor, chemokine (C-C motif) receptor (CCR)3, is primarily expressed on eosinophils.51 Among the 3 eotaxins, eotaxin-3 has been shown to have the strongest correlation with EoE pathogenesis.52 Analysis of 288 esophageal biopsies revealed that eotaxin-3 messenger RNA level alone had 89% sensitivity for distinguishing individuals with and without EoE.46 Collectively, these studies suggest that IL-5, IL-13, and eotaxin-3 can potentially serve as surrogate markers for diagnosis and disease activity. In addition, these studies have provided the impetus for the development of therapeutic agents aimed at blocking the action of eotaxins and/or CCR3. Indeed, small-molecule inhibitors of CCR3 and a humanized anti–human eotaxin-1 antibody have been developed.36,53,54 Results with a phase I trial of humanized anti-eotaxin-1 in patients with allergic rhinitis have shown no serious adverse responses when this drug is administered by intravenous or intranasal routes.53,55 Notably, anti-eotaxin-1 lowers levels of eosinophils in nasal washes and nasal biopsies and improves nasal patency.53,55 Anti-eotaxin-1 may be particularly helpful for patients with eosinophil-dominant asthma and/ or severe asthma in which eotaxin-1 is preferentially increased but this has not yet been tested clinically.56 In addition, antieotaxin-1 may have a benefit in other GI disorders characterized by eosinophilia such as IBD.57 However, important lessons from the anti-IL-5 antibody clinical trials suggest that researchers should focus on both histologic and clinical end points and target patients with higher eosinophil and eotaxin-1 levels.

The EoE diagnostic panel (EDP) has been introduced more recently (Table 30.1). The EDP is a set of 96 genes discretely expressed in the esophagus of EoE patients, with a 96% sensitivity and 98% specificity in pinpointing EoE in adult and pediatric patients, in addition to identifying those patients with swallowed glucocorticoid exposure. The EDP is also helpful as a predictive tool in patients with subclinical histology (50% of the time), indicating the potential significance of GI-specific mechanisms for regulating eosinophil levels; indeed, the importance of the eotaxin pathway in this process has been demonstrated.119,120 However, some patients with EGIDs (typically those with EG) can have substantially elevated levels of peripheral blood eosinophils and meet the diagnostic criteria for hypereosinophilic syndrome (HES)121; this syndrome is defined by sustained, severe peripheral blood eosinophilia (>1500 cells/ mm3) and the presence of end organ involvement in the absence of known causes for eosinophilia.122 Notably, while HES commonly involves the GI tract, the other end organs typically associated with HES such as the heart and skin are uncommonly involved in EGIDs. It has been appreciated that a subset of patients with HES have a microdeletion on chromosome 4 that generates an activated tyrosine kinase (FIP1L1-PDGFRA fusion gene) susceptible to imatinib mesylate therapy123; the possible occurrence

CHAPTER 30  Eosinophilic Disorders of The Gastrointestinal Tract

of this and other genetic events in patients with EGIDs, especially those with significant circulating eosinophilia, is currently being investigated.

Eosinophilic Esophagitis As the esophagus is normally devoid of eosinophils, finding esophageal eosinophils denotes pathology.8,73 It is now appreciated that many disorders are accompanied by eosinophil infiltration in the esophagus, such as EoE, eosinophilic gastroenteritis, GERD, parasitic and fungal infections, IBD, HES, esophageal leiomyomatosis, myeloproliferative disorders, carcinomatosis, polyarteritis nodosa, allergic vasculitis, collagen vascular diseases such as scleroderma, pemphigus vegetans, and drug injury.63 Eosinophil-associated esophageal disorders are classified into primary and secondary. The primary subtype is referred to as EoE and includes the atopic, nonatopic, and syndromic disorders, particularly those associated with inherited CTD such as hypermobility syndrome,124 and familial EoE variants.125 The familial form of EoE is seen in 5% to 10% of patients,1 and the sibling recurrence risk ratio has been estimated to be over 50-fold.126 Moreover, there are several other mendelian diseases associated with EoE: ERBIN deficiency, Netherton syndrome, PTEN hamartoma tumor syndrome, and severe atopy syndrome associated with metabolic wasting syndrome (see Table 30.3).86 The secondary subtype is divided into 2 groups, one composed of systemic eosinophilic disorders (i.e., HES) and the other of essentially noneosinophilic disorders.

Etiology EoE is a clinicopathologic condition that is commonly recognized among both pediatric and adult patients presenting to allergy and gastroenterology clinics throughout the world. The annual EoE incidence rates varying between 0.1 and 1.2 per 10,000 in several studies, with EoE representing the second most common cause of chronic esophagitis.2,103 The etiology of EoE is poorly understood, but food allergy has been implicated as a primary contributor. In fact, the majority of patients have evidence of a food allergen and aeroallergen sensitization as defined by skin prick and/or allergen-specific IgE tests; however, only a minority have a history of food anaphylaxis.73 Although considered a food allergen driven allergic disease, evidence has accumulated that the positive skin tests and allergen-specific IgE are markers of the involved immunologic response rather than reflective of the primary mechanism.86 It has also been suggested that esophageal eosinophilic inflammation is mechanistically linked with pulmonary inflammation. This latter theory is based on the finding that repeated delivery of specific allergens or the Th2 cytokine IL-13 to the lung of mice, as well transgenic overexpression of IL-13 in the lung of mice, induces experimental EoE47,127,128 and the observation of increased eosinophil accumulation in the esophagus of patients with seasonal allergic rhinitis with hypersensitivity to grass.129 Other studies have also indicated a strong relationship between atopy and EoE.130 Indeed, patients with EoE commonly report seasonal variations in their esophageal symptoms. In addition to eosinophils, T cells and mast cells are elevated in esophageal mucosal biopsies, suggesting chronic Th2-associated inflammation.131,132 Elevated TGF-β, produced by eosinophils and mast cells, has been shown to contribute to tissue remodeling and smooth muscle dysfunction.133 Furthermore, epicutaneous antigen exposure primes the esophagus for marked eosinophilic inflammation following a single airway antigen challenge.134 The genome-wide microarray expression profile analysis of esophageal tissue was a landmark advance in EoE research.3 Investigators compared gene transcript expression in the esophageal tissue of patients with EoE or chronic esophagitis (typical of GERD) and normal individuals. Notably, the dysregulated

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expression of approximately 1% of the entire human genome constituted an EoE genetic signature. Interestingly, eotaxin-3 was the most overexpressed gene in patients with EoE, and levels correlated with disease severity; in fact, overexpression of eotaxin-3 alone has a predictive value of 89% in diagnosing EoE from a single esophageal biopsy.46 The same investigators demonstrated that mice with a genetic ablation of the eotaxin receptor (CCR3) were protected from the development of experimental EoE. Collectively, these results strongly implicate eotaxin-3 in the pathoetiology of EoE and offer a molecular connection between Th2 inflammation and the development of EoE. The first genome-wide association study linked EoE to the genetic locus region 5q22, which harbors the TSLP gene; notably, TSLP has a known role in processes germane to EoE, including polarization of Th2 immunity and induction of eotaxins.135 Subsequent genome wide association studies validated the TSLP locus and also identified a strong genetic susceptibility locus at 2p23, at the CAPN14 gene locus.136 CAPN14 encodes for calpain-14, an esophageal-specific intracellular cysteine protease that regulates epithelial cell barrier function. Interestingly, calpain-14 is induced by IL-13, linking allergic type 2 adaptive immune responses with an innate epithelial cell response. As such, this esophageal specific pathway helps to explain why allergic individuals develop EoE, linking type 2 immunity (allergic) with esophageal specific responses.136 In support of this, genetic interplay (epistasis) of CAPN14 genetic variants with atopy susceptibility variants have been demonstrated.137 In addition, using a broad candidate-gene approach, genetic variants in TSLP and its receptor have been associated with EoE susceptibility.138 

Clinical Features and Diagnostic Studies EoE represents a chronic, antigen-driven, immune-mediated mediated disease characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophilpredominant inflammation.83 EoE should be diagnosed by clinicians, taking into consideration all clinical and pathologic information; neither of these parameters should be interpreted in isolation. The diagnostic criteria for EoE in 2011,83 emphasized that EoE requires finding 15 or more eosinophils/HPF (peak value) in the esophagus. This definition is based on a 2017 consensus recommendation that PPI-responsiveness is not considered in the diagnosis of EoE, as PPI-REE has phenotypic, genetic, and molecular features that overlap with PPI-resistant esophageal eosinophilia.84,85 With few exceptions, 15 eosinophils/ HPF (peak value) is considered a minimum threshold for a diagnosis of EoE. The consequences of this eosinophil-predominant inflammation of the esophagus can have a profound systemic and emotional impact for patients and their families.124,139 In regard to the history of EoE, this disorder has been identified in the pediatric and adult patient populations, typically in male patients with evidence of atopy, and the disease most often responds to either topical glucocorticoid therapies or dietary restrictions. At this time, therapy for EoE is chronic, with recurrence of disease activity being noted rapidly after cessation of either dietary or drug-based therapies.140 The primary symptoms of this disorder vary with the age of the patient. These symptoms include difficulties with eating, failure to thrive, chest and/or abdominal pain, dysphagia, and food impaction.105 These symptoms generally occur in chronological order depending upon patient age, providing supportive evidence that the natural history of pediatric EoE progresses into adult EoE.141 Infants and toddlers often present with feeding difficulties, whereas school-aged children are more likely to present with vomiting or pain. Dysphagia is a predominant symptom in adolescents. EoE in children is most often present in association with other manifestations of atopic diathesis (food allergy, asthma, eczema, chronic rhinitis, and environmental allergies) that also follows chronologic order

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PART IV  Topics Involving Multiple Organs

TABLE 30.4  Endoscopic Eosinophilic Esophagitis Reference Score Major Features Edema (Also referred to as decreased vascular markings, mucosal pallor) Grade 0: Absent. Distinct vascularity present Grade 1: Loss of clarity or absence of vascular markings Fixed rings (Also referred to concentric rings, corrugated esophagus, corrugated rings, ringed esophagus, trachealization) Grade 0: None Grade 1: Mild-subtle circumferential ridges

Fig. 30.1  Esophagus with furrowing and exudates.

in a similar fashion to the “allergic (or ‘atopic’) march.” Symptoms in adult patients with EoE are somewhat stereotypical and include dysphagia, non—swallowing-associated chest pain, food impaction, and upper abdominal pain. Solid-food dysphagia continues to be the most common presenting symptom.142 Food impaction necessitating endoscopic bolus removal occurs in 33% to 54% of adults with EoE.143 The assessment of EoE includes an allergy evaluation to look for coexisting allergic diseases, given the association of EoE with the atopic march. It is no longer considered necessary to look for food allergen and aeroallergen sensitization either by skin prick tests or measurement of allergen-specific IgE in serum, as this has little bearing on successful diet therapy compared with empiric avoidance of the most common allergens.144 However, these tests may be useful when deciding which foods to add back to the diet, especially when EoE patients have a history of acute reactions to food (anaphylaxis). Exclusion of GERD as the primary cause of esophageal eosinophilia should be considered when clinically appropriate. A study has suggested that evaluation of food protein sensitization by delayed skin patch testing increases the identification of food allergy compared with skin prick testing alone,5 but these findings have been primarily limited to one site and are not generally recommended. Physical examinations for patients with EoE are useful to identify normal growth patterns in children and to identify comorbid allergic diseases in both children and adults; however, no features on physical examination are specific in making the diagnosis of EoE. In addition, no oral or pharyngeal manifestations of EoE have been identified, although some children who have EoE might present with laryngeal symptoms. Esophageal abnormalities identifiable by means of endoscopy in patients with EoE include fixed esophageal rings/trachealization (a.k.a. fibrostenotic complications), transient esophageal rings, whitish exudates, longitudinal furrows (Fig. 30.1 showing furrowing and exudates), edema, diffuse esophageal narrowing, narrow-caliber esophagus, and esophageal lacerations induced by passage of the endoscope (a manifestation of mucosal fragility that, when severe, gives the esophagus the appearance of crepe paper). However, because all of these endoscopic features have been described in other esophageal disorders, none can be considered pathognomonic for EoE. Clinical guidelines from the ACG in 2013 suggest that evaluating gastroenterologists can use the EoE Endoscopic Reference Score to classify and grade EoE, this system is described in Table 30.4.145 Furthermore, the accuracy of the Endoscopic Reference Score has been evaluated and the classification system can successfully identify patients with EoE and can also be used to evaluate response to treatment.146 Endoscopy with esophageal mucosal biopsy remains the only reliable diagnostic test for EoE (Fig. 30.2). Typical histologic findings include presence of 15 or more eosinophils/HPF, dilated intercellular spaces and in some cases also elongated papillae, and inflammation and fibrosis in the lamina propria

Grade 2: Moderate-distinct rings that do not impair passage of a standard diagnostic adult endoscope (outer diameter 8-9.5 mm) Grade 3: Severe-distinct rings that do not permit passage of a diagnostic endoscope Exudates (Also referred to as white spots, plaques) Grade 0: None Grade 1: Mild-lesions involving less than 10% of the esophageal surface area Grade 2: Severe-lesions involving greater than 10% of the esophageal surface area Furrows (Also referred to as vertical lines, longitudinal furrows) Grade 0: Absent Grade 1: Vertical lines present Stricture Grade 0: Absent Grade 1: Present (specify estimated luminal diameter) Minor features Crepe paper esophagus (Mucosal fragility or laceration upon passage of diagnostic endoscope but not after esophageal dilation) Grade 0: Absent Grade 1: Present Narrow-caliber esophagus (Reduced luminal diameter of the majority of the tubular esophagus) Grade 0: Absent Grade 1: Present   

Adapted from Hirano I, Moy N, Heckamn MG, et al. Endoscopic assessment of the oesophageal features of eosinophilic oesophagitis validation of a novel classification and grading system. Gut 2013;62:489–95.   

* Fig. 30.2  Hematoxylin and eosin staining of esophagus from a ­patient with EoE. Arrows point to eosinophils, including at the surface, arrowhead points to dilated intercellular spaces, asterisk marks lamina propria showing inflammation and fibrosis, and the green arrow points to elongated papillae. There is also marked basal layer hyperplasia with the basal layer reaching almost to the surface.

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TABLE 30.5  Comparison of Eosinophilic Esophagitis and GERD Characteristic features

Eosinophilic esophagitis

GERD

Clinical Prevalence

∼1:1000

∼1:10

Prevalence of atopy

Very high

Normal

Prevalence of food sensitization

Very high

Normal

Gender preference

Male

None

Abdominal pain and vomiting

Common

Common

Food impaction

Common

Uncommon

Investigative Findings pH probe/impedance study

Normal

Abnormal

Endoscopic furrowing

Very common

Occasional

Histopathology/Pathogenesis Involvement of proximal esophagus

Yes

No

Involvement of distal esophagus

Yes

Yes

Epithelial hyperplasia

Severely increased

Increased

Eosinophil levels in mucosa

>15/HPF

0-7/HPF

Elevated eotaxin-3 level

Yes

No

EoE diagnostic panel positive

Yes

No

Treatment H2 receptor antihistamines

Not helpful

Helpful

Proton pump inhibitors

Helpful in subset

Helpful

Glucocorticoids

Helpful

Not helpful

Specific food antigen elimination

Helpful

Not helpful

Elemental diet

Helpful

Not helpful

Anti–IL-13 and anti–IL-4Rα

Helpful

Not helpful

  

HPF, High-power field; IL, interleukin. Modified from Rothenberg ME. Eosinophilic gastrointestinal disorders (EGID). J Allergy Clin Immunol 2004; 113:11–8. © 2004, with permission from the American Academy of Allergy, Asthma, and Immunology.   

(see Fig. 30.2). In 2017 a newly developed histologic scoring system (HSS) for EoE was validated. In addition to identifying 15 or more eosinophils/HPF, 8 other histologic features were shown to differentiate treated from untreated patients and that the HSS outperforms esophageal eosinophil levels for disease diagnosis and monitoring. The 8 HSS features include eosinophil density, basal zone hyperplasia, eosinophil abscesses, eosinophil surface layering, dilated intercellular spaces, surface epithelial alteration, dyskeratotic epithelial cells, and lamina propria fibrosis. Severity and extent are scored using a 4-point scale, with 0 being normal and 3 denoting maximum change.147 However, the finding of isolated esophageal eosinophilia without determining corroborating symptoms and ruling out other causes of esophageal eosinophilia is inadequate to make the diagnosis of EoE.83 Specifically, some of these presenting symptoms cannot easily distinguish EoE from GERD. The distinguishing features between GERD and EoE are summarized in Table 30.5. The number and location of eosinophils are helpful when trying to differentiate EoE from GERD. Up to 7 eosinophils/HPF (400×) is most indicative of GERD, 7 to 15 eosinophils/HPF likely represents a combination of GERD and food allergy, and at least 15 eosinophils/HPF is characteristic of EoE.63,148 The anatomic location of eosinophils to both the proximal and distal esophagus denotes EoE, while the accumulation of eosinophils mainly in the distal esophagus is characteristic of GERD.73 Some studies have also identified that mast cells are increased in biopsy specimens from patients with EoE compared with those from patients with GERD.149,150 IgE-bearing cells are more common in biopsy specimens from patients with EoE compared with those from patients with GERD and are also

not detected in control specimens.151 Esophageal pH monitoring (and pH impedance, where available) is a useful diagnostic test to evaluate for GERD in patients with esophageal eosinophilia. In addition, consensus guidelines indicated that barium contrast radiography can identify a number of the anatomic and mucosal abnormalities of EoE but that the sensitivity of radiography as a diagnostic test for this condition appears to be low. Therefore, radiology is not recommended as a routine diagnostic test for EoE but can be helpful in select cases to characterize anatomic abnormalities that can be difficult to define endoscopically and to gather more information regarding the length and diameter of complicated esophageal strictures. A newer technique using the endoluminal functional lumen imaging probe (EndoFLIP) offers a unique evaluation of esophageal function as it relates to EoE. It has been shown that esophageal distensibility is reduced in EoE with an associated risk of food impaction or need for therapeutic dilation. One study even demonstrated improvement in esophageal body distensibility with medical and diet therapies without dilation; this improved distensibility correlated with symptomatic improvement more than the reduction in esophageal mucosal eosinophil count. More studies will need to be completed before EndoFLIP can be used definitively as an outcome measure.152,153 

Treatment There are several first-line treatments for EoE, and they include: dietary therapy, topical glucocorticoids, and a PPI. It has been shown that dietary therapy frequently improves symptoms and reduces the number of eosinophils in the esophageal biopsies in

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patients with primary EoE (allergic or nonallergic subtypes).6,154 A trial of specific food allergen and aeroallergen avoidance is often indicated for patients with atopic EoE. If this approach is unsatisfactory or proves practically difficult (i.e., when patients are sensitized to many allergens), a diet consisting of an amino acid–based formula, termed the elemental diet, or avoidance of the most common allergenic foods (cow milk, soy, wheat, egg, peanut/tree nuts, and seafood/shellfish), termed the 6-food elimination diet (SFED)155 is advocated. Patients on elemental diets sometimes require placement of a gastrostomy tube in order to achieve adequate caloric support. Studies looking at the effectiveness of different dietary regimens focused on comparison between the empiric SFED, modified SFED (SFED plus elimination of foods identified by skin test or as causative), and elemental diet.100,144,156 In these studies, it was shown that the elemental diet is superior to the empiric SFED and skin test–directed diet (modified SFED). Furthermore, it has been shown that the empiric SFED is an effective therapy in adult EoE and that the response rate to the empiric SFED is similar to the response rate to skin test–directed diet therapy (74% to 81% response rate). Such response rates are similar to the reported response rates to swallowed glucocorticoids in both adult and pediatric EoE populations.157–160 Less-restrictive diets like the 2-food elimination diet (dairy and gluten) and 4-food elimination diet (dairy, gluten, egg, and legumes) have been used with decent efficacy rates of 43% and 54%, respectively, in the pediatric population. A step up approach for the elimination diet from 2-food elimination diet to 4-food elimination diet and then SFED has been proposed as it avoids unnecessary dietary restrictions.161,162 Preliminary findings suggest that a 1-food elimination diet (OFED) may have a role in the treatment of EoE.163,164 Kagalwalla et al. proposed using an OFED of cow’s milk, and results have shown clinical and histologic remission in 65% of pediatric patients.164 In addition, OFED with the elimination of cow’s milk has been compared with swallowed fluticasone, and 64% of OFED patients were found to have esophageal eosinophil counts of less than 15 eosinophils/HPF and a significant improvement in the symptom score as compared with 80% in the fluticasone group.163 Studies by Gonsalves et al.100 and Spergel et al.156 identified only 34% to 40% of EoE-related causative foods on the basis of both skin test and endoscopy response to elimination or reintroduction of food, implying that either EoE is triggered by non– food-related stimuli, or alternatively and more likely, that the methods of identifying food hypersensitivity are currently inadequate and therefore are not used routinely in the evaluation of EoE patients. The most common food triggers in the adult cohort were wheat (60%), milk (50%), soy (10%), nuts (10%), and eggs (5%), while in the pediatric cohort the most common triggers were milk (35%), eggs (13%), wheat (12%), and soy (9%). Based on these described frequencies, and the rationale of reintroducing the foods least likely to be triggers first, it was suggested that the sequence for reintroduction of food in pediatric patients should be seafood/nuts first, followed sequentially by soy, wheat, eggs, and finally milk, and in adults should be seafood first, followed sequentially by eggs, nuts/soy, milk, and finally wheat. Systemic79 or topical glucocorticoids165 have also been used to treat EoE with satisfactory results. Systemic glucocorticoids are used for acute exacerbations, whereas topical glucocorticoids are used to provide long-term control. A study that followed patients with EoE for 10 years supported the efficacy of continuing glucocorticoids and food elimination therapy for EoE.166 When using topical glucocorticoids in the form of fluticasone, a metered-dose inhaler without a spacer has been advocated83; alternatively, a slurry of budesonide (in the form used for nebulizers) with sucralose (Splenda) also has been recommended.83,159 The patient is instructed to swallow the dose to promote deposition on the esophageal mucosa. While the metered-dose inhaler is recommended with the topical fluticasone, other studies have shown

the success of using an oral suspension of budesonide for patients with EoE who are unable to use inhalers.158,167 In the first placebo-controlled, double-blind clinical trial for EoE, swallowed topical fluticasone was found to be effective in inducing disease remission, including reductions in eosinophil, mast cell, and CD8 T cell levels, as well as the degree of epithelial hyperplasia.157 However, it is important to point out that steroid resistance also occurs. Significant toxicity associated with glucocorticoids (e.g., adrenal suppression) is unlikely to be seen with swallowed fluticasone or budesonide because these drugs undergo first-pass metabolism in the liver following GI absorption.168 However, at Cincinnati Children’s, 10% of children whose EoE was treated with fluticasone greater than 440 μg daily showed evidence of adrenal suppression.169 In addition, patients can develop esophageal candidiasis, which is treatable with antifungal therapy (see Chapter 45).170 Although topical glucocorticoids are considered first line for EoE, thus far no topical formulation has been approved for EoE in the US; an orodispersible budesonide tablet has been approved in Europe.171 Several clinical trials are underway at present with viscous oral budesonide as well as budesonide effervescent tablets. PPI therapy can establish histologic remission and symptom amelioration in 50% and 60% of EoE patients, respectively.85,117 The 2017 European guidelines use high-dose PPI for 8 weeks as a first line in the treatment algorithm for EoE. In addition, several systematic reviews and meta-analyses corroborate evidence to support PPI use as first-line therapy, particularly at high dosage. Esophageal dilation with or without concomitant medical or dietary therapy can provide relief of dysphagia in select patients with EoE. However, in the absence of high-grade esophageal stenosis, a trial of medical or dietary therapy before dilation is reasonable. However, esophageal dilation as a primary therapy without concomitant medical or dietary therapy does not address the underlying inflammatory process. Techniques described for esophageal dilation in patients with EoE include the use of both through-the-scope and bougie dilators. Although the risk of perforation is low, a more conservative and careful approach in the esophageal dilation technique is advised for patients with EoE compared with those with other benign entities.172 The practice of gradual esophageal dilation with a target goal of 15 to 18 mm and of limiting the progression of dilation diameter per session to 3 mm or even less if resistance is encountered is reasonable but has not been specifically addressed in patients with EoE. Complications have been shown to be associated with younger patient age and higher number of dilations, narrowing in the upper third of the esophagus, and inability to traverse the narrowing with the scope before dilation.173 The risk of chest pain after dilation is significant and should be discussed with patients prior to dilatation. Therapy directed against the eosinophil growth factor IL-5 is effective in animal studies174 and has recently been tested in clinical trials.33,34 Two different humanized IL-5–specific antibodies, mepolizumab and reslizumab, have been developed and tested in clinical trials for EoE.33,34,175 Mepolizumab therapy resulted in a dramatic decline in blood eosinophilia and reduced esophageal eosinophil infiltration in patients with EoE but had variable effects on symptoms.33 Other therapies to reduce eosinophil tissue accumulation in EoE could potentially target IL-13. Animal models have shown that IL-13 is a key cytokine that regulates the recruitment of eosinophils at inflammatory sites, primarily through the induction of chemokine expression.176,177 The humanized IL-13– specific antibody lebrikuzumab was recently studied in patients with mild asthma; however, such therapy seems to have a variable effect on tissue eosinophilia and possibly causes an increase in the peripheral eosinophil counts.178 Preclinical data substantiate that anti–IL-13 agents may be particularly effective in EoE, and a clinical trial has been conducted, with some promising results demonstrating a mean esophageal eosinophil count reduction

CHAPTER 30  Eosinophilic Disorders of The Gastrointestinal Tract

of 60%.179 Multisite studies evaluating a human anti–IL-13 antibody (RPC 4046) as well as a human antibody against the IL-4 receptor α chain (dupilumab), which blocks IL-13 and the related cytokine IL-4, have been shown to improve histopathology (including esophageal eosinophilia), endoscopic and clinical features of EoE.86 Dupilumab is FDA approved for atopic dermatitis, whereas RPC4046 is in development. Another candidate for targeted EoE therapy is the chemoattractant receptor of Th2 cells (CRTH2, a.k.a. prostaglandin D2 receptor 2), which is thought to be an effecter of the Th2 response. CRTH2 is expressed on the surface of Th2 cells, eosinophils, and basophils180 and is a G protein–coupled receptor.181 Low-molecular-mass CRTH2 antagonists partially attenuate pulmonary eosinophilia in various models.182 Further, in a phase II clinical trial, patients with moderate persistent asthma had a significant reduction in sputum eosinophil count183 and improved asthma control.184 Preliminary data from a clinical trial of patients with active EoE show that treatment with a CRTH2 antagonist results in a moderate reduction in tissue eosinophilia.185 However, additional clinical data are needed to evaluate the effectiveness of such G protein–coupled receptor antagonists. 

Prognosis EoE requires prolonged treatment, similar to allergic asthma. The natural history of EoE has not been fully delineated; however, a 15-year follow-up of esophageal eosinophilia from childhood into adulthood revealed ongoing symptoms in the vast majority of patients.186 Thus, it is likely that chronic EoE, if left untreated, can develop into progressive esophageal scarring and dysfunction. EoE complications include food impaction, esophageal stricture, narrow-caliber esophagus, and esophageal perforation. The duration of untreated EoE is a good predictor of stricture risk.187 The prevalence of “food impaction,” defined as food retention requiring endoscopic extraction, in adults ranged from 30% to 55%.188,189 Stricture definition is problematic, given that esophageal rings are a common manifestation of the disease state in adults and because the presence of rings implies some degree of esophageal stricture. Consensus guidelines noted that radiographic definition might be preferable to endoscopic assessment in this regard since radiographic definition might provide supplemental information regarding the length of the narrowing, which might affect possible treatment options and dilatations. Stricture prevalence in adults with EoE ranged from 11% to 31%.172,188,190,191 A full-thickness tear is defined as permitting esophageal or gastric contents to enter the chest cavity and requires surgical treatment. A partial rupture is defined by limited air or contrast extravasation into the mediastinum and is managed conservatively. Esophageal intramural tears are identified endoscopically as deep lacerations extending into the esophageal submucosa or radiographically by contrast extending outside the esophageal lumen but contained within the esophageal wall. The risk for developing Barrett’s esophagus, especially in patients with coexisting EoE and GERD, has not been determined but does not seem to be a concern (see Chapter 47). In addition, patients with EoE are at increased risk for developing other forms of EGIDs6; thus, routine surveillance of the entire GI tract by endoscopy may be warranted. 

Eosinophilic Gastritis, Enteritis, and Gastroenteritis In contrast to the esophagus, the stomach and intestine have readily detectable baseline levels of eosinophils under healthy conditions. Making the diagnosis of EG, enteritis, or eosinophilic gastroenteritis (EGE) is therefore more complex than making the diagnosis of EoE. Since EG, enteritis, and gastroenteritis are clinically similar and since there is a paucity of information available concerning their pathogenesis, they will be discussed together.

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However, it is likely that these conditions are indeed distinct entities in most patients. In a population-based study the prevalences of EGE and EC were 5.1/100,000 persons and 2.1/100,000 persons, respectively.118 EGE is the second most common form of EGIDs, but no consensus recommendations regarding clinical or pathologic diagnosis exist. Lwin et al. has proposed that EG can be diagnosed when at least 30 eosinophils/HPF is identified in at least 5 distinct HPFs in the stomach192; Chehade et al. proposed at least 70 eosinophils/HPF in at 3 HPFs.193 The incidence and prevalence of EG, EGE, and EC are increasing; the reasons behind this are unknown.116 These diseases are characterized by the selective infiltration of eosinophils in the stomach and/or small intestine, with variable involvement of the esophagus and/ or large intestine.23,194,195 Secondary causes of gastric eosinophilic infiltration include parasitic and bacterial infections (e.g., Helicobacter pylori), IBD, HES, myeloproliferative disorders, polyarteritis nodosa, allergic vasculitis, scleroderma, drug injury, and drug hypersensitivity. The primary subtype includes the atopic, nonatopic, and familial variants, and the secondary subtype is divided into 2 groups, one composed of systemic eosinophilic disorders (HES) and the other of noneosinophilic disorders (see Table 30.3). Primary EG, enteritis, and gastroenteritis have also been called idiopathic or allergic gastroenteropathy. The familial form has not been well characterized but is seen in about 10% of these authors’ own patients (unpublished findings).1 Primary EGE encompasses multiple disease entities subcategorized into 3 types on the basis of the level of histological involvement: mucosal, muscularis, and serosal forms.196 Of note, any layer of the GI tract can be involved; thus, endoscopic mucosal biopsy can be normal in patients with the muscularis and/or serosal subtypes.

Etiology While EG, enteritis, and gastroenteritis are idiopathic in nature, an allergic mechanism has been suggested in at least a subset of patients.197 Indeed, elevated total IgE and food-specific IgE have been detected. On the other hand, syndromes with focal erosive gastritis, enteritis, and occasionally esophagitis with prominent eosinophilia, such as dietary (food) protein-induced enterocolitis and dietary protein enteropathy, are characterized by negative skin tests and absent specific IgE.198 Most patients have positive skin tests to a variety of food antigens but do not have typical anaphylactic reactions, consistent with a delayed type of food hypersensitivity syndrome. In one study, 23% of patients with EGE lacked peripheral eosinophilia, but up to 50% of patients with the mucosal form had a history of food allergy or intolerance.20,196 In another study of EG, increased levels of blood eosinophils were seen in nearly 90% of patients and shown to strongly correlate with levels of gastric eosinophils, indicating that blood eosinophil levels can serve as a noninvasive biomarker, unlike in EoE.199 Indeed, experimental induction of EGE (involving the esophagus, stomach, and intestine) in mice can be accomplished by oral allergen administration (in the form of enteric-coated allergen beads) to sensitized mice.102 Notably, the mice developed eosinophil-associated GI dysfunction including gastromegaly, delayed food transit, and weight loss, all strongly dependent upon the chemokine eotaxin-1.200 Ultrastructural analysis of intestinal tissue suggested that the eosinophils were mediating axonal necrosis, a finding that has been reported in patients with intestinal eosinophilia associated with IBD.201 Notably, mast cells are also increased in EGIDs, and a murine model of oral allergen-induced diarrhea has demonstrated a critical role for IL-9–driven mast cells in the pathogenesis of this specific cardinal feature (allergic diarrhea) of EGIDs.202,203 Increased secretion of IL-4 and IL-5 by peripheral blood T cells has been reported in patients with EGE.197 Furthermore, T cells derived from the lamina propria of the duodenum of patients with EGID preferentially secrete Th2 cytokines, especially IL-13,

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when stimulated with milk proteins.204 Gastric biopsies display a distinct transcriptome compared with control individuals including patients infected with H. pylori. The EG transcriptome expresses high levels of eotaxin-3 as well as other genes associated with Th2-associated immunity, yet overlaps with only 5% of the EoE transcriptome.199 IgA deficiency has also been associated with EGE; it is interesting to speculate that this could be related to the associated increased rate of atopy or to an occult GI infection in these patients.205 It is important to keep in mind that EGE and the dietary protein-induced syndromes (enterocolitis, enteropathy, and colitis) may represent a continuum of EGIDs with similar underlying immunopathogenic mechanisms. In addition, EGE can frequently be associated with protein-losing enteropathy (see Chapter 31).193 Of note, cases of eosinophilic enteritis have been reported with systemic lupus erythematosus with an unknown pathologic association.206,207 

Clinical Features and Diagnostic Studies In general, these disorders present with a constellation of symptoms that are related to the degree and area of the GI tract affected. However, even patients with isolated eosinophilic enteritis (e.g., duodenitis) can have a range of GI symptoms. The mucosal form of EGE, the most common variant, is characterized by vomiting, abdominal pain that can even mimic acute appendicitis, diarrhea, blood loss in the stools, iron-deficiency anemia, malabsorption, protein-losing enteropathy, and failure to thrive.193,208 The muscularis form is characterized by infiltration of eosinophils predominantly in the muscularis layer, leading to thickening of the bowel wall, which may result in symptoms of GI obstruction mimicking pyloric stenosis or other causes of gastric outlet obstruction. The serosal form occurs in a minority of patients with EGE, and it is characterized by exudative ascites with higher peripheral eosinophil counts compared with the other forms.20 The evaluation for EGIDs starts with a comprehensive history and physical examination followed by diagnostic testing (Box 30.1). Evaluation for intestinal parasites by examination of stool samples, intestinal aspirates obtained during colonoscopy, or specific blood antibody titers should be performed, especially when patients have high-risk exposure (e.g., foreign travel, living on a farm, drinking well water) (see Chapter 114). As a precaution, before using systemic immunosuppression for EGIDs, infection with Strongyloides stercoralis should be ruled out as this infection can become life-threatening in the setting of systemic immunosuppression.209 The evaluation of total IgE levels has significance in stratifying patients with atopic variants of EGIDs or suggesting further consideration for occult parasitic infections. Notably, skin prick testing to a panel of food allergens and aeroallergens helps to identify sensitizations to specific allergens. Cutaneous hypersensitivity testing (skin patch testing) for specific food antigens may be helpful in further identifying allergic variants of EoE.5 Indeed, patients with the atopic variant of EGIDs have evidence of IgE sensitization to a mean of 14 different foods.1 No standards for the diagnosis of EG, enteritis, or EGE exist.20,208 Some findings that support the diagnosis are: the presence of elevated eosinophils in biopsy specimens from the GI tract wall (in comparison with normal levels as shown in Table 30.2); the infiltration of eosinophils within intestinal crypts and gastric glands; the lack of involvement of other organs; and the exclusion of other causes of eosinophilia (e.g., infections, IBD). Histologic analysis of the small bowel from patients with these disorders reveals extracellular deposition of eosinophil granule constituents and extracellular MBP and ECP deposition as detected immunohistochemically.20,23,24,68 Patients with EG can have micronodules (and/or polyposis) noted on endoscopy, and these lesions often contain marked aggregates of lymphocytes and eosinophils. 

BOX 30.1 Considerations for Diagnostic Workup for Eosinophilic GI Disorders General Complete blood count and differential Total IgE Erythrocyte sedimentation rate and C-reactive protein (normal in EGIDs) Skin prick testing and tests for specific IgE (as part of comprehensive allergy workup) Infection workup (stool and colonic aspirate analysis) Upper and lower gastrointestinal endoscopy with biopsies pH probe impedance study EndoFLIP (compliance measure in esophagus) EoE diagnostic panel In the presence of hypereosinophilia Bone marrow analysis Serum tryptase Serum vitamin B12 Echocardiogram Chromosomal and cytogenetic screen Genetic analysis for FIP1L1-PDGFRA fusion gene and other genetic abnormalities based on chromosomal studies Evaluation and biopsy of any other potentially involved tissue   

EGIDs, Eosinophilic GI disorders; EoE, eosinophilic esophagitis, IgE, immunoglobulin E. Reproduced from Rothenberg ME. Eosinophilic gastrointestinal disorders (EGID). J Allergy Clin Immunol 2004; 113:11–28. © 2004, with permission from the American Academy of Allergy, Asthma, and Immunology.

Treatment Eliminating the dietary intake of the foods implicated by skin prick tests (or measurement of allergen-specific IgE levels) has variable effects, but complete resolution is generally achieved with amino acid–based elemental diets.193,210 Once disease remission has been obtained by dietary modification, the specific food groups are slowly reintroduced (at ∼3-week intervals for each food group), and endoscopy is performed every 3 months to identify either sustained remission or disease flare-up. Notably, a clinical trial at the author’s institution using the eosinophil-depleting antibody (anti–IL-5 receptor α) benralizumab (now FDA approved for eosinophilic asthma) for EG and EGE is now underway. Drugs such as cromoglycate, montelukast, ketotifen, suplatast tosilate, mycophenolate mofetil, and “alternative Chinese medicines” have been advocated,1,90 but they are generally unsuccessful in the authors’ experience. However, successful long-term remission of EGE following montelukast treatment has been reported.211 In the authors’ institution, an appropriate therapeutic approach includes a trial of food elimination if sensitization to food is found by skin prick tests and/or measurement of specific IgE levels. If no sensitization is found or if specific food avoidance is not feasible, elemental formula feedings are instituted. The management of EGIDs, in addition to an elemental diet as mentioned previously, includes the following: systemic and topical glucocorticoids, nonglucocorticoid anti-inflammatory therapy, management of EGID complications (such as iron-deficiency anemia), and the management of therapeutic toxicity.212 Anti-inflammatory drugs (systemic or topical glucocorticoids) are the main therapy if diet restriction is not feasible or has failed to improve the disease. For systemic steroid therapy, a course of 2 to 6 weeks of therapy with relatively low doses seems to work better than a 7-day course of burst glucocorticoids. There are several forms of topical glucocorticoids designed to deliver drugs to specific segments of the GI tract (e.g., budesonide tablets [Entocort

CHAPTER 30  Eosinophilic Disorders of The Gastrointestinal Tract

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A

Fig. 30.3  Eosinophilic colitis in an infant presenting with heme-positive stools and anemia. A, The endoscopic image of the rectum shows mucosal nodularity with central umbilication characteristic of nodular lymphoid hyperplasia, findings often associated with food allergies. B, Photomicrograph of a rectal mucosal biopsy show increased numbers of eosinophils in the lamina propria that are forming aggregates and occasionally encroaching on the epithelium and crypts (Hematoxylin and eosin, ×40.)

EC] designed to deliver the drug to the ileum and proximal colon). As with asthmatic treatment, topical glucocorticoids have a better benefit-to-risk effect compared with systemic glucocorticoids. In severe cases that are refractory to or dependent upon glucocorticoid therapy, intravenous alimentation or immunosuppressive antimetabolite therapy with azathioprine or 6-mercaptopurine are alternatives. Finally, even if GERD is not present, neutralization of gastric acidity with PPI may improve symptoms and the degree of esophageal and gastric pathology. 

Prognosis The natural history of EG, enteritis, and EGE has not been well documented; however, these diseases wax and wane chronically. In patients with clear food antigen–induced disease, abnormal levels of circulating IgE and eosinophils often serve as markers for tissue involvement. Because these diseases can often be a manifestation of another primary disease process, routine surveillance of the cardiopulmonary systems is recommended. When the disease presents in infancy and specific food sensitization can be identified, there is a high likelihood of disease remission by late childhood. 

Eosinophilic Colitis Eosinophils accumulate in the colon of patients with a variety of disorders, including eosinophilic gastroenteritis, allergic colitis of infancy, infections (e.g., pinworms, dog hookworms), drug reactions, vasculitis (e.g., eosionphilic granulomatosis with polyangiitis), and IBD.213,214 Allergic colitis in infancy, also known as dietary protein-induced proctocolitis of infancy syndrome, is the most common cause of bloody stools in the first year of life.215,216 Similar to other EGID, these disorders are classified into primary and secondary.

Etiology EC is usually a non–IgE-associated disease. Some studies point to a T lymphocyte–mediated process, but the exact immunologic

mechanisms responsible for this condition have not been identified.217 In a murine model of oral antigen–induced diarrhea associated with colonic inflammation, colonic T cells have been shown to transfer the disease to naive mice by a STAT-6–dependent mechanism.40 It has been reported that allergic colitis of infancy might be an early expression of protein-induced enteropathy or protein-induced enterocolitis syndrome. Cow’s milk and soy proteins are the foods most frequently implicated in allergic colitis of infancy, but other food proteins can also provoke the disease. In general, although data are lacking, EC is considered more aligned with autoimmune processes including IBD compared with EoE and gastritis which are more aligned with allergic diseases. 

Clinical Features and Diagnostic Studies A variety of symptoms associated with EC are noted depending upon the degree and location of tissue involvement. While diarrhea is a classic symptom, other symptoms that can occur independent of diarrhea commonly include abdominal pain, weight loss, and anorexia. There is a bimodal age distribution, with the infantile form presenting at a mean age at diagnosis of approximately 60 days71 and the other form presenting during adolescence and early adulthood.1 In infants, bloody diarrhea precedes diagnosis by several weeks, and anemia due to blood loss is not uncommon. Most infants do not have constitutional symptoms and are otherwise healthy. On endoscopic examination, patchy erythema, loss of vascularity, and lymphonodular hyperplasia are mostly localized to the rectum but may extend to the entire colon (Fig. 30.3A).217 Histologic examination often reveals that the overall architecture of the mucosa is well preserved; however, there are focal aggregates of eosinophils in the lamina propria, crypt epithelium, and muscularis mucosa and, occasionally, the presence of multinucleated giant cells in the submucosa (see Fig. 30.3B). No single test is the gold standard for diagnosis, but peripheral blood eosinophilia or eosinophils in the stool are suggestive of EC. 

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Treatment Treatment of EC varies primarily depending upon the disease subtype. For example, EC of infancy is generally a benign disease. Upon withdrawal of the offending protein trigger in the diet, the gross blood in the stools usually resolves within 72 hours, but gross and occult blood loss may persist longer.70,218 Treatment of EC in older individuals usually requires medical management; anti-inflammatory drugs including 5-aminosalicylates and systemic or topical glucocorticoids are commonly used and appear to be efficacious, but careful clinical trials have not been conducted. There are several forms of topical glucocorticoids designed to deliver drugs to the distal colon and rectum, but EC typically also involves the proximal colon. In severe cases that are refractory to or dependent upon systemic glucocorticoid therapy, alternatives include intravenous alimentation or immunosuppressive antimetabolite therapy with azathioprine or 6-mercaptopurine. 

Prognosis When EC presents in the first year of life, the prognosis is good, with the vast majority of patients being able to tolerate the culprit food(s) by 1 to 3 years of age. The prognosis for EC that develops later in life is more guarded than the infantile subtype. Similar to eosinophilic gastroenteritis, the natural history has not been

documented, and this disease is considered to be a chronic waxing and waning disorder. Because EC can often be a manifestation of other primary disease processes, routine clinical surveillance of the cardiopulmonary systems is important and periodic upper and lower GI endoscopy may be warranted. 

RESOURCES The recent mini-epidemic of EoE has led to the establishment of patient-founded support/advocacy groups such as the American Partnership for Eosinophilic Disorders (http://www.A PFED.org) and the Campaign Urging Research for Eosinophilic Disease (CURED, http://www.curedfoundation.org). In addition, the recent formation of the CEGIR (http://www.raredise asesnetwork.org/cms/cegir), which is part of the Rare Diseases Clinical Research Network of the National Institutes of Health, will allow a better understanding and treatment of EGID.219 While much progress has been made concerning GI eosinophils and EGIDs, there is still a paucity of knowledge compared with other cell types and GI diseases that may be even less common. It is anticipated that a better understanding of the pathogenesis and treatment of EGIDs will emerge by combining comprehensive clinical and research approaches involving experts in the fields of allergy, gastroenterology, nutrition, and pathology. F ull references for this chapter can be found on www.expertconsult.com

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Protein-Losing Gastroenteropathy David A. Greenwald

CHAPTER OUTLINE DEFINITION AND NORMAL PHYSIOLOGY������������������������ 435 PATHOPHYSIOLOGY�������������������������������������������������������� 435 CLINICAL FEATURES������������������������������������������������������� 436 DISEASES ASSOCIATED WITH PROTEIN-LOSING GASTROENTEROPATHY��������������������������������������������������� 437 Diseases Without Mucosal Erosions or Ulcerations ������ 438 Diseases with Mucosal Erosions or Ulcerations������������ 439 Diseases with Lymphatic Obstruction or Elevated Lymphatic Pressure 439 DIAGNOSIS���������������������������������������������������������������������� 439 Laboratory Tests���������������������������������������������������������� 439 Approach to the Patient with Suspected Protein-Losing Gastroenteropathy���������������������������� 440 TREATMENT AND PROGNOSIS���������������������������������������� 440 ��������������������������������������������������

DEFINITION AND NORMAL PHYSIOLOGY Protein-losing gastroenteropathy describes a diverse group of disorders associated with excessive loss of serum proteins into the GI tract.1-16 This excess serum protein loss can result in hypoproteinemia and may be manifested by edema, ascites, and malnutrition. Box 31.1 lists disorders associated with protein-losing gastroenteropathy.17-76 In 1947, Maimon and colleagues postulated that fluid emanating from the large gastric folds in patients with Ménétrier disease was rich in protein. In 1949, Albright and colleagues discovered, using IV infusions of albumin, that hypoproteinemia resulted from excessive catabolism of albumin rather than decreased albumin synthesis.1 By 1956, Kimbel and colleagues demonstrated an increase in gastric albumin production in patients with chronic gastritis. A year later, Citrin and colleagues2 were able to show that the GI tract was the actual site of excess protein loss in patients with Ménétrier disease. They showed that the excess loss of IV-administered radioiodinated albumin could be explained by the appearance of labeled protein in the gastric secretions of such patients. Subsequent research using radiolabeled polyvinylpyrrolidone, albumin, and other proteins, as well as immunologic methods measuring enteric loss of α1-antitrypsin (α1-AT), has further characterized the role of the GI tract in the metabolism of serum proteins. In fact, GI tract loss of albumin normally accounts for only 2% to 5% of the total body degradation of albumin, but in patients with severe protein-losing GI disorders, this enteric protein loss may extend to up to 60% of the total albumin pool.3-6 Under physiologic conditions, most endogenous proteins found in the lumen of the GI tract are derived from sloughed enterocytes and from pancreatic and biliary secretions.7,8 Studies of serum protein loss into the GI tract measured by various methods (e.g., 67Cu-ceruloplasmin, 51Cr-albumin, α1-AT clearance) have shown that daily enteric loss of serum proteins accounts for less than 1% to 2% of the serum protein pool in

healthy individuals, with enteric loss of albumin accounting for less than 10% of total albumin catabolism. In normal women and men, the total albumin pool is approximately 3.9 g/kg and 4.7 g/kg, respectively, with a half-life of 15 to 33 days and a rate of hepatic albumin synthesis of 0.15 g/kg/day, equaling the rate of albumin degradation.9,10 Excess proteins that enter the upper GI tract are metabolized by existing proteases much like other peptides, broken down to constituent amino acids, and then reabsorbed. In healthy individuals, GI losses play only a minor role in total protein metabolism, and serum protein levels reflect the balance between protein synthesis and total protein metabolism. However, this balance can be altered markedly in patients with protein-losing gastroenteropathy.5,11 

PATHOPHYSIOLOGY Excessive plasma protein loss across the GI epithelium can result from several pathologic mucosal processes. Mucosal injury can result in increased permeability to plasma proteins; mucosal erosions and ulcerations can result in weeping of an inflammatory protein-rich exudate, and lymphatic obstruction or increased lymphatic hydrostatic pressure can result in direct leakage of lymph, which contains plasma proteins. Changes in vascular permeability can affect the concentration of serum proteins in the interstitial fluid, thereby influencing the amount of enteric mucosal protein loss.12,16 Examining the pathogenesis of protein-losing gastroenteropathy, Bode and colleagues have suggested that the condition might be related to loss of heparan sulfate proteins that are normally present on the surface of intestinal epithelial cells.11,13,14 Heparan sulfate proteoglycans appear to affect the intestinal barrier by having large extracellular domains that bind to the plasma membrane, known as syndecans, or are attached to a membrane glycolipid called a glypican.15 These syndecans are important in the maintenance of tight intercellular junctions. Mice that were genetically altered to lack syndecans or other heparan sulfate proteins have alterations to the normal tight intercellular barrier and leak protein via paracellular pathways into the intestinal lumen (Fig. 31.1). Moreover, treatment of such mice with proinflammatory cytokines such as TNF-α or interferon-γ leads to significantly defective intercellular junctions and even greater protein loss into the intestine.13 The combination of a syndecan-deficient state and exposure to proinflammatory cytokines leads to even greater albumin flux and protein loss. Finally, reintroduction of heparin sulfate or other syndecans abolishes the protein loss into the lumen of the bowel.13 The loss of serum proteins in patients with protein-losing gastroenteropathy is independent of their molecular weight, and therefore the fraction of the intravascular pool degraded daily remains the same for various proteins, including albumin, immunoglobulin (IgG, IgA, IgM), and ceruloplasmin.5,11,16 In contrast, patients with nephrotic syndrome selectively lose lower molecular weight proteins such as albumin. As proteins enter the GI tract, synthesis of new proteins occurs in a compensatory fashion. Proteins that enter the GI tract are metabolized into constituent amino acids by gastric, pancreatic, and small intestinal enzymes, reabsorbed by specific transporters, and recirculated. When the rate of gastric or enteric protein loss, or both, exceeds the body’s capacity to synthesize new protein, hypoproteinemia

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BOX 31.1 Disorders Associated with Protein-Losing Gastroenteropathy DISEASES WITHOUT MUCOSAL EROSIONS OR ULCERATIONS AIDS-associated gastroenteropathy17 Acute viral gastroenteritis18 Allergic gastroenteropathy19 Celiac disease20 Cobalamin deficiency21 Collagenous colitis22 Cytomegalovirus infection23 Eosinophilic gastroenteritis24 Giant hypertrophic gastropathy (Ménétrier disease)25,26 Giardiasis, schistosomiasis, nematodiasis (capillariasis), strongyloidiasis Graft-versus-host disease Hp gastritis Henoch-Schönlein purpura27 Hypertrophic hypersecretory gastropathy Intestinal parasitosis28-30 Lymphocytic colitis22 Lymphocytic gastritis Mixed connective tissue disease31 Paracoccidiomycosis Postmeasles diarrhea SIBO32 Sjögren syndrome33 Systemic lupus erythematosus (SLE)34-40 Tropical sprue41 Vascular ectasia (gastric, colonic)42 Whipple disease43  DISEASES WITH MUCOSAL EROSIONS OR ULCERATIONS α-Chain disease44 Amyloidosis45 Behçet disease46 Carcinoid syndrome Crohn disease47,48 Duodenitis49 Erosive gastritis49 GI carcinomas

develops.7,8 Hypoalbuminemia, for example, is common in protein-losing gastroenteropathy and results when there is an imbalance between hepatic albumin synthesis, which is limited and can increase only by 25%, and albumin loss, with reductions in the total body albumin pool and albumin half-life.12 Adaptive changes in endogenous protein catabolism may compensate for excessive enteric protein loss, resulting in unequal loss of specific proteins. For example, proteins like insulin, some clotting factors, and IgE have rapid catabolic turnover rates (short half-lives) and, as such, are relatively unaffected by GI losses, because rapid synthesis of these proteins ensues. On the other hand, enhanced synthesis of proteins such as albumin and most immunoglobulins, except IgE, is limited, and thus protein loss from the gut will be manifested by hypoproteinemia (hypoalbuminemia and hypoglobulinemia).11 Other factors also can contribute to the excessive enteric protein loss seen in various diseases. These include impaired hepatic protein synthesis and increased endogenous degradation of plasma proteins. In addition to causing hypoproteinemia, protein-losing gastroenteropathy can be associated with reduced concentrations of other serum components (e.g., lipids, iron, trace metals).11 Lymphatic obstruction can result in lymphopenia, with resultant alterations in cellular immunity. 

Graft-versus-host disease50 Hp gastritis51-53 Idiopathic ulcerative jejunoileitis54 Infectious diarrhea (e.g., Clostridium difficile,55 Shigella spp.56) Ischemic colitis Kaposi sarcoma57 Leukemia/lymphoma Melanoma Multiple myeloma Neurofibromatosis58 NSAID enteropathy59 Sarcoidosis60 Toxic shock syndrome (Streptococcus pyogenes) Waldenström macroglobulinemia62  DISEASES WITH LYMPHATIC OBSTRUCTION OR ELEVATED LYMPHATIC PRESSURE Budd-Chiari syndrome68 Cardiac disease63,64 CD 55 deficiency69 Constrictive pericarditis, heart failure, tricuspid regurgitation, Fontan procedure70,71 Crohn disease47,48 Intestinal endometriosis65 Intestinal lymphangiectasia (congenital, acquired)66,67 Lymphatic-enteric fistula28 Lymphoma, including mycosis fungoides Mesenteric TB and sarcoidosis60 Mesenteric venous thrombosis73 Neoplastic disease involving mesenteric lymphatics Portal hypertensive gastroenteropathy74 Post-transplant lymphoproliferative disease75 Retroperitoneal fibrosis Sclerosing mesenteritis76 Superior vena cava thrombosis SLE35-40 TB peritonitis Whipple disease43

CLINICAL FEATURES Hypoproteinemia and edema are the principal clinical manifestations of protein-losing gastroenteropathy. Pleural and pericardial effusions, as well as malnutrition, are also commonly seen. Most other clinical features reflect the underlying disease process and, as such, the clinical presentation of patients with protein-losing gastroenteropathy is varied (Box 31.2).17-76 Protein-losing gastroenteropathy is seen in both pediatric and adult populations.77 Hypoproteinemia, the most common clinical sequela, is manifested by a decrease in serum levels of albumin, most immunoglobulins (IgG, IgA, and IgM, but not IgE), fibrinogen, lipoproteins, α1-AT, transferrin, and ceruloplasmin.11 Levels of rapid-turnover proteins, such as retinal binding protein and prealbumin, are typically preserved, despite hypoproteinemia.78 Dependent edema is frequently a clinically significant issue, and results from diminished plasma oncotic pressure. Anasarca is rare in protein-losing gastroenteropathy. Unilateral edema, upper extremity edema, facial edema, macular edema (with reversible blindness), and bilateral retinal detachments have been seen as a consequence of intestinal lymphangiectasia.79 Despite the decrease in serum gamma globulin levels, increased susceptibility to infections is uncommon. Although clotting factors may be lost into the GI tract,

CHAPTER 31  Protein-Losing Gastroenteropathy

Normal mouse intestine

Syndecan-1–deficient

Ions, nutrient solutes, proteins, bacteria, toxins Intestinal lumen

Fig. 31.1  Diagrams illustrating the factors that contribute to intestinal integrity in the mouse. A, The normal mouse intestine is an effective barrier against the free diffusion of certain ions, nutrient solutes, proteins, bacteria, and toxins to separate the intestinal lumen (outside) from the lamina propria (inside) effectively. B, Syndecan-1–deficient mice have decreased intestinal barrier function as a result of defective intercellular junctions and increased paracellular leaks (dashed line) or increased transcellular protein transport (solid line).13 C, Syndecan-1–deficient mice that were given inflammatory cytokines (TNF-α and interferon-γ) or operated on to increase their portal venous pressure have massively defective intercellular junctions and large intercellular protein leaks (dashed lines), consistent with protein-losing enteropathy. D, Infusions of heparin sulfate analogs completely reverse the intestinal barrier dysfunction seen in syndecan-1– deficient mice given inflammatory cytokines. See text for more details. (From Lencer WI. Patching a leaky intestine. N Engl J Med 2008;359: 526–8, with permission.)

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Solutes, serum proteins

Lamina propria

A

Solutes, serum proteins

Syndecan-1–deficient + TNF-α and interferon-γ (or increased venous pressure)

B

Syndecan-1–deficient + TNF-α and interferon-γ + heparin sulfate analogs Ions, nutrient solutes, proteins, bacteria, toxins

Solutes, serum proteins

C

Solutes, serum proteins

resynthesis is rapid and in general, coagulation status typically remains unaffected. On the other hand, angiopathic thrombosis has been noted in certain situations (discussed later).69 Circulating levels of proteins that bind hormones, such as cortisol-binding globulin and thyroid-binding globulin, may be substantially decreased, but levels of circulating free hormones are not significantly altered. Most of the clinical findings in patients with protein-losing diseases are the result of the underlying disease state and are not caused by the protein loss itself. For example, small bowel disorders with protein loss as a feature (e.g., celiac disease, tropical sprue) may be associated with malabsorption and resultant diarrhea, fat-soluble vitamin deficiencies, and anemia. Lymphatic

Solutes, serum proteins

D

Solutes, serum proteins

obstruction, as occurs with lymphangiectasia, may result in lymphopenia or abnormal cellular immunity.80 

DISEASES ASSOCIATED WITH PROTEIN-LOSING GASTROENTEROPATHY Diseases associated with protein-losing gastroenteropathy can be divided into 3 broad categories: (1) diseases without GI mucosal erosions or ulcerations; (2) diseases with GI mucosal erosions or ulcerations; and (3) diseases leading to elevated lymphatic and interstitial pressure (see Box 31.1). More than one of these mechanisms may be operative in some disease states, as is the situation for some infectious diseases.

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Diseases Without Mucosal Erosions or Ulcerations Diseases that damage the GI epithelium without causing erosions or ulcers may lead to surface epithelial cell shedding, resulting in excess protein loss. Lesions of the small intestine that cause malabsorption are often associated with enteric leakage of plasma proteins. Protein loss also may be caused by alterations in vascular permeability caused by vascular injury, such as in lupus vasculitis, allergic IgE-mediated type 1 hypersensitivity reactions, infection (parasitic, viral, and bacterial overgrowth), increased intercellular permeability, or increased capillary permeability.28-38,36

Ménétrier Disease Giant hypertrophic gastropathy (Ménétrier disease; see Chapter 52) is the most common gastric lesion causing severe protein loss.25,26 Patients usually have dyspepsia, nausea, emesis, edema, and weight loss and are found to have hypoproteinemia.

BOX 31.2 Clinical Manifestations of Protein-Losing Gastroenteropathy SYMPTOMS AND SIGNS Edema (dependent, upper extremity, facial, macular; unilateral in lymphangiectasia) Diarrhea Retinal detachment (in lymphangiectasia)79  LABORATORY ABNORMALITIES Hypoproteinemia Hypoalbuminemia Decreased serum gamma globulins (IgG, IgA, and IgM) Decreased serum proteins—ceruloplasmin, α1-antitrypsin, fibrinogen, transferrin, hormone-binding proteins Decreased serum lipoproteins Evidence of fat malabsorption Evidence of carbohydrate malabsorption Evidence of fat-soluble vitamin malabsorption or deficiency Altered cellular immunity80 Lymphopenia Ig, immunoglobulin.

A

Prominent and thick gastric folds with substantial mucus and protein-rich exudates are seen; normal gastric glands are replaced by mucus-secreting cells, reducing the number of parietal cells and resulting in hypochlorhydria or achlorhydria. An increase in intercellular permeability results in protein loss. In this disorder, tight junctions between cells are wider than those found in healthy subjects, and it is believed that proteins traverse the gastric mucosa through these widened spaces. H2RAs, anticholinergic agents, and octreotide may be used to improve symptoms, but patients with persistent abdominal pain or severe unrelenting protein loss require subtotal or total gastrectomy.26 As discussed in Chapter 52, there is a possible causal relationship between Hp infection and Ménétrier disease with protein-losing gastroenteropathy, and resolution of the hypoproteinemia and return of the gastric folds to their normal configuration may occur after eradication of the organism from the stomach.51-53 

HP Gastritis Hp gastritis in the absence of Ménétrier disease (see Chapter 52) has been associated with protein-losing gastropathy and responds to eradication of Hp infection.51-53 Some of these patients may have gastric erosions through which protein may be lost. 

Allergic Gastroenteropathy Although allergic gastroenteropathy (see Chapters 10, 30, and 52) is often considered a disease of childhood, it may be seen in adults as well. This syndrome is manifested by abdominal pain, vomiting, and sporadic diarrhea; findings include hypoproteinemia, iron deficiency anemia, and peripheral eosinophilia. Serum levels of total protein and albumin, as well as IgA and IgG, are markedly reduced, whereas levels of IgM and transferrin are only moderately diminished. Characteristic histology of the small bowel in patients with this disorder includes a marked increase in the number of eosinophils in the lamina propria, and Charcot-Leyden crystals may be found on stool examination.19 

SLE SLE is a systemic autoimmune disease not infrequently associated with protein-losing gastroenteropathy; the entity has been termed lupus protein-losing enteropathy (Fig. 31.2).34-39 Mesenteric

B Fig. 31.2 A, CT of the abdomen in a 29-year-old woman with severe watery diarrhea and diffuse nonradiating abdominal pain. The serum albumin level was 2.9 g/dL, and the creatinine level was 0.6 mg/dL. Stool studies were negative for pathogens. The CT shows diffuse small bowel wall thickening. The titer of antinuclear antibodies was 1:1280, and she was started on methylprednisolone. Her symptoms improved rapidly, with much less diarrhea and resolution of abdominal pain. B, Repeat CT 5 days later showed marked improvement of the bowel wall thickening, at which time the serum albumin level was 3.4 g/dL. Renal biopsy confirmed changes consistent with lupus nephritis.  

CHAPTER 31  Protein-Losing Gastroenteropathy

vasculitis can result in intestinal ischemia, edema, and altered intestinal vascular permeability. In addition, gastritis and mucosal ulcerations, both of which may contribute to excess protein loss, can develop in patients with SLE. Protein-losing gastroenteropathy may be the initial clinical presentation of SLE. Therapy with systemic glucocorticoids, as well as other immunomodulatory agents such as azathioprine, cyclophosphamide, and tacrolimus, can lead to remission with resolution of clinical symptoms, including protein-losing gastroenteropathy.38-40 

Diseases with Mucosal Erosions or Ulcerations Mucosal erosions or ulcerations resulting in protein-losing gastroenteropathy can be localized or diffuse and can be caused by benign or malignant disease (see Box 31.1). The severity of protein loss depends on the degree of cellular loss and the associated inflammation and lymphatic obstruction. Diffuse ulcerations of the small intestine or colon, as seen with Crohn disease, ulcerative colitis, and pseudomembranous colitides, can result in severe protein loss.47,48,61 Hypoalbuminemia is common in patients with GI tract malignancies; although this is most often the result of a decrease in albumin synthesis, excessive enteric protein loss has been reported. Protein-losing gastroenteropathy has also been related to therapy for malignant disease, including chemotherapy, radiation-related injury, and bone marrow transplantation. 

Diseases with Lymphatic Obstruction or Elevated Lymphatic Pressure Lymphatic obstruction results in dilatation of intestinal lymphatic channels and can result in rupture of lacteals rich in plasma proteins, chylomicrons, and lymphocytes. When central venous pressure is elevated, such as in heart failure or constrictive pericarditis, bowel wall lymphatic vessels become congested, resulting in a loss of protein-rich lymph into the GI tract.8,63,64 Tortuous, dilated mucosal and submucosal lymphatic vessels are also seen in patients with primary intestinal lymphangiectasias (Fig. 31.3). These patients often present by 30 years of age with edema, hypoproteinemia, diarrhea, and lymphopenia from both lymphatic leakage and rupture.66,67 Patients with an autosomal dominant homozygous loss of function mutation in the gene encoding CD55 (decay accelerating factor) have been identified; these patients have abdominal pain, diarrhea, and protein-losing

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gastroenteropathy with intestinal lymphangiectasia, edema, malabsorption, recurrent infections, and angiopathic thromboembolic disease.69 Retroperitoneal processes such as adenopathy, fibrosis, and pancreatitis can also impair lymphatic drainage. Budd-Chiari syndrome after liver transplantation has been associated with protein-losing gastroenteropathy.68 An association between protein-losing gastroenteropathy and heart disease is seen after the Fontan procedure, a surgical correction for a congenital univentricular heart or severely hypoplastic left ventricle. The surgery creates a wide anastomosis between the right atrium and pulmonary artery, with venous blood bypassing the right ventricle; protein-losing gastroenteropathy has been noted in up to 15% of patients in the ensuing 10 years.8,70,71,72 Hemodynamic studies in such patients reveal increased central venous pressures. 

DIAGNOSIS Laboratory Tests Because hypoproteinemia and edema are seen in many other disorders in addition to protein-losing gastroenteropathy, documentation of excessive protein loss from the GI tract is important. Patients with unexplained hypoproteinemia in the absence of proteinuria, liver disease, and malnutrition should be investigated for evidence of protein-losing gastroenteropathy. The previous gold standard for diagnosing protein-losing gastroenteropathy, measurement of the fecal loss of radiolabeled IV-administered macromolecules (e.g., 51Cr-albumin), has significant limitations, such as exposure to radioactive material and a 6- to 10-day collection period. Therefore, this test is not clinically practical.81 α1-AT is a useful marker of intestinal protein loss. α1-AT is a 50-kd glycoprotein similar in size to albumin (67 kd). Like albumin, α1-AT is synthesized in the liver and is neither actively absorbed nor secreted in the intestine; it is also resistant to luminal proteolysis. α1-AT is normally present in the stool in low concentrations.81-83 Enteric protein loss can be demonstrated by quantifying the concentration of α1-AT in the stool or by measuring its clearance from plasma; the latter is the more reliable indicator. Therefore, the optimal test is to measure the clearance of α1-AT from the plasma during a 72-hour stool collection, with α1-AT plasma clearance expressed in milliliters/day using this formula: α1‐AT plasma clearance = ([Daily stool volume] × [Stool α1‐AT])/Serum α1‐AT

Fig. 31.3  Intestinal lymphangiectasia. This small intestinal biopsy specimen was obtained from a patient with protein-losing enteropathy. It shows focal lymphangiectasia (i.e., 2 villi are involved and 2 are spared), consistent with an acquired (secondary) lymphangiectasia. A more diffuse lymphangiectasia would favor a congenital type of lymphangiectasia. (Courtesy Dr. Edward Lee, Washington, DC.)

Plasma clearance of α1-AT can also be used to monitor response to therapy. An α1-AT clearance in excess of 24 mL/day in patients without diarrhea is abnormal. Diarrhea alone can increase α1-AT clearance; thus, an α1-AT clearance exceeding 56 mL/day in patients with diarrhea is considered abnormal. In addition, there is an inverse correlation between α1-AT plasma clearance and serum albumin concentration; as serum albumin levels fall below 3 g/dL, the clearance of α1-AT exceeds 180 mL/day. In infants, meconium can interfere with α1-AT results (false positives) because of the higher concentration of α1-AT in meconium; therefore, this test should not be performed on infants suspected of having protein-losing enteropathy.81-84 Intestinal bleeding also leads to false elevations of α1-AT clearance. In patients who test positive for fecal occult blood, interpretation of α1-AT clearance can be difficult because of increased clearance rates.81-84 Finally, α1-AT is degraded by pepsin at a gastric pH below 3 and thus may be falsely negative in patients with gastric protein loss (false negatives); use of a PPI to prevent peptic degradation of α1-AT in the stomach may allow detection of protein-losing gastropathy.84

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Nuclear medicine studies are available to aid in the diagnosis of protein-losing gastroenteropathy; these include technetium99m (99mTc)-labeled human serum albumin (99mTc-HSA), 99mTclabeled methylene diphosphonate (99mTc-MDP), 99mTc-labeled dextran scintigraphy, 99mTc-labeled human immunoglobulin, and indium-111 (111In)-labeled transferrin.85-89 Nuclear imaging may be useful to quantify protein loss or localize a site-specific area of protein loss and can be helpful in establishing a diagnosis when the α1-AT clearance results are equivocal. Of these tests, 99mTclabeled dextran scintigraphy may be more sensitive than 99mTcHSA, although neither test is widely available. Studies in children and adults have used 99mTc-HSA for detecting the specific site of gastric or enteric protein loss, and this test can also be used to monitor response to therapy. 99mTc-labeled human immunoglobulin and 111In-labeled transferrin also may help quantify and localize protein loss into the GI tract.85-89 MRI has been described as a useful tool for the diagnosis of primary proteinlosing gastroenteropathy, readily characterizing lesions that may be associated with protein loss into the gut, such as dilated mesenteric lymphatics in the abdomen and prominent subcutaneous lymphatics in the extremities.90 MR enterocolonography has been reported as a useful diagnostic tool in confirming suspected protein-losing gastroenteropathy detected on scintigraphy, identifying inflamed areas of the colon and small bowel where protein was being lost.91 Characteristic changes suggestive of protein-losing gastroenteropathy may be seen on video capsule endoscopy, and biopsy samples may be obtained through deep enteroscopy.92 

Approach to the Patient with Suspected ­ Protein-Losing Gastroenteropathy The diagnosis of protein-losing gastroenteropathy is usually made on the basis of an increase in α1-AT clearance, in the absence of confounding variables just discussed, with nuclear testing such as 99mTc-HSA helping confirm and quantitate the extent and location of the disorder in certain patients, and directing the evaluation to a specific organ (Fig. 31.4).85,86 Testing to confirm protein loss from the GI tract is critical to establishing the diagnosis of protein-losing gastroenteropathy, because many other diseases can present with edema and hypoproteinemia without enteric protein loss. Examples include nephrotic syndrome, cirrhosis, malignancy, eating disorders including bulimia and anorexia, malnutrition, and diuretic or laxative abuse. Following confirmation of enteric protein loss, further evaluation is necessary to identify the underlying disease process. Initial evaluation should include a thorough history and physical examination. Blood testing typically would include a complete blood count with differential (specifically looking for eosinophilia) and red cell indices, electrolytes, calcium, magnesium, serum protein electrophoresis and immunoelectrophoresis, C-reactive protein, erythrocyte sedimentation rate, antinuclear antibody (ANA) and rheumatoid factor, coagulation studies, HIV testing, iron and iron-binding capacity, and thyroid studies. In those patients with diarrhea, a 72-hour fecal fat determination may be useful if not performed earlier, as well as collection of stool specimens for ova and parasites, Giardia antigen, Clostridium difficile toxin, and Charcot-Leyden crystals if peripheral eosinophilia is present. A chest radiograph may reveal granulomatous disease or evidence of cardiomegaly. Electrocardiography or echocardiography may be indicated if increased venous pressure is suspected. In the presence of steatorrhea, diagnostic studies should concentrate on the upper GI tract, and radiologic and endoscopic evaluation of the small intestine, including capsule endoscopy, deep enteroscopy, and MR enterography, might be performed.92,91 EGD and colonoscopy may help detect mucosal inflammation, ulceration, neoplastic disease, or other abnormalities. Biopsies of abnormal-appearing areas should be taken; random biopsies also may have a yield because conditions such as collagenous or

Initial evaluation

Normal α1-AT clearance

Increased α1-AT clearance

Nephrotic syndrome Liver disease (cirrhosis) Malignancy Eating disorders Diuretic/laxative abuse Malnutrition

Steatorrhea

No steatorrhea

SBFT or capsule endoscopy

Endoscopy/biopsy

Abnormal

Normal

Small bowel biopsy

US CT Cardiac evaluation Laparoscopy Lymphangiogram, if available

Fig. 31.4  Approach to the patient with protein-losing gastroenteropathy. Initial evaluation includes a complete history and physical examination, laboratory evaluation (see text), and determination of α1-antitrypsin (α1-AT) plasma clearance. SBFT, small bowel follow-through.

lymphocytic colitis can appear endoscopically normal. Contrast studies of the small and large bowel may demonstrate ulcers and mucosal abnormalities. Disorders that might lead to lymphatic obstruction (e.g., retroperitoneal fibrosis, pancreatic diseases, malignancies) can be evaluated by CT or MRI of the abdomen and pelvis. Videocapsule endoscopy is useful in evaluating for protein-losing gastroenteropathy to identify the presence of intestinal lymphangietases.93 Lymphangiography may be considered for selected patients, but this test is rarely performed in most centers. When the diagnosis remains unclear, exploratory laparotomy to exclude the possibility of occult malignancy is sometimes appropriate. 

TREATMENT AND PROGNOSIS Because protein-losing gastroenteropathy is a syndrome and not a specific disease, treatment is directed not only at correction of the underlying disease but also includes supportive care and dietary modifications. Protein loss may be offset in part by a high-protein diet, and a diet lower in fat appears to have a beneficial effect on albumin metabolism.94 Moreover, octreotide may be useful for some patients with protein-losing gastroenteropathy to decrease fluid secretion and protein exudation from the bowel.95 There is some suggestion in experimental mouse models that infusion of heparin analogs may restore intestinal mucosal tight junctions and prevent protein loss across the surface of the bowel; further clinical work is needed to define efficacy.15 For diseases affecting the stomach, such as giant hypertrophic gastropathy (Ménétrier disease), gastrectomy reverses protein loss. However, evidence of an infection with Hp should be sought before surgical consideration and treated if present (see Chapter 52).51,52 Protein loss from the small bowel should be treated according to the individual disease process present. For example, diseases involving bacterial pathogens such as small intestinal bacterial overgrowth and Whipple disease should be treated with appropriate antibiotic therapy, whereas inflammatory processes

CHAPTER 31  Protein-Losing Gastroenteropathy

such as Crohn disease or lupus may require immunosuppressive therapy.38,40,96,97 In the colon, protein loss seen in diseases like ulcerative colitis and collagenous colitis may require longterm immunomodulators or surgery, and infectious colitides require antibiotic treatment. Malignancy-induced enteric protein loss requires cancer-specific therapy. Enteric protein loss and lymphocytopenia seen in cardiac diseases (e.g., heart failure, constrictive pericarditis) can be ameliorated with medical and surgical management of the underlying cardiac condition.8,64,97 Budesonide and high-dose spironolactone have been advocated for some patients with protein-losing gastroenteropathy after the Fontan procedure.98,99 Acquired intestinal lymphangiectasia should be treated by correction of the primary disease, whereas congenital intestinal lymphangiectasia can be partially controlled with dietary restrictions. Enteric protein loss in patients with the latter condition can be reduced by a low-fat diet enriched with medium-chain triglycerides, which do not require lymphatic transport and therefore do not stimulate lymph flow.100,101 Supportive care can reduce the incidence of secondary symptoms. Diuretics typically are not indicated because the

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edema is caused by a decrease in plasma oncotic pressure; however, diuretics may reduce dependent edema from hypoalbuminemia, thereby improving comfort. Support stockings, if used appropriately, can reduce lower extremity edema in patients with lymphedema and hypoalbuminemia. Exercise and adequate ambulation should be encouraged to reduce the risk of venous thrombosis. Meticulous skin care is critical to prevent skin breakdown and cellulitis. Although these measures do not affect enteric protein loss, they can minimize secondary complications. Most causes of the protein-losing disorders of the GI tract are easily detectable and treatable, and many can be cured. As such, the goal of therapy in protein-losing gastroenteropathy is to identify the cause and direct dietary, medical, or surgical intervention, or a combination, at the underlying disease.5,11 With reversal or control of the primary disease, a significant proportion of patients will have a partial or complete remission of enteric protein loss, edema, and other associated conditions. F ull references for this chapter can be found on www.expertconsult.com

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Gastrointestinal Lymphomas* Praveen Ramakrishnan Geethakumari, Syed Mujtaba Rizvi

CHAPTER OUTLINE GENERAL PRINCIPLES OF LYMPHOMA MANAGEMENT���� 443 Diagnosis��������������������������������������������������������������������� 443 Staging and Prognostic Assessment����������������������������� 443 Treatment�������������������������������������������������������������������� 443 GASTRIC LYMPHOMAS��������������������������������������������������� 443 Gastric Marginal Zone B Cell Lymphoma of Mucosa-Associated Lymphoid Tissue (Lymphomas)���� 443 Diffuse Large B Cell Lymphoma of the Stomach����������� 448 SMALL INTESTINAL LYMPHOMAS���������������������������������� 449 Marginal Zone B Cell Lymphoma of Malt Type��������������� 450 Diffuse Large B Cell Lymphoma������������������������������������ 450 Mantle Cell Lymphoma������������������������������������������������� 450 Follicular Lymphoma���������������������������������������������������� 451 Burkitt Lymphoma�������������������������������������������������������� 451 Immunoproliferative Small Intestinal Disease��������������� 451 Enteropathy-Associated T Cell Lymphoma�������������������� 454 Uncommon Small Intestinal Lymphomas���������������������� 455 OTHER GASTROINTESTINAL SITES��������������������������������� 455 IMMUNODEFICIENCY-RELATED LYMPHOMAS���������������� 456 Posttransplantation Lymphoproliferative Disorders������� 456 IATROGENIC LYMPHOPROLIFERATIVE DISORDERS�������� 456 HIV–ASSOCIATED NON-HODGKIN LYMPHOMA��������������� 457

Lymphomas are solid malignancies of the lymphoid system and are subdivided into Hodgkin and non-Hodgkin lymphomas (NHLs). It was estimated that in 2017 there would be 8260 and 72,240 new diagnoses of Hodgkin and NHL, respectively, in the US.1 The GI tract is very rarely involved with Hodgkin lymphoma and will not be discussed in this chapter. This chapter deals with primary GI lymphoma (PGIL), where the main bulk of disease is in the GI tract, with or without involvement of adjacent lymph nodes. PGILs constitute 1% to 4% of all GI malignancies, 10% to 15% of all NHLs, and 30% to 40% of all extranodal NHLs,2 making the GI tract the most common site of extranodal NHL. The incidence of PGIL between nations varies from 0.58 and 1.31 per 100,000 people and the usual age of diagnosis is between 50 and 70 years. Lymphomas that involve the GI tract but have the bulk of the disease in nodal areas are managed in a similar fashion to those that do not involve the GI tract. In broad terms, the immune system can be thought of as a highly structured and tightly regulated interaction between lymphoid and nonlymphoid tissues aimed at protecting the host from harmful agents (see Chapter 2).3 Lymphoid cells are produced in the bone marrow and thymus and then arrayed in the lymphoid tissues, which include the lymph nodes, spleen, Waldeyer ring, and mucosa-associated lymphoid tissue (MALT). The GI tract lymphoid tissue is MALT, typified by the Peyer patches of the *Hsiao

C. Li and Robert H. Collins, Jr. contributed to an earlier version of this chapter.

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terminal ileum. MALT contains B cells at various stages of differentiation, organized into different zones (Fig. 32.1A). B cells that have encountered antigen diffusing across the mucosa enter the germinal center of MALT and undergo repeated immunoglobulin gene mutations (somatic mutations).4 The resultant B-cell sub-clones whose immunoglobulins are highly specific for antigen have a survival advantage over B cells whose immunoglobulins are less specific. These more specific B cells then leave the germinal center, enter the circulation, differentiate into memory B cells or antibody-producing plasma cells, and return to the intestinal mucosa. Memory B cells reside in the marginal zone of MALT. Some marginal zone B cells occupy the epithelial tissue that covers the Peyer patches; these cells are called intraepithelial marginal zone B cells. B cells that have not encountered antigen make up the mantle zone of MALT. T cells play a role in the coordination and delivery of the immune system and thus are also found in MALT (see Fig. 32.1A). Therefore, MALT is composed of B and T cells at various stages of differentiation; immune cells at a given stage of differentiation have characteristic histologic, immunophenotypic, and genetic features. Malignant transformation may occur in a cell at any one of these stages of differentiation, leading to a malignancy with distinct clinical pathologic features (see Fig. 32.1B). This way of understanding lymphomas has led to the WHO lymphoma system, which recognizes over 60 different clinical pathologic subtypes of NHL.5 Most lymphomas of the GI tract are B cell lymphomas, with most of these resulting from transformation of marginal zone B cells, classified by the WHO system as extranodal marginal zone B cell lymphomas. However, B cell lymphomas can also arise from other cells of MALT, such as centrocytes of the germinal center (follicular lymphomas [FLs]) or cells of the mantle zone (mantle cell lymphoma [MCL]). The precise histogenesis of large B cell lymphomas likely varies from case to case. T cell lymphomas of the GI tract are less common and usually involve malignant transformation of intraepithelial T cells in patients with celiac disease (see Chapter 107). PGILs most commonly involve the stomach or small intestine; the oral pharynx, esophagus, colon, or rectum may be involved uncommonly. In developed countries, the stomach is the most common site of involvement (approximately 60% of cases), but in the Middle East, the small intestine is the most common site of GI involvement. The first definition of PGIL was proposed by Dawson et al. (1961) using restricted criteria, namely the presence of a predominant GI lesion with or without expansion to regional lymph nodes but without involvement of distant lymph nodes and the exclusion of patients with a leukemic presentation and those with bone marrow, spleen, or liver involvement.6 This definition was later expanded to include cases involving the adjacent liver and spleen, and allowing for distant nodal disease, provided the extranodal GI lesion was the presenting site and the site of predominant bulk (>75% of total tumor volume), to which primary treatment should be directed.7-9 Clinicians dealing with GI lymphoma are faced with a specific pathologic diagnosis of a lymphoma occurring in a specific site and, in some cases, modified by important patient characteristics, such as HIV infection. This chapter discusses the main clinicopathologic entities that a clinician may encounter.

CHAPTER 32  Gastrointestinal Lymphomas

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32

B GC

T

MZ

Mar

B

A

Fig. 32.1 A, Normal mucosa-associated lymphoid tissue of small intestine. The T zone is situated toward the serosal aspect (T ). Intraepithelial B cells are also present (B). B, Large B cell lymphoma of the small intestine. Note the infiltration and expansion of the mucosa by the neoplastic cells, with atrophy of the native epithelial structures. GC, germinal center; Mar, pale external marginal zone; MZ, dark surrounding mantle zone. (Courtesy of Dr. Pamela Jensen, Dallas, TX.)  

GENERAL PRINCIPLES OF LYMPHOMA MANAGEMENT Diagnosis Because of the many subtypes of NHL, lymphoma should be diagnosed and categorized accurately by an expert. Sufficient tissue is required for an accurate diagnosis. In the GI tract, this often means multiple endoscopic biopsies. Fine-needle aspiration biopsy is not considered sufficient for diagnosis because it only permits analysis of the morphology of individual cells and not an in-depth examination of the background milieu in which those cells reside. The minimal pathologic workup should include light microscopy and immunophenotypic analysis, either by flow cytometry or immunohistochemistry (IHC). Staining for immunoglobulin light chains assists in the documentation of monoclonality when there is a clear-cut light chain restriction (κ/λ ratio or λ/κ ratio ≥10:1), strongly suggesting B cell lymphoma. Occasionally, molecular genetic analysis by Southern blot testing or PCR assay is indicated to document monoclonal immunoglobulin or T cell receptor gene rearrangements, or to assess characteristic oncogene rearrangements. One must keep in mind though that clonality markers might be positive in various inflammatory conditions and are not necessarily pathognomonic of a malignancy. Therefore, an evaluation of a biopsy sample by an expert hematopathologist is extremely important to render an accurate diagnosis. 

Staging and Prognostic Assessment The extent of involvement by NHL is assessed by careful history and physical examination; CT of the neck, chest, abdomen, and pelvis; PET in cases of high-grade NHL; bone marrow examination; and EUS for PGILs.10 Waldeyer ring is often involved in GI lymphomas, and examination of the pharynx is therefore indicated. Prior to the initiation of treatment, serologies for HIV, hepatitis B, and hepatitis C and screening for Hp in gastric lymphomas should also be obtained. The Ann Arbor staging system11 was originally developed for Hodgkin lymphoma and is also used for NHL, but is deemed by many to be inadequate for staging of PGILs. Alternative systems have been proposed (Table 32.1).12 Prognosis is assessed by defining the distinct lymphoma subtype and evaluating clinical features, including tumor stage, age

of the patient, performance status, and serum LDH level. The International Prognostic Index (IPI) is a model used to predict outcome in patients with aggressive NHL.13 This model has been revised as R-IPI to reflect the use of the monoclonal antibody, rituximab, directed against CD20,14 and has been prospectively validated; retaining its predictive value in the rituximab era. 

Treatment Treatment varies according to lymphoma subtype and stage, but it should be noted that the best treatment for many GI lymphomas remains controversial. Whereas many large controlled trials have defined the best treatment for many nodal lymphomas, this is not the case for GI lymphomas. Thus, many treatment recommendations are based on small case series and extrapolation from results with nodal lymphomas. Prior to the initiation of treatment with systemic chemotherapy, interested patients should receive counseling regarding fertility preservation in addition to the side effect profile of drugs being used.15 We also routinely screen patients for chronic infections such as HIV, HBV, HCV, and Hp in lymphomas involving the MALT. We consider this important because a sizeable percentage of low-grade lymphomas will undergo spontaneous regression after the chronic infection driving them is adequately treated. 

GASTRIC LYMPHOMAS Primary gastric lymphomas account for 5% of gastric neoplasms, with an increasing trend worldwide.16 The stomach is the most common extranodal site of lymphoma and accounts for 68% to 75% of PGILs.17 Most of these gastric lymphomas are classified as marginal zone B cell lymphoma of the MALT type or as diffuse large B cell lymphoma (DLBCL).2

Gastric Marginal Zone B Cell Lymphoma of Mucosa-Associated Lymphoid Tissue (Lymphomas) Extranodal marginal zone B cell lymphoma of MALT, also known as MALT lymphoma, was first described by Isaacson and Spencer in 198318 and comprises about 8% of all NHLs.19 These lymphomas arise from malignant transformation of B cells from the marginal zone of MALT.20 They may arise from MALT that

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TABLE 32.1  Staging Systems for Primary Gastrointestinal Lymphomas

Stage

Modified Paris Staging System*

I

TI N0 T2 N0

II

Extending into abdomen II1 = local nodal involvement II2 = distant nodal involvement

TNM Staging System (Modified for Gastric Lymphoma)

Ann Arbor Staging System

Tumor Involvement

T1 N0 M0 T2 N0 M0 T3 N0 M0

IE IE IE

Mucosa, submucosa Muscularis propria Serosa

T1-3 N1 M0 T1-3 N2 M0

IIE IIE

Perigastric or peri-intestinal lymph nodes More distant regional lymph nodes

IIE

Penetration of serosa to involve adjacent organs or tissues

T4 N0 M0

IIE

Invasion of adjacent structures

IV

Disseminated extranodal ­involvement or concomitant supradiaphragmatic nodal ­involvement

T1-4 N3 M0

IIIE

Lymph nodes on both sides of the diaphragm

T1-4 N0-3 M1

IVE

Distant metastases (e.g., bone marrow or additional extranodal sites)

  

*Modified from Ruskoné-Fourmestraux A, Dragosics B, Morgner A, et al. Paris Staging System for primary gastrointestinal lymphomas. Gut 2003; 52:912–3. GI, Gastrointestinal; TNM, tumor node metastasis.   

exists under normal physiologic circumstances (e.g., in Peyer patches of the gut) or from MALT associated with infection or an autoimmune process. For example, gastric tissue normally does not contain MALT but may acquire it in response to chronic Hp infection (see Chapter 52).21 The phenomenon of “lymphocytic homing” which involves interaction between circulating lymphocytes and endothelial venules mediated by lymphocyte integrins and tissue-specific addressins is key to extranodal lymphomagenesis.22 Malignant transformation occurs in a small percentage of patients with acquired gastric MALT and results in a lymphoma with generally indolent behavior. The malignant process appears to be driven to a large degree by chronic Hp infection because eradication of this infection leads to regression of the lymphoma in 50% to 80% of cases.23,24

Epidemiology Gastric marginal zone B cell lymphoma of MALT represents 38% to 48% of gastric lymphomas.25 The incidence varies according to the incidence of Hp in the population being assessed. Thus, the incidence in northeastern Italy, where the rate of Hp infection is very high, is roughly 13 times the incidence in the United Kingdom.26 The median age at diagnosis of gastric MALT lymphoma is approximately 60 years, with a wide age range, with men and women affected equally. The male-to-female ratio is equal.27 

Cause and Pathogenesis Hp Infection. Several lines of evidence support the key role of Hp in the development of gastric MALT lymphoma (see Chapter 52). Infection by Hp is present in the vast majority of cases of gastric MALT lymphoma.28 The epidemiologic studies cited earlier have shown a close correlation between the prevalence of Hp infection and gastric lymphoma in a given population,29,30 and casecontrol studies have shown an association between previous Hp infection and subsequent development of gastric lymphoma.31 In vitro studies have shown that gastric MALT lymphoma tissue contains T cells that are specifically reactive to Hp. These Hp– reactive T cells support the proliferation of neoplastic B cells.32 Gastric MALT lymphoma can be induced in murine models by chronic Helicobacter infection.33 Many groups have documented the regression of gastric MALT lymphoma after eradication of

Hp.23,24,34 Of interest, responses of small intestinal and rectal lymphoma to Hp eradication have been reported,35,36 although a consistent role of the organism at these nongastric sites is not clear. Lymphomas have also been reported in patients with Helicobacter heilmannii infections, with resolution after eradication of the infection.37  Evidence for Antigen-Driven B Cell Proliferation. As noted previously, the B cell immunoglobulin variable region (V) genes undergo somatic hypermutation during the T cell– dependent B cell response to antigen,4 which leads to the production of new antigen receptors with altered antigen-binding affinity. Resultant B cell clones that express higher affinity antigen receptors have a survival advantage over B cell clones containing receptors with lower affinity. Thus, somatic mutation is a marker for antigen-driven selection of B cell clones. Sequence analysis of malignant B cells from gastric MALT lymphoma shows that the immunoglobulin genes have undergone somatic mutation.38  Genetic Studies. There are 4 main chromosomal translocations in extranodal marginal zone lymphomas: t(11;18)(q21;q21), t(14;18)(q32;q21), t(1;14)(p22;q32), and t(3;14)(p14.1;q32). The most common translocation, t(11;18)(q21;q21), is found in 30% of cases, but its incidence varies with disease site: it is more common in cases involving the stomach (and lung), but rare in other sites.39,40 The t(11;18)(q21;q21) translocation results in the reciprocal fusion of the API-2 and MALT-1 genes. API-2 is an apoptosis inhibitor, and MALT-1 is involved in nuclear factor κB (NFκB) activation. MALT lymphomas with this translocation do not respond as well to antibiotic therapy aimed at eradicating Hp infection similar to lymphomas without this infection.23 However, these lymphomas are also less likely to have other chromosomal translocations or transform to more aggressive large cell lymphomas.39,41 The t(14;18)(q32;q21) variant results in the translocation of the MALT-1 gene on chromosome 18q21 to the immunoglobulin gene heavy chain enhancer region, leading to its overexpression, thus differing from the t(14;18) translocation of FL, which involves the bcl-2 gene. The t(14;18)(q32:q21) translocation occurs in about 20% of MALT lymphomas overall, although the incidence varies according to the disease site; it is rare in the GI tract but more common in lymphomas occurring in the salivary glands and ocular adnexa.39

CHAPTER 32  Gastrointestinal Lymphomas

Approximately 5% of gastric MALT lymphomas have a t(1;14) (p22;q32) translocation.42 In this translocation, the bcl-10 gene is brought under the control of the immunoglobulin heavy-chain gene enhancer, deregulating its expression. This translocation has been detected only in patients with MALT lymphomas, but those with it often have concurrent trisomies of chromosomes 3, 12, and 18. It is more commonly found in advanced-stage cases, which are less likely to respond to Hp eradication. Finally, the t(3;14)(p14.1;q32) translocation results in the juxtaposition of the gene for the transcription factor FOXP1 on 3p14.1, next to the immunoglobulin gene heavy chain enhancer region, leading to deregulation of FOXP1,43 that is necessary for B-cell development.44  Common Molecular Pathways From MucosaAssociated Lymphoid Tissue Lymphoma Chromosomal Translocations. The first 3 translocations listed earlier all activate nuclear factorκB (NF-κB), a transcription factor that increases cell activation, proliferation, and survival (see Chapters 1 and 2).45,46 In unstimulated B and T lymphocytes, NF-κB is sequestered in the cytoplasm because it is bound to IκB, an inhibitory protein. Phosphorylation of IκB targets it for ubiquitination and degradation, thus releasing NF-κB, which then translocates to the nucleus to function as a transcription factor. The pathways through which IκB is phosphorylated are tightly regulated and involve BCL-10 and MALT-1. Excessive BCL-10 or MALT-1 activity occurring as a consequence of t(11;18), t(14;18), or t(1;14) leads to constitutive NF-κB activation.39  Model for the Pathogenesis of Gastric MucosaAssociated Lymphoid Tissue Lymphoma. A model for the pathogenesis of gastric MALT lymphoma suggests that the evolution of the disease is a multistage process, comprising the sequential development of Hp gastritis, low-grade B cell lymphoma, and then high-grade B cell lymphoma.42 This model is supported by gastric biopsies obtained from patients with chronic gastritis taken years before the onset of lymphoma showing B-lymphocytic clones that later gave rise to a clinically evident lymphoma. In this model, Hp infection elicits an immune response in which T and B cells are recruited to the gastric mucosa, where MALT is then formed. Hp– specific T cells provide growth help to abnormal B cell clones. The abnormal B cells may not be Hp–specific and may even be autoreactive. However, their continued proliferation, initially, depends on T cell help. The pivotal role of Hp–reactive T cells in driving B cell proliferation may explain why tumor cells tend to remain localized and why the tumor regresses after eradication of Hp. However, continued B cell proliferation eventually leads to accumulation of additional genetic abnormalities, resulting in autonomous growth and more aggressive clinical behavior. Because only a small percentage of Hp–infected individuals develops lymphoma, additional currently unknown environmental, microbial, or genetic factors must play a contributory role. Genetic polymorphisms affecting genes such as IL1RN and GSTT1 involved in inflammatory responses and anti-oxidative capacity may be partly responsible for the genetic background for MALT lymphomagenesis.47 Hp strains expressing certain proteins such as CagA and oxidative damage have been suggested to play a role in the development of gastric lymphoma.48 

Pathology Gross Appearance and Location. Low-grade gastric MALT lymphomas may present as a single lesion or as multiple lesions. Unifocal disease usually presents as ulcerated, protruding, or infiltrating masses, but may also manifest as erosions or simply erythema. They are most commonly located in the antrum. 

445

Histology The key histologic feature of low-grade MALT lymphoma is the presence of “lymphoepithelial lesions” (Fig. 32.2).18,49 These lesions are defined as the unequivocal invasion and partial destruction of gastric glands or crypts by tumor cell aggregates. It should be noted, however, that these lesions can sometimes be seen in cases of florid chronic gastritis. Tumor cells are small to medium-sized lymphocytes, with irregularly shaped nuclei and moderately abundant cytoplasm. The morphology of these cells can vary from small lymphoplasmacytoid cells to monocytoid cells that have abundant pale cytoplasm and welldefined borders.50 Scattered larger cells or transformed lymphoblasts may also be seen. The lymphoma cells infiltrate the lamina propria diffusely and grow around reactive follicles; the germinal centers may be invaded, a phenomenon termed follicular colonization. Because there is a continuous spectrum from the transition of gastritis to lymphoma, diagnosis of borderline cases can be difficult. Various parameters may assist in the distinction, such as the prominence of lymphoepithelial lesions, degree of cytologic atypia, and presence of plasma cells with Dutcher bodies (periodic acid–Schiff –positive intranuclear pseudoinclusions). The presence of large cells can add further complexity to the diagnosis.16 The low-grade MALT lymphoma may have scattered large cells, but the tumor is composed predominantly of small cells. At the other end of the spectrum, gastric lymphomas that contain only large cells or only small areas of small cell MALT-like lymphoma should be classified as DLBCLs (see later).5 In between the ends of this spectrum are low-grade lymphomas in the process of evolving into more aggressive lymphoma, with increasing numbers of large cells being observed with ­transformation.  Immunophenotype Gastric MALT lymphoma cells have the typical immunophenotype of marginal zone B cells. They express pan-B antigens (CD19, CD20, and CD79a) and they lack expression of CD5, CD10, CD23, and cyclin D1.2 Further immunostaining by experienced pathologists can aid in identifying lymphoepithelial lesions (see Fig. 32.2) and in distinguishing follicular colonization from FL (a rare occurrence in the stomach; see later). 

Fig. 32.2  Photomicrograph showing a “lymphoepithelial lesion” characteristic of gastric mucosa–associated lymphoid tissue lymphoma. Cytokeratin stain demonstrates invasion and destruction of some gastric glands by a monomorphic population of lymphocytes. Note for comparison the uninvolved normal glands in the bottom center of the photograph. Special stains (not shown) demonstrated Hp. (Courtesy Dr. Edward Lee, Washington, DC.)

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Molecular Tests of Monoclonality Southern blotting or PCR assay of immunoglobulin heavy chain rearrangement can assist in the documentation of monoclonality. It should be noted that B cell monoclonality may be detected in Hp–associated gastritis (see Chapter 52). Although monoclonality may predict for later development of lymphoma, monoclonality alone does not allow a diagnosis of lymphoma; thus, molecular tests should always be considered in the context of histologic findings. 

Clinical features Symptoms, Signs, and Laboratory Tests The most common symptoms are dyspepsia and epigastric pain. Other less common symptoms include anorexia, weight loss, nausea and/or vomiting, and early satiety.42 Gastric bleeding and B symptoms (fevers, night sweats, weight loss) are rare. Serum levels of LDH and β2-microglobulin are usually normal.51  Diagnosis and Staging Patients are evaluated by EGD. PPI therapy should ideally be withheld for at least 2 weeks prior to endoscopy to avoid a falsenegative result for Hp. Endoscopic findings include erythema, erosions, and/or ulcers. Diffuse superficial infiltration is typical for MALT lymphoma, whereas masses are more commonly seen in DLBCL (Fig. 32.3), an aggressive NHL. The most common site of involvement in the stomach is the antrum, but biopsies should be taken from all abnormal areas and randomly from each area of the stomach, as well as the duodenum and gastroesophageal junction, because disease is often multifocal. Because some lymphomas infiltrate the submucosa without involving the mucosal membrane, biopsies need to be sufficiently deep and large for histopathologic and immunohistochemical analyses. Hp infection should be established by histologic studies, breath test, or fecal antigen testing (see Chapter 52).52 EUS can determine the depth of infiltration and assess for the presence of enlarged perigastric lymph nodes.10 Additional staging consists of upper airway examination, CT of the chest, abdomen, and pelvis, bone marrow aspiration and biopsy, and measurement of the serum LDH level.

Fig. 32.3  Endoscopic appearance of diffuse large B cell lymphoma of the stomach with multiple umbilicated lesions adjacent to the gastroesophageal junction. One large ulceration is seen just beyond the squamocolumnar junction.

PET is not usually helpful in gastric MALT lymphoma because of low uptake of fluorodeoxyglucose (FDG).53,54  Staging System and Prognostic Assessment In 1994, an international workshop on the staging of GI tract lymphomas proposed the Lugano staging system,55 a modification of the Blackledge system. The Paris staging system (see Table 32.1) is a modification of the TNM system and incorporates the depth of infiltration as well as lymph node involvement based on EUS.56 Approximately 75% of gastric MALT lymphomas are confined to the stomach (stage I) at diagnosis42 and behave in a clinically indolent fashion; thus, prognosis is good for most patients, with overall survival rates of 80% to 95% at 5 years. Prognosis is poor in the rare patient with more advanced disease. Additional features associated with a worse prognosis are deep infiltration of the stomach wall, which is associated with a higher likelihood of regional lymph node involvement,57 and a high percentage of large cells on histologic evaluation. A MALT lymphoma specific prognostic index (MALT-IPI) has been developed and validated with these 3 key parameters: age ≥70 years, stage III or IV disease and an elevated LDH serum level. The 5-year event free survival rates in the low-, intermediate-, and high-risk groups per the MALT-IPI in the studied patient cohort were 70%, 56%, and 29%, respectively. This easily reproducible tool retained utility in both gastric and nongastric MALT-lymphomas and in different treatment strategies used in the study group.58 

Treatment Large, randomized clinical trials have not been performed in MALT lymphoma because of the rarity of the disorder. Therefore, treatment recommendations are based on case series and expert opinion. Wotherspoon and colleagues24 first reported that gastric MALT lymphoma could completely regress by endoscopic, histologic, and molecular criteria after eradication of Hp. Numerous studies have confirmed these observations,59-62 and antibiotics aimed at eradicating Hp (see Chapter 52) have become the mainstay of therapy for low-grade gastric MALT lymphoma. Even patients with advanced stages of disease can regress with eradication of Hp. However, it is important to recognize that the current literature in this field is less than optimal in several respects. Older studies are limited by insufficient staging procedures and outdated classification systems. Also, none of the reports is a controlled or randomized trial, and long follow-up is lacking. Nevertheless, the current literature is sufficient to suggest that early-stage disease is best managed with a trial of Hp-directed antibiotics (Chapter 52), reserving more toxic therapies such as radiation, chemotherapy, or surgery for cases without concomitant Hp infection or for those that do not respond to antibiotics, keeping in mind that it may take several months before remission is achieved. Table 32.2 indicates treatment options by stage using the Lugano staging system. Stage I Disease Most patients fall into this category and can be treated with antibiotic therapy aimed at eradication of Hp. Any of the treatment regimens discussed in Chapter 52 may be used. Follow-up endoscopy with multiple biopsies should be done 3 to 6 months after the completion of therapy to document clearance of infection and to assess lymphoma regression.57 Regression of lymphoma, but not necessarily complete regression, is usually evident at this initial posttreatment examination. Patients with persistence of infection should be treated with a second-line antibiotic regimen (see Chapter 52).63 Histopathology at this initial posttreatment examination can predict ultimate response, with biopsies showing only small foci of lymphoma being predictive

CHAPTER 32  Gastrointestinal Lymphomas

of subsequent complete regression and biopsies showing diffuse persistent disease predicting a low likelihood of subsequent complete regression. The Wotherspoon index was initially proposed (1993) as a histologic tool to evaluate therapy response, but its utility has been more for initial diagnosis. The Groupe d’Etude des Lymphomas de l’Adulte posttreatment histologic evaluation system (2003)64 is an effective, reproducible criteria to monitor therapeutic courses of gastric lymphomas (Table 32.3). Patients are then followed with endoscopy approximately every 6 months for 2 years and then yearly. Overall, approximately 75% of patients with stage I disease confined to the mucosa and submucosa achieve complete remission.30 The median time to remission is 5 months, with remission usually occurring within 12 months. However, time to remission has been reported to be as long as 45 months.23,65 Of patients in clinical remission, a majority will still have tumor clones detected by PCR.59 With continued follow-up of these patients, the malignant clone decreases; current studies have suggested that a positive PCR at histologic remission does not predict subsequent relapse, but longer follow-up of this issue is necessary. Approximately 90% of patients who had a complete clinical remission to Hp eradication remain in remission,30 but late relapses can occur. Relapse may occur in association with Hp reinfection and can be cured by eradicating the organism again. In the absence of Hp reinfection, relapse is frequently transient.66 A randomized trial of patients who responded to Hp treatment did not show a benefit with chlorambucil when compared to observation.67 Approximately 25% of patients do not respond to Hp eradication.68 Lack of response is more common in patients with the TABLE 32.2  Treatment of Gastric Marginal Zone B Cell Lymphoma of MALT Type* Lugano Stage

Treatment†‡

I, with disease limited to mucosa and submucosa

Antibiotics alone

II, with involvement of muscularis propria or serosa

Best treatment unknown currently. Radiation or chemotherapy is probably a better option than surgery (see text)

IV, with involvement beyond stomach wall

Chemotherapy for symptomatic disease. Local management with radiation or surgery may be indicated in selected cases

  

*According to Lugano staging system. with Hp infection should be treated with antibiotics to clear the infection, regardless of stage (see Chapter 52). ‡Patients with a high percentage of large cells and disease limited to the mucosa may respond to antibiotics alone, although further study of this issue is necessary. Patients with a high percentage of large cells and more advanced-stage disease should be treated as in Table 32.4 for diffuse large B cell lymphoma. MALT, Mucosa-associated lymphoid tissue.

†Patients

  

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t(11;18)(q21;q21) translocation; in one study, 67% of nonresponders harbored this abnormality, whereas only 4% of responders did.69,70 Lack of response to antibiotic therapy used in Hp infection is also seen in Hp-negative gastric MALT lymphomas71 and in patients with lymph node involvement at diagnosis.57 The optimal management of disease unresponsive to Hp eradication is not certain. Options include surgical resection, chemotherapy, and radiation. These options are discussed in the section on treatment of stage IIE disease (see later). The management of patients with localized disease but a significant percentage of large cells is also uncertain. More recent studies have documented remission after Hp eradication, in contrast to earlier studies. For example, in one study of 34 patients with high-grade histology, 18 had disease regression with Hp eradication and were free of lymphoma after a median follow-up of 7.7 years.72 If this approach is taken, the patient should be followed closely and, if the response is suboptimal, treated with one of the approaches discussed in the following section. As mentioned, occasional cases of gastric MALT lymphoma are Hp–negative and these patients are much less likely to respond to antibiotic treatment. However, anti-Hp treatment should still be attempted because of possible false-negative results for Hp or in the event that another helicobacter, H. heilmannii, caused the lymphoma.57 Locally Advanced Disease: Stage I with Involvement of Muscularis or Serosa or Poor Response to Hp Eradication (stage IIE). Patients with more advanced-stage disease who are Hp–positive should also receive antibiotic therapy, but antibiotic therapy alone is usually not sufficient to eradicate the lymphoma. There is currently no consensus regarding the optimal management of this group of patients. Total gastrectomy can cure more than 80% of patients with stage IIE disease but diminishes patients’ quality of life and has not been shown to achieve superior results when compared with more conservative approaches.73 Involved field radiation therapy (30 to 40 Gy delivered in 15 to 20 fractions to the stomach and peri-gastric nodes) produces excellent results with a complete remission rate of 90% to 100% and a 5-year disease-free survival of approximately 80%.74,75 Radiation therapy is usually well tolerated and preserves gastric function. Thus, it has become the preferred therapy for patients with advancedstage disease, those who are negative for Hp, and those with persistent disease despite Hp treatment.76 Other treatment options in this group include chemotherapy, immunotherapy, combined chemo-immunotherapy or newer novel, target-specific chemotherapeutics such as ibrutinib. Older data suggests that singleagent oral chemotherapy drugs such as cyclophosphamide23 or chlorambucil have activity, as does treatment with purine analogs such as cladribine (2 CdA), which may be more effective in patients with t(11;18)(q21;q21).77 Chemoimmunotherapy with rituximab, a monoclonal antibody against CD20, in combination with chlorambucil,78,79 fludarabine,80 cladribine,81 and bendamustine,42 an approach similar to treatment of other low grade B-NHL, has shown response rates of 80% to 100% with acceptable toxicity. 

TABLE 32.3  Histological Evaluation System Proposed to Evaluate MALT Gastric Lymphomas Following Antibiotic Therapy (As Proposed by the Groupe d’Etude des Lymphomas de l’Adulte) Treatment Outcome

Definition

Histological Characteristics

CR

Complete histological remission

Normal or empty lamina propria and/or fibrosis with absent or sparse plasmacytes and lymphoid cells in the lamina propria without lymphoepithelial lesions

pMRD

Probable minimal residual disease

Empty lamina propria and/or fibrosis with disease aggregates or lymphocyte nodules in the lamina propria, in the muscularis mucosae, and/or in the submucosa

rRD

Residual disease in regression

Lamina propria focally empty and/or fibrosis; dense, diffuse, or nodular-infiltrated lymphoid, which extends around the glands in the lamina propria. Focal or absent lymphoepithelial lesions

NC

No change

Lymphocytic infiltration dense, diffuse, or nodular, +/− lymphoepithelial lesions

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Stage II or IV Disease Low-grade gastric MALT lymphoma that has spread to distant lymph nodes or extranodal sites should be treated as advanced lowgrade B-cell NHL. Various regimens are used, most incorporating rituximab.82,83 Such disease is usually not considered curable, but is generally indolent, with transient responses to chemotherapy.84 Asymptomatic patients may be followed ­expectantly. 

Diffuse Large B Cell Lymphoma of the Stomach Epidemiology Approximately 50% of gastric lymphomas are DLBCLs. The incidence may be higher in developing than in developed nations, but clinical features appear to be similar. The median age is approximately 60 years, with a slight male predominance.17 

Cause and Pathogenesis The pathogenesis of gastric DLBCL is poorly understood. Many large cell tumors have components of low-grade MALT tissue and are assumed to have evolved through transformation of lowgrade lesions. Frequently, these bear identical rearranged immunoglobulin genes. According to the WHO classification, this is now referred to as “diffuse large B cell lymphoma with areas of marginal zone–MALT-type lymphoma.”5 However, other DLBCLs have no evidence of associated low-grade MALT tissue. It is unclear whether de novo gastric DLBCL has a worse prognosis than DLBCL with areas of marginal zone–MALT-type lymphoma.85 If the large cell lesions commonly arise from progression of low-grade lesions, then conceivably Hp may have a role in the initial pathogenesis. One study has suggested that Hp infection is more common in patients whose large cell lesions had a lowgrade component.86 Also, observation of a response of early-stage large cell lymphomas to Hp eradication has suggested a role for the organism, at least in some cases.72,87 As outlined earlier in the discussion of tentative models for Hp–induced lymphoma, large cell transformation resulting from genetic events, including loss of p53 and p16, may lead to tumor cells losing their dependence on Hp for growth.2 A high incidence of somatic mutations in rearranged immunoglobulin heavy-chain variable genes in one study of DLBCLs of the stomach has implicated antigen selection in the genesis of the lymphoma.

translocation involving myc, the lymphoma is referred to as a “double hit” DLBCL, or based on WHO 2016 classification, High Grade B cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements.5 MYC translocation along with rearrangements in either BCL2 and/or BCL6 are increasingly being recognized as adverse prognostic features and most experts modify treatments based on it, using more intense chemo-immunotherapy regimens. Similarly, increased expression of myc and bcl2 by IHC staining is associated with relatively poor outcomes; although colloquially referred to as “double expressor,” this category is not formally recognized by WHO yet and outside of the setting of a clinical trial, most experts continue to use standard R-CHOP for it. It is worth discussing the evolution in terminology regarding DLBCLs of the stomach. Many pathologists have referred to lymphomas arising in MALT with high-grade features (with or without a component of low-grade disease) as high-grade gastric MALT lymphomas. However, those involved in the development of the WHO classification were concerned that many clinicians had come to regard the term gastric MALT lymphoma as synonymous with a lesion that responds to antibiotics. This is usually not the case with high-grade lesions arising in MALT. Therefore, those involved in formulating the WHO classification5 agreed to use the term extranodal marginal zone B cell lymphoma of MALT type for low-grade lesions, and the term diffuse large B cell lymphoma for high-grade lesions, leaving out the term MALT. Lowgrade lesions involving MALT often contain varying proportions of large cells, with a worse prognosis in relation to increased percentage of large cells. However, at this point, a precise grading system for this situation has not been devised and remains a goal of ongoing research. 

Clinical Features Patients present with epigastric pain (70%) or dyspepsia (30%), symptoms similar to those patients with gastric adenocarcinoma.88,91 Large tumors may cause obstruction. Ulcerating lesions may be associated with GI bleeding. B symptoms (fevers, night sweats, weight loss) and elevated serum LDH levels are uncommon. Staging consists of EGD (see Fig. 32.3), upper airway examination, CT of the chest, abdomen, and pelvis or PET-CT scan, bone marrow aspiration and biopsy, and measurement of the

Pathology DLBCL may appear grossly as large ulcers, protruded tumors (see Fig. 32.3), or multiple shallow ulcers.88,89 The most common sites of involvement are the body and antrum of the stomach. Tumors with a low-grade component are more likely to be multifocal than tumors with no low-grade component. Large cell lymphomas typically invade the muscularis propria layer or even more deeply. Microscopic examination reveals compact clusters, confluent aggregates, or sheets of large cells that resemble immunoblasts or centroblasts, most often with a mixture of the 2 (Fig. 32.4).2 From 25% to 40% of cases show evidence of derivation from MALT, including dense infiltration of centrocyte-like cells in the lamina propria and typical lymphoepithelial lesions.86 Immunophenotypic analysis shows expression of one or more B cell antigens (CD19, CD20, CD22, CD79a) and CD45. Lesions with evidence of low-grade MALT tissue do not express CD10, consistent with their having evolved from the CD10negative marginal zone low-grade lesions. Lesions without evidence of MALT may or may not express CD10. Genetic analysis reveals monoclonal immunoglobulin gene rearrangements. BCL6 is frequently mutated or rearranged90; if this is seen along with

Fig. 32.4  Photomicrograph showing diffuse large B cell lymphoma in stomach. There is a dense infiltrate of medium-sized to large Blymphoid cells within gastric mucosa. (Courtesy Dr. Weina Chen, UT Southwestern Medical Center, Dallas, TX.)

CHAPTER 32  Gastrointestinal Lymphomas

serum LDH level. In addition, EUS plays an important role in assessing depth of stomach wall involvement. Hp infection should be assessed; it is detected in 35% of patients with DLBCL of the stomach and is more common in those with concomitant gastric MALT.88 Most patients have stage I or II disease by the Ann Arbor Staging System.92 However, as other staging systems have been developed, the use of various systems has made it difficult to compare results of different series. 

Treatment The optimal management of DLBCL of the stomach is controversial, but the current consensus recommends chemo-immunotherapy with or without radiotherapy as a replacement for surgery (Table 32.4).88 Traditionally, localized disease was approached with surgery alone or surgery followed by radiation and/or chemotherapy for patients with poor prognostic features.93 This approach had the advantage of providing diagnostic and staging information and avoided the risk of gastric perforation or bleeding that was believed to result from treatment with chemotherapy or radiation. Approximately 70% of patients with stage I disease are disease-free 5 years after surgery.94 However, several investigators have questioned the role of surgery in the management of localized gastric DLBCL. They noted that with the availability of endoscopy, surgery was no longer necessary for diagnosis and, with the availability of CT and EUS, surgery was no longer necessary for staging. In addition, the risk of gastric bleeding or perforation during chemotherapy is lower than 5% and only a few of those who bleed require urgent gastrectomy.95 Surgery, however, carries a 5% to 10% risk of mortality and is associated with significant morbidity. Thus, chemotherapy and radiation were investigated as alternatives to surgery. Retrospective studies have shown similar outcomes in patients treated with surgery alone versus chemotherapy alone.17 A prospective study of patients with DLBCL of the stomach who were randomized to surgery, surgery plus radiotherapy, surgery plus chemotherapy, or chemotherapy alone showed improved complete response rates and overall survival for patients who received surgery plus chemotherapy and chemotherapy alone when compared with those who received surgery alone or surgery plus radiotherapy.96 The German Multicenter Study GIT NHL 01/92 was a prospective nonrandomized study of surgery in conjunction with chemotherapy and radiation versus chemotherapy and radiation alone for primary gastric lymphoma in localized stages. Whether the treatment included surgery was left to the discretion of each participating center. There was no difference in survival rate between those who received surgery followed by chemoradiotherapy and those who received chemoradiotherapy

TABLE 32.4  Treatment of Diffuse Large B Cell Lymphoma of the Stomach* Lugano Stage

Treatment

I

CHOP† × 3-4 cycles + RT‡ + rituximab§

II, II1, II2, IIE

CHOP × 3-4 cycles + RT + rituximab

IV

CHOP × 6-8 cycles + RT + rituximab

  

*According to the Lugano staging system, optimal management of this entity is controversial. However, the developing consensus seems to favor combined chemotherapy and radiation and avoidance of surgery (see text). †Cyclophosphamide, doxorubicin [hydroxydaunorubicin], vincristine [Oncovin], prednisone). ‡RT (radiotherapy); usually, 30-40 Gy in 20-30 fractions. §The suggestion for the addition of rituximab in this setting involves extrapolation of randomized data from nodal diffuse large B cell lymphoma.   

449

alone.97 These results were confirmed in a subsequent, larger, prospective nonrandomized trial, GIT NHL 02/96.98 For patients with advanced-stage nodal DLBCL, the addition of rituximab, a monoclonal antibody against CD20, to CHOP (cyclophosphamide, doxorubicin [hydroxydaunorubicin], vincristine [Oncovin], prednisone) chemotherapy improves overall survival when compared with CHOP alone.99-102 This combination has also been administered to patients with gastric DLBCL and found to be safe and effective.103,104 The necessity of radiation therapy in the management of gastric DLBCL is controversial. A small retrospective study of patients with stage I or II primary gastric high-grade DLBCL treated with chemotherapy with or without radiotherapy has shown decreased relapse rates in patients who received consolidative radiotherapy.95 However, this study included only 21 patients, of whom 3 relapsed, and it is thought that a prospective randomized trial is needed. Thus, standard management of gastric large B cell lymphoma follows standard management of nodal large B cell lymphomas. The treatment of localized (stage I or II) nodal large B cell lymphoma consists of 3 to 6 cycles of combination chemotherapy (typically the CHOP regimen) given with rituximab, with radiation generally given if using abbreviated chemotherapy (3 cycles instead of 6).105,106 Experts are increasingly using a more intense regimen, DA-R-EPOCH (rituximab, etoposide, prednisone, vincristine [Oncovin], cyclophosphamide, doxorubicin [hydroxydaunorubicin]) for patients with double hit DLBCL or high-grade B cell lymphoma with myc/bcl2/bcl6 rearrangement. This regimen is primarily based on retrospective data, which shows increasing numbers of complete remissions achieved with this regimen and patients achieving complete remission having the best chance of long-term disease-free survival. No prospective data comparing the 2 regimens based on “double hit” status of DLBCL is available. DA-R-EPOCH, however, for garden variety DLBCL does not lead to better outcomes and carries a risk of more prominent side effects based on data from a prospective trial (CALGB/ Alliance 50303) presented at American Society of Hematology Annual Meeting in 2016.107 Similarly, increased expression of myc and bcl2 by IHC staining is associated with relatively poor outcomes. Although colloquially referred to as “double expressor,” this category is not formally recognized by WHO as yet and, outside of the setting of a clinical trial, most experts continue to use the standard R-CHOP regimen for it. DLBCL patients with evidence of Hp infection should be treated, as response of large cell lymphoma has been reported after eradication of Hp.108,109 However, these studies must be considered preliminary, and most patients treated with antibiotics alone have had disease limited to the mucosa; most patients with DLBCL of the stomach have more advanced disease, and antibiotics alone are considered inadequate treatment. For patients with relapsed/refractory DLBCL after failing 2 lines of therapy (including anthracycline-based regimen), chimeric-antigen receptor T cell therapy is an emerging treatment option recently approved by the FDA. Although durable remissions are being seen with this treatment, long-term data on treatment outcomes is being discerned.110,111 

Uncommon Gastric Lymphomas B cell lymphomas other than marginal zone or diffuse large B cell may involve the stomach uncommonly (e.g., MCL [1%], FL [0.5% to 2%]). Gastric lymphomas of T cell origin have rarely (1.5 to 4%) been reported.112-114 

SMALL INTESTINAL LYMPHOMAS Small intestinal lymphomas may be divided into B and T cell tumors and account for 20% to 30% of PGILs.115 The B cell

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tumors include immunoproliferative small intestinal disease (IPSID) and various non-IPSID subtypes, including marginal zone B cell lymphoma of MALT, DLBCL, MCL, FL, and Burkitt lymphoma. Relatively few reports have described the various non-IPSID small intestinal lymphomas, and large series have tended to group together all the lymphoma subtypes when cataloguing manifestations and treatment outcomes.116-118 Given the lack of information about these diseases with regard to their behavior in the intestine, it is probably best to consider them in light of the well-described features of their nodal counterparts. Thus, marginal zone and FLs are regarded as indolent processes, incurable but controllable by chemotherapy, and often associated with a relatively long survival. DLBCLs, MCLs, and Burkitt lymphomas are more aggressive processes, which generally require chemotherapy as part of their management. T cell lymphomas of the small intestine are usually enteropathy-type intestinal T cell lymphomas; other forms of T cell lymphoma have been rarely reported. Recent reports have suggested the existence of a rare natural killer (NK) cell or NK-type T cell intestinal ­lymphoma.119-122

Marginal Zone B Cell Lymphoma of Malt Type Lymphoma arising in the small intestine may have the characteristics of marginal zone B cell lymphoma, with the same histologic and immunophenotypic features described earlier for gastric marginal zone B cell lymphoma.121,123 However, an association with Hp infection has not been documented, although rare responses to antibiotics have been reported. Most cases occur in older patients who present with melena. The disease usually presents as a single annular or exophytic tumor,124 which may be present anywhere in the small intestine; disease is usually confined to the intestine or to local nodes. Treatment is generally surgical. Some patients have received chemotherapy, but few data are available regarding regimens and outcome. It should be noted that in nodal marginal zone lymphoma, chemotherapy is usually reserved for patients with symptoms, because the disease is slow-growing and sensitive to chemotherapy, but not curable by it. The 5-year survival rate is approximately 75%. As in gastric marginal zone B cell lymphoma, the small intestinal variety may have varying components of large cell transformation. This feature probably confers a worse prognosis, but data are scanty. 

A

Diffuse Large B Cell Lymphoma DLBCL of the small intestine is similar to its gastric counterpart in histology and clinical behavior. Patients may present with abdominal pain, weight loss, obstruction, abdominal mass, bleeding, and/or perforation. The tumor is usually an exophytic or annular lesion. Histologic findings are similar to those described earlier for gastric DLBCL, with some patients having a lowgrade component and others having only a large-cell component. Approximately half of patients have localized disease, and half have disease spread to regional or distant nodes. Surgery is usually required because of obstruction or perforation,125 and additional therapy includes anthracycline-containing chemotherapy and the anti-CD20 monoclonal antibody, rituximab.126 In addition, radiotherapy is sometimes indicated. Prognosis depends on disease stage and patient factors, such as age and performance status. 

Mantle Cell Lymphoma MCL is a subtype of B cell NHL.127 It is a heterogeneous lymphoma in terms of its clinical behavior, with disease in some patients having an indolent course like a low-grade B-NHL and in others an extremely aggressive course akin to high-grade B cell malignancies. Patients typically present with widespread adenopathy and frequently have bone marrow and extranodal involvement. The GI tract is involved in more than 80% of patients (Fig. 32.5), although not all patients with GI involvement are symptomatic.128 The most common manifestation of GI disease is multiple “lymphomatous polyposis,” in which multiple lymphoid polyps are present in the GI tract.129,130 The most common site of involvement is the ileocecal region, but any other area may be involved from the stomach to the rectum; occasionally patients have involvement of all these regions (Fig. 32.6; see also Fig. 32.5). Involvement of the GI tract may also occur without the appearance of multiple polyps, and the GI tract as the only site of involvement has been reported. When patients have symptoms related to GI involvement, they usually include pain, obstruction, diarrhea, or hematochezia. It should be noted that multiple lymphomatous polyposis can also be seen with other lymphomas, especially marginal zone B cell lymphomas of MALT and FLs. Microscopically, MCL involves the mucosa and submucosa and the malignant cells have the appearance of small

B Fig. 32.5 Endoscopic appearance of mantle cell lymphoma presenting as multiple lymphomatous polyposis in the stomach (A) and in the colon (B).  

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32

A

B Fig. 32.6  Multiple lymphomatous polyposis (mantle cell lymphoma). A, Gross specimen showing numerous small polypoid lesions in the cecum. Additional synchronous and metachronous lesions were present or later developed in the ileum and the duodenum, as well as the rectum and sigmoid colon. B, Low-power photomicrograph of ileum shows multiple discrete sites of mucosal and submucosal involvement by lymphomatous polyposis. (Courtesy Dr. Edward Lee, Washington, DC.)

Fig. 32.7  Photomicrograph showing follicular lymphoma, World Health Organization grade II. Neoplastic lymphoid follicles are evident, involving the wall of the small intestine and effacing the normal architecture (Hematoxylin and eosin, low power). (Courtesy Dr. Imran Shahab and Dr. Pamela Jensen, Dallas, TX.)

atypical lymphocytes, which may surround benign-appearing germinal centers or may efface the lymphoid tissue. The tumor cells express pan-B markers and the T cell marker CD5. The disease is characterized by t(11;14)(q13;q32), a translocation that results in rearrangement and overexpression of the bcl-1 gene encoding the protooncogene cyclin D1.131 Patients with obstructive tumor masses require surgical therapy, but the mainstay of treatment is chemo-immunotherapy. Aggressive presentations of MCL are also usually consolidated with an autologous stem cell transplant in first remission after induction chemotherapy followed by maintenance rituximab.132 Although MCL is initially responsive to chemotherapy, it eventually becomes refractory; median survival is 3 to 5 years. The Bruton tyrosine kinase inhibitor ibrutinib has been approved for use in refractory or relapsed MCL.133,134 

Follicular Lymphoma Follicular B cell lymphomas of the GI tract are rare.135 The most common presentation is as an obstructing lesion in the terminal ileum. As noted, patients with this diagnosis may also present with the gross appearance of multiple lymphomatous polyposis. Microscopically, most FLs are composed of small cleaved lymphocytes, or centrocytes (Fig. 32.7), with a varying admixture of

large cells. The disease is characterized by t(14;18)(q24;q32), a translocation that results in overexpression of the bcl-2 gene.136 Obstructing lesions require surgical management. Chemotherapy and radiation are sometimes indicated for the management of this indolent but incurable disorder. Duodenal-type FL (D-FL) is a newly recognized entity in the 2016 WHO classification update. Unlike other FLs, D-FL is almost always incidentally detected on endoscopy (solitary or multiple nodules, or polypoid lesions, between 1 and 5 mm), diagnosed at a low grade and stage, and stays localized to most commonly the second portion of the duodenum. By gene expression profile and pathogenesis, it appears more closely related to MALT lymphoma than FL. Due to the excellent prognosis (median survival >12 years) associated with this disorder, most experts recommend a “wait and watch” strategy to management.137,138 

Burkitt Lymphoma Burkitt lymphoma is a highly aggressive malignancy that in patients who are HIV-negative presents either as an endemic form, observed in Africa, or a sporadic form.139 In the sporadic form, patients usually present with disease in the abdomen, with involvement of the distal ileum, cecum, and/or mesentery. Burkitt tumor cells are monomorphic, medium-sized cells with round nuclei, multiple nucleoli, and basophilic cytoplasm (Fig. 32.8). The involved lymphoid tissue microscopically has a starry sky appearance caused by numerous benign macrophages that have ingested apoptotic tumor cells.140 The tumor cells express B cell–associated antigens and surface immunoglobulin. Most cases have a translocation of the c-myc gene on chromosome 8, either to the immunoglobulin heavy-chain region on chromosome 14 or to one of the immunoglobulin light-chain regions on chromosomes 2 or 22, resulting in a t(8;14), t(2;8), or t(8;22) translocation.141 Burkitt lymphoma is rapidly fatal without treatment but responds immediately to institution of aggressive chemotherapy. Treatment carries a high risk of tumor lysis syndrome. Cure rates are 50% to 90%, depending on the extent of the disease.142,143 

Immunoproliferative Small Intestinal Disease Epidemiology IPSID (also known as α heavy-chain disease and as Mediterranean lymphoma) is confined to certain regions of the world, especially

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PART IV  Topics Involving Multiple Organs

A

B Fig. 32.8 Burkitt lymphoma. A, Diffuse involvement of the small bowel by Burkitt lymphoma. Note infiltration around native glandular structures. B, High-power view showing brisk mitotic activity and background macrophages. CD20 immunostaining (not shown) was strongly positive within the tumor population. (A, H&E, ×20; B, H&E, ×600.) (Courtesy Dr. Pamela Jensen, Dallas, TX.)  

 

North Africa, Israel, and surrounding Middle Eastern and Mediterranean countries.144 IPSID is seen less often in other areas, including Central and South Africa, India and East Asia, and South and Central America. A diagnosis in North America or Europe should be questioned, unless the patient has previously lived in an endemic area. The disease occurs in individuals with lower socioeconomic status who live in conditions of poor hygiene and sanitation.145 The disease generally occurs in the second or third decade of life, although it has been observed in older individuals. The incidence in males and females is equal. 

Cause and Pathogenesis Several observations suggest that IPSID may be initiated by an infectious agent or agents146: (1) an association of the disease with lower socioeconomic status and poor sanitation; (2) a high prevalence of intestinal bacterial overgrowth and parasitosis; (3) a decrease in incidence when living conditions have improved in endemic areas; and (4) a response of early lesions to antibiotic therapy. In addition, it is known that enteric microbiota stimulate IgA-producing cells, and intestinal biopsies from apparently normal individuals from endemic regions have shown an increase in lamina propria lymphocytes and plasma cells, reminiscent of findings in patients with IPSID. An association with Campylobacter jejuni infection has been demonstrated.147,148 As discussed later, IPSID is associated with the production of an unusual IgA heavy-chain protein, called α heavy chain, which is secreted by plasma cells and is detectable in various body fluids.149,150 The plasma cells, which are the predominant histologic feature in the superficial mucosa, possess surface and cytoplasmic α chain protein. Centrocyte-like cells proliferating deeper in the mucosa have mainly cytoplasmic α chain protein. It is likely that these centrocyte-like cells, stimulated by microbial antigens, differentiate into the plasma cells that secrete the α chain protein characteristic of the disease. Genetic analyses have revealed that cellular proliferations are monoclonal, even in early lesions.151,152 Thus, it can be proposed that in a way somewhat analogous to Hp–associated gastric MALT, lymphocytes in intestinal MALT may be stimulated by infectious agents, in particular C. jejuni,153 and proliferate in response. The lymphocytic response becomes monoclonal and initially depends on the presence of antigen. However, with time, the malignant cells acquire additional genetic changes, causing them to lose their dependence on

antigen persistence. This loss of antigen dependence is associated with the development of more aggressive clinical features. 

Pathology Gross lesions are generally confined to the proximal small intestine, with adenopathy of adjacent mesenteric nodes.154 Although some patients have thickening of mucosal folds only, others have a generalized thickening of the bowel wall, discrete masses, nodules, or polypoid lesions. Although grossly only the proximal bowel wall is involved, histologically the disease is characterized by a dense mucosal and submucosal cellular infiltrate that extends continuously throughout the length of the small intestine. Various pathologic staging systems have been proposed (Table 32.5).154,155 In early-stage disease, the cellular infiltrate is composed of benign-appearing plasma cells or lymphoplasmacytic cells. However, as already noted, various studies assessing immunoglobulin gene rearrangements or light chain restriction have suggested that even the earliest infiltrate is monoclonal. This early infiltrate broadens villi and shortens and separates crypts, but epithelial cells remain intact. A histologic variant, the follicular lymphoid type, has been described in some patients (see Fig. 32.7). This variant features a diffuse involvement of the mucosa, with lymphoid follicle-like structures. As the disease progresses to intermediate and late stages, the villi are further broadened and may become completely effaced, crypts are fewer, and the immunoproliferation extends more deeply. Atypical lymphoid cells infiltrate the benign-appearing plasma cells and lymphoplasmacytic cells. With time, the process evolves into overt lymphoma. Mesenteric lymph nodes are enlarged in early lesions, with preserved architecture, although follicles may be encroached on by a histologically benign-appearing lymphocytic or plasmacytic infiltrate. As the disease progresses, the lymph node may acquire a more dysplastic appearance. 

Clinical Features Patients usually present with diarrhea, colicky abdominal pain, anorexia, and significant weight loss, with a duration of symptoms from months to years. The diarrhea initially may be intermittent but becomes voluminous and foul-smelling as malabsorption develops. About half of patients have fever. Physical examination reveals evidence of malnutrition, digital clubbing, and peripheral edema. Late physical manifestations are ascites,

CHAPTER 32  Gastrointestinal Lymphomas

453

TABLE 32.5  Pathologic Staging Systems for Immunoproliferative Small Intestinal Disease

32

World Health Organization (a) Diffuse, dense, compact, and apparently benign lymphoproliferative mucosal infiltration (i) pure plasmacytic (ii) mixed lymphoplasmacytic (b) As in (a), plus circumscribed “immunoblastic” lymphoma, in either the intestine and/or mesenteric lymph nodes (c) Diffuse “immunoblastic” lymphoma with or without demonstrable, apparently benign, lymphoplasmacytic infiltration Salem et al.146 Stage 0: Benign-appearing lymphoplasmacytic mucosal infiltrate (LPI), no evidence of malignancy Stage I: LPI and malignant lymphoma in either intestine (Ii) or mesenteric lymph nodes (In), but not both Stage II: LPI and malignant lymphoma in both intestine and mesenteric lymph nodes Stage III: Involvement of retroperitoneal and/or extra-abdominal lymph nodes Stage IV: Involvement of noncontiguous nonlymphatic tissues Unknown or inadequate staging Galian et al.147

Stage

Mesenteric Other Abdominal and Lymph Nodes: Retroperitoneal Lymph Site IIA Nodes: Site IIB

Small intestine: Site I

Other Lymph Nodes: Site III

Other Sites: Site IV

A

Mature* plasmacytic infiltration of lamina with no or limited disorganization of general lymph node architecture; inconstant and variable villus atrophy

Infiltrate in these sites cytologically like that in site I

B

Atypical plasmacytic or lymphoplasmacytic infiltrate, with presence of more or less atypical immunoblast-like cells, extending at least to the submucosa; subtotal or total villus atrophy

Atypical plasmacytic or lymphoplasmacytic infiltrate, with presence of more or less atypical immunoblast-like cells; total or subtotal obliteration of nodal architecture

Infiltrate cytologically similar to that in site I

C

Lymphomatous proliferation invading the whole depth of intestinal wall

Lymphomatous proliferation with total obliteration of nodal architecture†

Lymphomatous proliferation similar to that in site I

propria†,

  

*Rare cells may show an immature pattern. and superficial extensions to submucosa may be observed. Modified from Fine KD, Stone MJ. Alpha-heavy chain disease, Mediterranean lymphoma, and immunoproliferative small intestinal disease: a review of clinicopathological features, pathogenesis, and differential diagnosis. Am J Gastroenterol 1999; 94:1139–52.

†Limited

  

hepatosplenomegaly, an abdominal mass, and peripheral lymphadenopathy. Endoscopy may reveal thickened mucosal folds, nodules, ulcers, or evidence of submucosal infiltration, rendering the intestine immobile, tender, and indistensible. Small bowel barium radiographs show diffuse dilation of the duodenum, jejunum, and proximal ileum, with thickened mucosal folds. Patients are frequently anemic because of vitamin deficiencies, and the erythrocyte sedimentation rate is elevated in one third of cases. The circulating lymphocyte count is low, and measures of humoral and cellular immunity are impaired. Stool examination frequently reveals Giardia lamblia infestation. As noted, C. jejuni has been implicated in a high percentage of patients by PCR assay, DNA sequencing, fluorescence in situ hybridization, and immunohistochemical studies on intestinal biopsy specimens.153 Serum IgG and IgM levels may be high or low; IgA levels are usually low or undetectable. The characteristic and unique laboratory abnormality is the presence of the α chain protein.156 This 32- to 34-kd protein is a free α1 heavy chain with an internal deletion of the variable (VH) and CH1 regions. It is devoid of light chains and thus corresponds to the Fc portion of the α1 subunit of IgA. The α chain protein amino terminal contains sequences that are not homologous to any known immunoglobulin sequence. These changes are often the result of insertions or deletions, usually involving the VH-JH and CH2 regions,147 but the source of inserted genetic material is unknown. The α chain production migrates as a broad band within the α2 and β regions on serum protein electrophoresis. In addition to electrophoresis, the protein can be detected by immunoelectrophoresis or immunoselection (the most sensitive and specific methods)147 in serum, urine, saliva, or intestinal secretions.

Detection of α chain protein from these sources is more likely in patients with early disease than in patients with more advanced disease, but, regardless of stage, α chain protein can be detected in tissue sections in most cases of IPSID by immunofluorescence or immunoperoxidase staining of plasma or lymphoma cells.156 It has been postulated that chronic antigenic stimulation of the intestinal IgA secretory apparatus results in the expansion of several plasma cell clones. Eventually, a structural mutation occurs in a particular clone, resulting in an internal deletion of part of the α heavy chain. This leads to an inability to make light chains and results in secretion of α chain protein rather than intact IgA.144,147 

Diagnosis and Staging Because the more malignant-appearing histology may be present only in deeper layers of the intestine, endoscopic biopsy alone is often considered an inadequate evaluation; staging laparotomy is therefore strongly recommended by some authors to allow full-thickness intestinal biopsy and biopsy of mesenteric lymph nodes.157 However, some investigators do not routinely perform laparoscopy or laparotomy; instead, upper and lower GI endoscopy, small bowel series, bone marrow biopsies, and fine-needle aspiration of enlarged lymph nodes are performed.158 One of the staging systems may then be applied (see Table 32.5). More advanced disease, poor performance status, and comorbid illnesses portend a worse prognosis. 

Treatment Because of the relative rarity of this lymphoma, no large trials investigating therapy have been carried out.158,159 Patients often

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PART IV  Topics Involving Multiple Organs

require intensive nutritional support.160 Patients with early disease (e.g., Salem stage 0 disease; see Table 32.5) are generally treated with antibiotics for 6 months or more. The 2 most commonly used regimens are tetracycline alone and a combination of metronidazole and ampicillin. Response rates have ranged from 33% to 71%161; in one study, the complete response rate was 71%, with a disease-free survival of 43% at 5 years.158 In patients who do not significantly improve by 6 months or who do not achieve complete remission by 12 months, or who have advanced disease at presentation, chemotherapy should be given. Most investigators recommend anthracycline-containing regimens such as CHOP.162,163 For example, one investigator has reported a complete response rate of 67% and a survival of 58% at 3.5 years in patients treated with antibiotics, total parenteral nutrition, and anthracycline-based combination chemotherapy.163 However, good results have been reported with nonanthracycline-containing regimens as well; in one report, 56% of patients with advanced disease were free of disease at 5 years.158 Finally, because total abdominal radiotherapy has been used in only a small number of patients, it is difficult to assess its proper role.164 

Enteropathy-Associated T Cell Lymphoma Enteropathy-associated T cell lymphoma (EATL) occurs as a complication of celiac disease (see Chapter 107).165 Malignant transformation of intraepithelial T cells leads to an aggressive malignancy, causing most patients to die within a few months of diagnosis.166,167 Treatment of celiac disease with a gluten-free diet may decrease the risk of this malignancy.168

Epidemiology EATL is a rare malignancy with an incidence of only 0.016 per 100,000 population, though the overall age-adjusted incidence is increasing.169 Celiac disease has a prevalence of 0.5% to 1% in the US and Europe170,171 and is more common in whites compared with African Americans and Asians. In patients with symptomatic celiac disease, the most common cause of death was NHL.172 The diagnosis of lymphoma is usually made concomitantly with or shortly after the diagnosis of celiac disease, although the 2 conditions are commonly diagnosed simultaneously, especially in patients who have a long history of malabsorption. Adherence to a strict gluten-free diet appears to reduce mortality.173 The median age at diagnosis of EATL is 60 years and the incidence in men and women is equal.174 

Cause and Pathogenesis EATL occurs in patients with adult celiac disease.175 As discussed in Chapter 107, celiac disease is characterized by a hereditary sensitivity to gluten.176 Gluten peptides are presented by celiac disease–specific HLA-DQ2 and HLA-DQ8 positive antigenpresenting cells and thus elicit an immune response in which gluten-specific intraepithelial lymphocytes damage intestinal epithelium. Intraepithelial T cells in celiac disease have a normal immunophenotype (CD3+/CD8+) and are polyclonal.177,178 Malignant transformation of these T cells results in a monoclonal population of intraepithelial T cells that have an abnormal phenotype.179-182 Monoclonal populations of intraepithelial T cells in celiac mucosa may result in any one of several interrelated processes.182,183 The first condition is refractory celiac disease, a condition in which patients lose responsiveness to a gluten-free diet.184 The second condition, ulcerative jejunitis, is characterized by inflammatory jejunal ulcers and unresponsiveness to a gluten-free diet.185 The third condition is EATL, an aggressive malignancy of the small intestine.180,181 In patients with any of these 3 conditions, uninvolved mucosa adjacent to the lesions can contain monoclonal T cells containing the same rearranged T

Fig. 32.9  Photomicrograph of enteropathy-type intestinal T cell lymphoma in a patient with celiac disease. Mesenteric fat of the small bowel wall is involved with a monomorphic population of small-tointermediate-sized irregular T lymphocytes. Cells were positive for CD2, CD3, and CD7, and negative for CD5. T cell gene rearrangement studies were positive (i.e., showed a clonal band indicating a clonal T cell process). (Courtesy Dr. Edward Lee, Washington, DC.)

cell receptor genes.186 In addition, patients with ulcerative jejunitis can subsequently develop EATL, in which the same clone is isolated in the jejunitis and the subsequent lymphoma. Thus, these 3 conditions have come to be considered to represent a spectrum of disorders mediated by monoclonal intraepithelial T cells. Comparative genomic hybridization studies have shown recurrent chromosomal gains in EATL at chromosomes 9q, 7q, 5q, and 1q and recurrent losses at 8p, 13q, and 9p. A gain at 9q is the most common, seen in 58% of cases examined.187 Another study has shown that loss of heterozygosity at 9q21 is a frequent finding.188 In addition, one study has suggested that gain of chromosome 1q may be an early event in lymphomagenesis.189 

Pathology Tumors typically occur in the jejunum but may be seen in other sites of the small intestine. Lymphoma may occur in single or multiple sites. Grossly, the lymphomas commonly appear as ulcerating lesions, with circumferential involvement of the small bowel. Lesions may also appear as nodules, plaques, or strictures, but large masses are uncommon. Mesenteric lymph nodes are often enlarged, either because of tumor involvement or of edema and reactive changes. Distant sites, especially the bone marrow or the liver, are sometimes involved. Histologically, the lymphoma is generally characterized by large, highly pleomorphic cells with numerous, bizarre, multinucleated forms, with an inflammatory background. A minority of patients (10% to 20%) may have monomorphic medium-sized cells (Fig. 32.9). This was previously termed type II EATL and is currently called monomorphic epitheliotropic intestinal T cell lymphoma (MEITL),5 and may occur in the absence of celiac disease. MEITL has an increased incidence in Asian and Hispanic populations. Uninvolved mucosa usually has the typical appearance of celiac disease, with villous atrophy, crypt hyperplasia, plasmacytosis in the lamina propria, and an increase in intraepithelial lymphocytes (see Chapter 107). However, the enteropathy may be subtle in some cases, with only an increase in the intraepithelial lymphocytes. According to 62 patients identified to have EATL in the International Peripheral T cell Lymphoma Project, immunophenotyping typically shows that the malignant cells are CD3+,

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CD2+, CD5−, CD4−, CD8+, CD30+, CD103+, and contain cytotoxic granules recognized by the antibody TIA-1.190 Monoclonal T cell populations can also be detected in mucosa not involved by lymphoma. Whole genome analysis and HLA genotyping has identified 2 subtypes of EATL.191 Type I is CD56 negative, pathogenically linked to celiac disease, and shares an HLADQB1 genotype pattern with refractory celiac disease. MEITL (previously type II EATL) is CD56+, MYC+, and shows an HLA-DQB1 genotype pattern like that of the normal Caucasian ­population. 

anti-CD30 monoclonal antibody conjugated to monomethyl auristatin E, an antimitotic agent.197 Conceivably, earlier diagnosis may improve the outcome. The diagnosis should be considered for patients who present in midlife with celiac disease and for those who have clinical deterioration after having been stable on a gluten-free diet. 

Clinical Features

Extranodal NK T cell lymphoma, nasal type, is a distinct pathologic entity in the WHO classification of hematolymphoid malignancies.5 Very rare cases of intestinal NK cell lymphomas have been described.198 Most of the cases reported have not involved patients with celiac sprue or sensitivity to gluten.120,121 Optimal management of this very rare disorder has not been determined. Most data come from East Asian countries and traditional regimens such as CHOP and CHOEP have high treatment failure rates. Aggressive regimens such as DeVIC (dexamethasone, etoposide, ifosfamide, carboplatin) and SMILE (dexamethasone, methotrexate, ifosfamide, l-asparaginase, etoposide), with and without radiation, have been used with some degree of success. Immunotherapy with Anti-PD1 check-point inhibitors such as pembrolizumab is showing promising responses in the relapsed/ refractory subset of patients with this disease entity.199 

Patients may have a history of documented celiac disease, with the time to development of lymphoma varying widely. However, at least half of patients have celiac sprue diagnosed at the same time as the lymphoma. The most common symptoms at presentation are abdominal pain, weight loss, diarrhea, or vomiting. Less common symptoms may include fever, night sweats, and small bowel obstruction or perforation. It is rare for patients to have palpable abdominal masses or peripheral lymphadenopathy, but extraintestinal sites of involvement may include the liver, spleen, thyroid, skin, nasal sinus, and brain.165 In one series, β2-microglobulin and serum LDH were elevated in 85.7% and 62% of patients, respectively, and anemia and low serum albumin levels were seen in 91% and 88% of patients, respectively.192 Diagnosis is usually made by endoscopic biopsies or full-thickness, laparoscopic small bowel biopsies. Traditionally, patients were staged with CT and bone marrow biopsies, but 18F-FDG PET-CT appears to be more sensitive and specific than CT in differentiating EATL from refractory celiac disease.193 The Lugano system been proposed as a staging system, but its utility in assessing prognosis is unclear.55 

Treatment No large controlled trials of therapy for EATL have been reported. Thus, standard treatment is not well defined. Typically, patients are treated with a combination of surgery and chemotherapy.192 Surgery involves removal of as much tumor as is feasible. Intensive chemotherapy is then administered postoperatively, with the most common regimens being ones that contain anthracyclines such as CHOP in older adults and CHOEP (CHOP with etoposide) in younger adults.174 The 5-year overall survival rate with anthracycline-based chemotherapy alone is approximately 10% to 20%. For this reason and based on retrospective data, most experts recommend an autologous stem cell transplant in first remission for the more robust patients with no or minimal medical comorbidities. Nutritional status is commonly poor, requiring parenteral nutrition. Because of poor nutritional and performance status, less than 50% of patients are candidates for systemic chemotherapy and of those, less than 50% can complete the prescribed treatment regimen. Relapse occurs at a median of 6 months from the time of diagnosis in approximately 80% of patients, usually in small bowel sites. Various salvage regimens have been tried for patients with relapsed disease, but few relapsed patients have survived.194 Poor results with conventional chemotherapy has led to the investigation of high-dose chemotherapy followed by autologous stem cell transplantation in the minority of patients with an adequate performance status. A retrospective study of autologous stem cell transplantation by the European Group for Blood and Marrow Transplantation including 44 patients transplanted between 2000 and 2010 showed a 4-year relapse incidence, progression-free survival, and overall survival of 39%, 54%, and 59%, respectively.195 Therapy with novel agents has also been attempted. Alemtuzumab (Campath), an anti-CD52 monoclonal antibody, has been used to treat refractory celiac disease,196 as well as brentuximab vedotin, an

Uncommon Small Intestinal Lymphomas Natural Killer Type T Cell Intestinal Lymphoma

OTHER GASTROINTESTINAL SITES NHL less commonly occurs in other sites of the GI tract, including the oropharynx, esophagus, liver, pancreas, biliary tree, appendix, colon, and rectum. Signs and symptoms reflect the site of presentation. Because of the relative rarity of these disorders, literature is fairly limited. Therefore, definitive conclusions cannot be reached about the optimal management of these more unusual GI lymphomas. Standard principles of lymphoma management dictate diagnostic procedures, staging, prognostic assessment, and treatment. As is the case for all lymphomas, histology, and stage guide treatment. Waldeyer ring lymphomas are usually diffuse large cell lymphomas, but other histologies may be present instead.200,201 Endoscopy and imaging of the remainder of the GI tract should be included in the staging workup, because lymphomatous involvement in other sites may accompany Waldeyer ring involvement. Ann Arbor stage I or II diffuse large cell lymphoma is managed with combined anthracycline-based chemotherapy and/or local radiotherapy.106 Primary hepatic lymphoma is more common in men and has a median age of onset of approximately 50 years.202,203 Primary hepatic lymphoma can present as a single, large, multilobulated mass or as single or multiple nodules. The histology is usually diffuse large B cell, but MALT lymphoma (extranodal marginal B cell lymphoma) has been reported as well. Rare cases of T cell hepatic lymphoma have been reported. Diagnosis is usually made by needle biopsy. Because of the rarity of the disease, optimal therapy is uncertain. Long-term disease-free survival has been reported after resection, but multiagent chemo-immunotherapy is probably most appropriate for DLBCL. Less aggressive chemo-immunotherapy or single-agent rituximab may be appropriate for lymphomas with marginal zone histology. An association of HCV with hepatic and splenic marginal zone lymphoma has been established, and response of the lymphoma to hepatitis C treatment has been documented204,205; whether there may be an association with other hepatitis viruses and hepatic lymphomas is unknown. Pancreatic lymphomas are rare (95%) exhibit expression of CD117 (mast/stem cell factor receptor).1 Other names for this receptor include proto-oncogene c-KIT, tyrosine kinase receptor KIT, or simply KIT. CD117 is encoded by the KIT gene. Levels of expression of CD117 are generally diffuse and strong in the spindle cell GIST subtype (Fig. 33.1). In contrast, in the epithelioid GIST subtype, CD117 expression is typically focal and weakly positive in a dot-like pattern (Fig. 33.2). As discussed later, there are rare CD117-negative GISTs. True leiomyosarcomas express 2 smooth muscle markers, smooth muscle actin and desmin, but fail to express CD117. Schwannomas are usually positive for the neural antigen S100 but

CHAPTER 33  Gastrointestinal Stromal Tumors

459

33

B

A

Fig. 33.1 A, Photomicrograph of a typical spindle cell GIST. The cells are monomorphic, have abundant pale, eosinophilic, fibrillary cytoplasm, and lack mitotic activity. (H&E, ×100.) B, KIT (CD117) immunostaining. This medium-power photomicrograph of a spindle cell GIST shows diffuse and strong cytoplasmic immunoreactivity for KIT. The entrapped muscle fibers from the bowel wall are negative by CD117 immunostaining for KIT. (CD117 immunostain, ×100.) (Courtesy Dr. Brian P. Rubin, Cleveland, OH.)  

Fig. 33.2  Photomicrograph of a gastrointestinal stromal tumor showing epithelioid cytomorphology, fibrillary cytoplasm, and lack of mitotic activity. (H&E, ×200.) (Courtesy Dr. Brian P. Rubin, Cleveland, OH.)

are also negative for CD117. Normal mast cells and ICCs within the surrounding stromal tissues serve as ideal positive internal controls because these normal cells strongly express CD117. GIST lesions can be heterogeneous in the expression of CD117, even within a single tumor. It is, therefore, possible that a needle biopsy may yield cells histologically consistent with a GIST yet be CD117-negative simply due to sampling bias. There are rare subsets of GISTs (95%) of GISTs, but KIT is not expressed by true smooth muscle tumors of the GI tract (i.e., leiomyomas and leiomyosarcomas) nor by stromal tumors at other anatomic locations, such as endometrial stromal tumors. Although the origin of the neoplastic cells of GISTs remains a matter of active investigation, some data suggest that GISTs originate from CD34-positive stem cells residing within the wall of the gut, which can then differentiate incompletely toward the ICC phenotype.30,31 Activating mutations in KIT were identified in 5 of 6 cases of human GISTs originally analyzed by Hirota and colleagues,28 with evidence that the mutations resulted in uncontrolled ligandindependent activation of KIT, or constitutive activation of KIT resulting in phosphorylation of the receptor in the absence of ligand. Genetically engineered cells harboring the mutant overactive KIT proteins were tumorigenic in nude mice, serving as proof of concept that the malignant phenotype was directly induced by the aberrant signaling pathways associated with uncontrolled ligand-independent KIT activation. The oncogenic potential of mutant constitutively activated KIT in the pathogenesis of GISTs in humans has also been supported by identification of familial syndromes (see section on Familial GIST) with an autosomal-dominant inheritance pattern and an abnormally high incidence of GISTs, usually occurring as multiple foci within any affected individual.29,32,33 Genetic analysis of such kindreds reveals that they harbor germline-activating KIT mutations similar to the mutations that were first described in sporadic cases of GISTs. Importantly, the vast majority of GIST cells at initial presentation demonstrate a single site of mutation in KIT; a variety of other genetic and cytogenetic changes are found, some of which are related to an aggressive malignant behavior.34,35 Gain of function mutations have been identified most commonly in exon 11 of KIT, an exon that encodes the intracellular juxtamembrane domain of KIT.36-41 Certain mutations in exon 11 that result in stop codons or deletions convey a poorer prognosis.41 Mutations have also been identified in KIT exon 9,38 the extracellular domain of the kinase and less commonly in exons 13 and 17 (kinase domain),35-39 with rare occurrences of mutations in exon 8.40 The distribution of mutations varies based upon those with primary tumors compared with those seeking therapy for advanced disease (Table 33.1).42,43 Structural biology studies have revealed the mechanism whereby normal (wild-type) KIT is kept in an auto-inhibited conformation until its ligand, SCF, binds and leads to dimerization of 2 KIT kinases; mutational changes lead to protein conformations

TABLE 33.1  Frequency of Particular KIT and PDGFRA Mutations in Newly Diagnosed Gastrointestinal Stromal Tumors as Compared With Metastatic Gastrointestinal Stromal Tumors Newly Diagnosed42

Metastatic Disease43

GISTs (N)

106

414

KIT Mutations

67%

81%

Exon 8

Not reported

20% Ki67 index

Neuroendocrine carcinoma, grade 3 (large-cell or small-cell type)

  

HPF, High-powered fields; NET, neuroendocrine tumors.   

increasingly recognized, particularly in pancreatic NETs. The 2017 WHO classification for pNETs has, therefore, expanded the well-differentiated category to include low-, intermediate-, and high-grade tumors (Table 34.2b).47 It is important to note that current classifications use the term “neuroendocrine tumor” to describe well-differentiated NETs, and “neuroendocrine car­ cinoma or NEC” to denote poorly differentiated morphology. Formal TNM staging classifications have been introduced for GEP-NETs in the past decade by the American Joint Committee on Cancer (AJCC) and the European Neuroendocrine Tumor Society (ENETS). Validations of both staging systems have been performed on population and institutional databases. 

MOLECULAR PATHOGENESIS Until recently, the molecular pathogenesis of NETs was largely unknown.48-51 In contrast to many nonendocrine GI tumors (e.g., colonic or pancreatic adenocarcinoma), mutations in common oncogenes (e.g., ras, fos, myc, src, jun) and tumor suppressor genes (e.g., p53, rb) are rare in well-differentiated NETs.12,28 Recent genomic analyses of pNETs have provided significant insight into the genetic landscape of these tumors. In a landmark whole-exome study of 68 sporadic pNETs, somatic mutations of MEN1 were observed in 44% of cases, whereas mutations in DAXX (death-domain-associated protein) or ATRX (α-thalassemia/men­ tal retardation syndrome X-linked) were seen in 43%.50 All 3 genes are associated with chromatin remodeling. Also, 14% of samples had mutations in mammalian target of Rapamy­ cin (mTOR) pathway genes including PTEN, TSC2, and PIK3CA. Similar findings were reported in a whole-genome sequencing study of 102 primary pNETs. Four dysregulated signaling path­ ways were described: (1) DNA damage repair; (2) chromatin remodeling; (3) telomere maintenance; (4) mTOR activation. A higher-than-expected proportion of germline mutations was found in clinically-sporadic pNETs, with mutations of MUTYH, CHEK2, and BRCA2 occurring in 11% of patients.52 The precise sequence of gene mutations driving the develop­ ment and progression of pNETs is currently unknown. Loss of DAXX/ATRX expression is associated with activation of the alter­ native lengthening of telomeres (ALT) pathway and chromosomal instability (CIN). Additional mutations can accumulate over time and are associated with clinical progression. The genetic landscape of poorly-differentiated pNECs is markedly distinct from well-dif­ ferentiated pNETs. Mutations of KRAS and loss of Rb have been reported in 55% and 49% of patients with pNECs. Overall, fre­ quency of mutations is substantially higher in NEC versus NET.53 The molecular landscape of GI-NETs is much less well under­ stood than pNETs. Loss of chromosome 18 has been reported in over 60% of small intestinal (SI) NETs, but the biological signifi­ cance of this alteration is uncertain.54 Overall, a low mutational rate (0.1 somatic single nucleotide variants/105 nucleotides) has been observed in SI NETs, with mutations or deletions of the cyclin-dependent kinase inhibitor gene CDKN1B observed in 8% of patients.55 Epigenetic changes appear to play a fundamental role in progression of SI NETs. Global DNA hypo methylation is a characteristic feature of SI NETs, whereas tumors with high methylation index tend to be clinically aggressive. Progressive

changes in DNA methylation have been detected between pri­ mary tumors and their metastases.56,57 The mTOR pathway appears to be significantly dysregulated in many GEP-NETs, even in the absence of identifiable mutations in pathway components. mTOR is a serine/threonine kinase that modulates cell survival and proliferation, angiogenesis, and metabo­ lism. Overexpression of mTOR and/or its downstream targets is frequently detected in NETs, and is associated with poorer progno­ sis.58 Expression of tuberous sclerosis-2 (TSC-2) and phosphatase and tensin homolog (PTEN), inhibitors of the mTOR pathway, is decreased in the majority of pNETs. Furthermore, decreased expression of TSC-2 and PTEN correlate with reduced survival.59 NETs are highly vascular tumors, and angiogenesis has been identified as a key event in NET progression. Overexpression of pro­ angiogenic factors, including fibroblast growth factor (FGF), plate­ let-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF), as well as of their receptors, has been reported.60 

MULTIPLE ENDOCRINE NEOPLASIA AND OTHER INHERITED SYNDROMES MEN-1 MEN-1 (Wermer syndrome) is characterized principally by hyperparathyroidism, multifocal pancreaticoduodenal NETs, and pituitary adenomas. The genetic defect in MEN-1 is located on chromosome 11q13 and is caused by germline mutations in a 10-exon gene encoding for a 610–amino acid protein, menin (Table 34.3).61,62 Menin is a nuclear protein that interacts with many pro­ teins, including the AP1 transcription factor, nuclear factor (NF)-κβ, RPA2 (a DNA processing factor), FAN CD2 (a DNA repair factor), and various cytoskeleton-associated proteins and histone-modifying enzymes.61-63 Menin has important roles in transcriptional regula­ tion, genomic stability, cell division, and cell cycle control.61,63,64 The exact mechanism of carcinogenesis is unclear.65,66 Development of endocrine tumors in patients with MEN-1 conforms to Knudsen’s11,61 2-hit model theory of neoplasm, with an inherited (germline) mutation in one chromosome unmasked by a somatic deletion or mutation of the other normal chromosome, thereby removing the tumor suppressor effect of the normal gene product.61,62 Numerous (>1300) different mutations have been described in MEN1, with over 75% of them being inactivating.62 Hyperparathyroidism is the most common clinical abnormal­ ity in patients with MEN-1 (Table 34.4).61,67-69 Characteristically, hyperparathyroidism is the initial manifestation of MEN-1, usually presenting in the third decade of life, followed by the development of a pNET in the fourth to fifth decades.61 Pituitary adenomas occur in roughly 20% of patients. Nonfunctional pNETs are nearly universal in patients with MEN-1 and pathology studies12,61,68,70 have demonstrated that in almost every patient with MEN-1, the pancreas demonstrates diffuse microadenomatosis, with or without larger tumors. Among functional tumors, gastrinomas are most common (typically occurring in the duodenum). It is important to recognize when a patient with a pNET has MEN-1, because patients with and without MEN-I differ in their clinical presenta­ tions, the need for family screening, in the likelihood of surgical cure, and in the clinical and diagnostic approach to the tumor.61,71-73 

34

476

PART IV  Topics Involving Multiple Organs

TABLE 34.3  Inherited GI Neuroendocrine Tumor Syndromes Syndrome

Prevalence/105

Genetic Defect(s): Altered Protein(s)

NET Frequency

Types of pNET

Multiple endocrine neoplasia type I (MEN-I)

1-10

11q13: Menin, a 610–amino acid nuclear protein that interacts with pathways involved in cell growth, cell cycle regulation, genomic stability, and apoptosis

pNETs 80%-100% (microscopic), 20%-80% (clinical) Carcinoids: gastric (15%-35%), pulmonary (0%-8%), thymic (0%-8%)

NF-pNETs: 80%-100% microscopic; 0%-20% large) Functional pNETs: Gastrinoma (54%) Insulinoma (18%) Glucagonoma (3%) VIPoma (3%) GRFoma (98%) asymptomatic and nonfunctional. The mean age at diagnosis of pNET in VHL is 29 to 38 years. Most patients have a single pNET that may be malignant.75 Liver metastases occur in 9% to 37% of VHL patients with pNETs. 

Neurofibromatosis-1 NF1 is caused by a defect on chromosome 17q11.2 encoding for a 2845–amino acid protein, neurofibromin, which functions as a Ras signaling cascade inhibitor (see Table 34.3).61,76 From 0% to 10% of NF1 patients develop a GI-NET (carcinoid), usually in the periampullary region of the duodenum.61,77,78 These tumors frequently contain round calcium concretions (psammoma bod­ ies) typical of somatostatinomas, although the somatostatinoma syndrome is rarely present. Metastases to liver and or lymph nodes occur in 30%.61,78 

Tuberous Sclerosis Tuberous sclerosis is caused by mutations in either the 1164– amino acid protein, hamartin (TSC-1) or the 1807–amino acid protein, tuberin (TSC-2) (see Table 34.3).61 These 2 proteins regulate the PI3K signaling cascade and the small guanosine triphosphatase (GTP)-binding protein RHEB (Ras homolog enriched in brain), which play important roles in the regulation of protein translation and synthesis, growth, and proliferation, as

well as maintenance of cellular energy levels. pNETs are present in 4% of patients with TSC-2. 

FUNCTIONAL TUMORS Insulinomas Insulinomas are insulin-secreting pNETs that primarily origi­ nate in the pancreas and cause symptoms as a result of hypogly­ cemia (Table 34.5).

Pathophysiology and Pathology Insulinomas are almost always located in the pancr­eas.12,28,31,39,79-81 Insulinomas are evenly distributed in the pancreas and are usually fairly small.12,28,31,39,79-82 In one series, 39% were smaller than 1 cm and only 8% were larger than 5 cm.82 Insulinomas occur as multiple tumors in only 2% to 13% of patients,28,82 in which case MEN-1 should be suspected.61 Insulinomas are usually well encapsulated, firmer than normal pancreas, and highly vascu­ lar. Only 5% to 16% of insulinomas are malignant.83 Malignant insulinomas, generally large (average size, 6 cm in one series84), metastasize most often to the liver and/or regional lymph nodes. Insulin is synthesized as preproinsulin by beta cells of the pancreatic islets in the rough endoplasmic reticulum. Proin­ sulin is liberated from preproinsulin and transferred to the Golgi apparatus.32 Proinsulin, consisting of a 21–amino acid alpha chain and a 30–amino acid beta chain joined together by a 33–amino acid connecting peptide (C-peptide), is stored in beta cell secretory granules. Within these granules, a protease excises the C-peptide, and the C-peptide and the double-stranded insulin molecule are secreted in equimolar amounts.32 Some proinsulin is also detected in normal subjects but represents less than 25% of total immunoreactive plasma insulin, whereas in almost all (>90%) patients with insulino­ mas, there are elevated proportions of proinsulin relative to total insulin.85 

CHAPTER 34  Neuroendocrine Tumors

TABLE 34.4  Clinical Features of Patients With Multiple Endocrine Neoplasia Type I Features

Frequency (%) [Range]

Hyperparathyroidism

97 [78-100]

Pancreatic endocrine tumor (any)

TABLE 34.5  Symptoms, Signs, and Laboratory Abnormalities in Patients With Insulinoma Frequency (%) Anytime during the Clinical Course Neuropsychiatric symptoms (loss of consciousness, confusion, dizziness, diplopia)

92

a

  Any, including PPoma or nonfunctional

80-100

Confusion or abnormal behavior

80

 Gastrinoma

54 [20-61]

Obesity

52

 Insulinoma

18 [7-31]

Amnesia or coma

47

 Glucagonoma

3 [1-6]

Seizures (grand mal)

12

 VIPoma

1 [1-12]

Cardiovascular symptoms, palpitations, tachycardia

17

 Somatostatinoma

0-1

GI symptoms (hunger, vomiting, abdominal pain)

9

5 mEq/hr proposed to distinguish patients with ZE from those without ZES. Left upper, Prominent gastric folds found on endoscopy in a ZES patient, compared with a normal subject. Left lower, Fasting serum gastrin levels in ZES expressed as a multiple of the upper limit of normal on the horizontal axis. Very few patients had normal values; 60% had less than 10-fold serum gastrin increases.40,73,130,142,150 CU, Clinical units.

has decreased the number of cases of ZES diagnosed, and at the same time has been associated with an increase in patients with a false diagnosis of ZES.137 A false diagnosis may occur because chronic treatment with PPIs causes hypergastrinemia in 80% to 100% of patients with PUD or GERD, and the serum gastrin level frequently reaches 5 times normal, a level seen in 60% of ZES patients.130,134-136 In the past, when H2RAs were in wider use, a diagnosis of ZES was frequently suggested when the con­ ventional doses of H2RAs failed to control acid hypersecretion and ulcer disease.7 Presently, conventional doses of potent PPIs may mask the diagnosis of ZES because they control symptoms in most patients, and treatment failures uncommonly occur with PPIs.10,129,134,138

Another factor complicating and sometimes delaying the diagnosis of ZES is the reliability of current plasma gastrin assays.134,139,140 One study139 examining 12 different commercially available plasma gastrin kits (7 radioimmunoassays and 5 ELISA assays) reported that 7 assays inaccurately measured plasma gas­ trin concentrations, with both overestimations and underestima­ tions. Thus, a reliable gastrin assay must be used.134,139 There are a number of clinical and laboratory features that should suggest the diagnosis of ZES in a patient with acid peptic disease or diarrhea (see Fig. 34.3 and Table 34.6). First, diarrhea occurs in 73% of ZES patients, but is infrequent in patients with routine PUD or GERD. Diarrhea alone can be the presenting symptom in up to 27% of patients with ZES.40,112,129 Second, because MEN-1

481

CHAPTER 34  Neuroendocrine Tumors

No liver mets (n = 158)

100

Probability of survival (%)

90 80

PRIMARY GASTRINOMA LOCATION

Primary location Lymph Pan node Duod mets Pan Liver mets Duod

P 1 month duration) can be familial, and are usually due to diaphragmatic irritation, gastric distention, thoracic or central nervous system irritation or tumors, hyponatremia, or other metabolic derangements. There is a paucity of evidence to guide therapy among attempted treatments including acupuncture, pharmacologic agents, noninvasive phrenic nerve stimulation, phrenic nerve crush, or implantable diaphragmatic pacemakers. Drugs that have been reported to be successful include chlorpromazine, metoclopramide, quinidine, phenytoin, valproic acid, baclofen, sertraline, gabapentin, and nifedipine. Postoperative hiccups after abdominal surgery may be due to subphrenic abscess or other sources of diaphragmatic irritation such as acute gastric dilatation, and this should be considered before assuming a more benign cause. 

LAPAROSCOPY IN THE EVALUATION OF PERITONEAL DISEASES General Considerations Diagnostic laparoscopy, as first described by Kelling in 1901, is a safe and effective means of evaluating the abdominal cavity. It allows direct visualization of the liver surface, peritoneal lining, and mesentery for directed biopsies. Ascitic fluid can be collected easily. Although less invasive imaging techniques such as CT have reduced its necessity, laparoscopy continues to have a role in the evaluation of liver and peritoneal diseases. In a large retrospective review of diagnostic laparoscopy, the procedure had a mortality rate of 0% and an overall morbidity rate of 1.2%. Possible complications include prolonged abdominal pain, vasovagal reaction, viscus perforation, bleeding (either from biopsy sites or within abdominal wall), splenic laceration, ascites fluid leakage, and fever. It has been shown in animal models of peritonitis that abdominal insufflation during laparoscopy could increase bacterial translocation,60 raising the concern that laparoscopy is dangerous in the clinical setting of septic peritonitis. Despite these concerns, laparoscopy is becoming a common technique in patients requiring operation for diseases causing peritonitis. The adverse hemodynamic consequences of abdominal insufflation can be overcome in the vast majority of patients with aggressive resuscitation and careful anesthetic management. A laparoscopic approach has been effective in treating perforated gastroduodenal

Fig. 39.9  Laparoscopy revealing left hemidiaphragmatic disease not visualized on preoperative imaging.

ulcer. Laparoscopic appendectomy is advocated as the treatment of choice for patients with acute appendicitis and complicated appendicitis. Laparoscopic cholecystectomy is safe and effective treatment of acute cholecystitis. Laparoscopic colectomy can be performed for complicated diverticulitis.61 Evidence-based guidelines for the application of laparoscopic operation in surgical peritonitis have been developed. 

Evaluation of Ascites of Unknown Origin Clinical presentation, conventional laboratory examinations, and ascitic fluid analysis identify the cause of ascites in the majority of patients (see Chapter 93). However, conventional paracentesis occasionally fails to make a diagnosis. In these instances, diagnostic laparoscopy affords direct and sensitive technique for obtaining specimens for histology and culture. In the USA, occult cirrhosis and peritoneal malignancy account for the majority of cases. In studies from Asian countries, peritoneal malignancy is also the most common cause of unexplained ascites, but tuberculous peritonitis accounts for an increasing number of cases. In patients with HIV, peritoneal involvement may result from a variety of opportunistic infections and neoplasms (see earlier section and Chapter 35). Non-Hodgkin lymphoma accounts for the majority of these peritoneal lesions revealed by laparoscopy, but M. tuberculosis, M. avium-intracellulare, and P. jiroveci may be revealed. 

Staging Laparoscopy Laparoscopy has found increasing utility in the staging of malignant solid tumors of the GI tract (Fig. 39.9). Diagnostic laparoscopy coupled with laparoscopic US, peritoneal fluid cytology, and biopsy allow for improved selection of patients that will benefit from larger, definitive operations for curative intent. In GI malignancies, the use of diagnostic laparoscopy finds that some patients with potentially resectable disease have metastatic or locally advanced disease and can be spared unnecessary laparotomy with both reduction of costs and preservation of quality of life.62 In laparoscopic staging for pancreatic cancer 11% to 48% of patients will be shown to have metastatic disease after an initial negative CT. Laparoscopic staging has been recommended for gastric cancer and changes management for 12% to 60% of patients.63 The finding of metastatic disease on staging laparoscopy in esophageal and gastric cancers may obviate the need for palliative operations. Full references for this chapter can be found on www.expertconsult.com

.

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29. Sugrue M. Abdominal compartment syndrome. Curr Opin Crit Care 2005;11:333–8. 30. Mulier S, Penninckx F, Verwaest C, et al. Factors affecting mortality in generalized postoperative peritonitis: multivariate analysis in 96 patients. World J Surg 2003;27:379–84. 31. Dalal P, Sangha H, Chaudhary K. In: Peritoneal dialysis, is there sufficient evidence to make “PD first” therapy? Int J Nephrol 2011; 2011:239515. 32. Piraino B, Bernardini J, Brown E, et al. ISPD position statement on reducing the risks of peritoneal dialysis-related infections. Perit Dial Int 2011;31:614–30. 33. Wiggins KJ, Craig JC, Johnson DW, Strippoli GF. Treatment for peritoneal dialysis-associated peritonitis. Cochrane Database Syst Rev 2008:CD005284. 34. Bargman JM. Advances in peritoneal dialysis: a review. Semin Dial 2012;25:545–9. 35. Guirat A, Koubaa M, Mzali R, et al. Peritoneal tuberculosis. Clin Res Hepatol Gastroenterol 2011;35:60–9. 36. Sanai FM, Bzeizi KI. Systematic review: tuberculous peritonitis— presenting features, diagnostic strategies and treatment. Aliment Pharmacol Ther 2005;22:685–700. 37. Kang SJ, Kim JW, Baek JH, et al. Role of ascites adenosine deaminase in differentiating between tuberculous peritonitis and peritoneal carcinomatosis. World J Gastroenterol 2012;18:2837–43. 38. Cho OH, Park KH, Park SJ, et al. Rapid diagnosis of tuberculous peritonitis by T cell-based assays on peripheral blood and peritoneal fluid mononuclear cells. J Infect 2011;62:462–71. 39. Vadwai V, Boehme C, Nabeta P, et al. Xpert MTB/RIF: a new pillar in diagnosis of extrapulmonary tuberculosis? J Clin Microbiol 2011;49:2540–5. 40. Byun SS, Lee S, Lee SE, et al. Recent changes in the clinicopathologic features of Korean men with prostate cancer: a comparison with Western populations. Yonsei Med J 2012;53:543–9. 41. Mikamo H, Sato Y, Hayasaki Y, Tamaya T. Current status and fluconazole treatment of pelvic fungal gynecological infections. Chemotherapy 2000;46:209–12. 42. Edlich RF, Long 3rd WB, Gubler DK, et al. Dangers of cornstarch powder on medical gloves: seeking a solution. Ann Plast Surg 2009;63:111–5. 43. Tian XP, Zhang X. Gastrointestinal involvement in systemic lupus erythematosus: insight into pathogenesis, diagnosis and treatment. World J Gastroenterol 2010;16:2971–7. 44. Attard JA, MacLean AR. Adhesive small bowel obstruction: epidemiology, biology and prevention. Can J Surg 2007;50:291–300. 45. Gutt CN, Oniu T, Schemmer P, et al. Fewer adhesions induced by laparoscopic surgery? Surg Endosc 2004;18:898–906. 46. Fazio VW, Cohen Z, Fleshman JW, et al. Reduction in adhesive small-bowel obstruction by Seprafilm adhesion barrier after intestinal resection. Dis Colon Rectum 2006;49:1–11. 47. Pinto A, Eveno C, Pocard M. Update on clinical trials in colorectal cancer peritoneal metastasis. Int J Hyperthermia 2017;33:543–7. 48. Sugarbaker PH. New standard of care for appendiceal epithelial neoplasms and pseudomyxoma peritonei syndrome? Lancet Oncol 2006;7:69–76. 49. Ceelen WP, Flessner MF. Intraperitoneal therapy for peritoneal tumors: biophysics and clinical evidence. Nat Rev Clin Oncol 2010;7:108–15. 50. Helm JH, Miura JT, Glenn JA, et al. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for malignant peritoneal mesothelioma: a systematic review and meta-analysis. Ann Surg Oncol 2015;22:1686–93. 51. Heyns CF. Pelvic lipomatosis: a review of its diagnosis and management. J Urol 1991;146:267–73. 52. Velmahos GC, Chahwan S, Falabella A, et al. Angiographic embolization for intraperitoneal and retroperitoneal injuries. World J Surg 2000;24:539–45. 53. Lucey BC, Varghese JC, Anderson SW, et al. Spontaneous hemoperitoneum: a bloody mess. Emerg Radiol 2007;14:65–75. 54. Tan JJ, Tan KK, Chew SP. Mesenteric cysts: an institution experience over 14 years and review of literature. World J Surg 2009;33:1961–5. 55. Schwartz RW, Reames M, McGrath PC, et al. Primary solid neoplasms of the greater omentum. Surgery 1991;109:543–9. 56. van Rhee F, Greenway A, Stone K. Treatment of idiopathic Castleman disease. Hematol Oncol Clin North Am 2018;32:89–106. 57. Mahajan VS, Mattoo H, Deshpande V, et al. IgG4-related disease. Annu Rev Pathol 2014;9:315–47.

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References

58. Vaglio A, Salvarani C, Buzio C. Retroperitoneal fibrosis. Lancet 2006;367:241–51. 59. Wat SY, Harish S, Winterbottom A, et al. The CT appearances of sclerosing mesenteritis and associated diseases. Clin Radiol 2006;61:652–8. 60. Horattas MC, Haller N, Ricchiuti D. Increased transperitoneal bacterial translocation in laparoscopic surgery. Surg Endosc 2003;17:1464–7. 61. Mbadiwe T, Obirieze AC, Cornwell 3rd EE, et al. Surgical management of complicated diverticulitis: a comparison of the laparoscopic and open approaches. J Am Coll Surg 2013;216:782–8; discussion 788–90.

62. Jayakrishnan TT, Nadeem H, Groeschl RT, et al. Diagnostic laparoscopy should be performed before definitive resection for pancreatic cancer: a financial argument. HPB 2015;17:131–9. 63. Leake PA, Cardoso R, Seevaratnam R, et al. A systematic review of the accuracy and indications for diagnostic laparoscopy prior to curative-intent resection of gastric cancer. Gastric Cancer 2012;15(Suppl. 1):S38–47.

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Gastrointestinal and Hepatic Disorders in the Pregnant Patient Shilpa Mehra, John F. Reinus

CHAPTER OUTLINE GASTROINTESTINAL AND HEPATIC FUNCTION IN NORMAL PREGNANCY ��������������������������������������������������������������������593 Esophageal Function������������������������������������������������������593 GI Function��������������������������������������������������������������������593 Immune Function and the Intestinal Microbiota��������������593 Gallbladder Function������������������������������������������������������594 Hepatic Function������������������������������������������������������������594 DRUG SAFETY IN PREGNANT PATIENTS��������������������������594 ENDOSCOPY DURING PREGNANCY����������������������������������594 IMAGING AND RADIATION EXPOSURE DURING PREGNANCY ��������������������������������������������������������������������594 GI DISORDERS AND PREGNANCY ������������������������������������595 Nausea, Vomiting, and Hyperemesis Gravidarum������������595 GERD ����������������������������������������������������������������������������596 PUD��������������������������������������������������������������������������������596 IBD��������������������������������������������������������������������������������596 Appendicitis ������������������������������������������������������������������597 GALLBLADDER AND PANCREATIC DISORDERS AND PREGNANCY ��������������������������������������������������������������������597 Gallstone Disease����������������������������������������������������������597 Acute Pancreatitis����������������������������������������������������������597 HEPATIC DISORDERS UNIQUE TO PREGNANCY����������������598 Cholestasis of Pregnancy ����������������������������������������������598 Preeclampsia ����������������������������������������������������������������599 HELLP Syndrome������������������������������������������������������������599 Hepatic Rupture, Hematoma, and Infarct������������������������600 Acute Fatty Liver of Pregnancy ��������������������������������������601 OTHER HEPATIC DISORDERS AND PREGNANCY��������������603 Viral Hepatitis����������������������������������������������������������������603 Chronic Liver Disease and Portal Hypertension ��������������604 Wilson Disease��������������������������������������������������������������605 Autoimmune Liver Diseases ������������������������������������������605 Hepatic Tumors and Mass Lesions����������������������������������605 Hepatic Vein Thrombosis (Budd-Chiari Syndrome)����������605 Pregnancy After Liver Transplantation����������������������������605

GASTROINTESTINAL AND HEPATIC FUNCTION IN NORMAL PREGNANCY The GI tract undergoes dramatic modifications during pregnancy. Intra-abdominal organs must move to accommodate uterine growth, hormonal factors alter motility, and the immunologic adaptation to pregnancy affects response to disease. Heartburn, nausea, abdominal cramps, and altered bowel habits, the most common GI symptoms of pregnant women, are caused by normal physiologic changes in gut motility. These symptoms are

usually transitory and easily treated with conservative measures. It may be a challenge, however, to distinguish between symptoms of altered motility and those that signal the onset or worsening of problems that require immediate medical attention.

Esophageal Function The amplitude and duration of esophageal muscle contractions in pregnant and nonpregnant women are similar.1 In the distal esophagus, the velocity of peristaltic waves has been found to decrease by approximately one third during pregnancy, but remains within the normal range.2 In contrast, resting lower esophageal sphincter tone progressively declines during gestation, most likely a consequence of inhibition of smooth muscle contraction by progesterone.2-4 This effect coupled with increased abdominal pressure during gestation is responsible for the gastroesophageal reflux symptoms that occur in 70% of pregnant women.5 

GI Function The effects of pregnancy on gastric motility are unclear. Delayed gastric emptying has been demonstrated by some authors, especially during delivery,6 whereas no effect on gastric emptying has been found by others.7 Pregnant women have normal gastric secretion.8 Intestinal transit time is prolonged during gestation. Delayed small-bowel transit is most pronounced during the third trimester and is associated with slowing of the migrating motor complex.9,10 Colonic transit time is prolonged in pregnant animals. Progesterone is thought to have a direct inhibitory effect on gut smooth muscle cells that slows motility.11A role for endogenous opioids has also been suggested.12 Together, these changes often result in mild physiologic constipation. The absorptive capacity of the small intestine increases during pregnancy to meet the metabolic demands of the fetus; increased absorption of calcium, amino acids, and vitamins has been demonstrated.13-16 Animal experiments have revealed pregnancyinduced increases in small intestinal weight and villous height in conjunction with mucosal hypertrophy.17,18 The activity of some brush border enzymes increases during lactation and then decreases after weaning.19,20 

Immune Function and the Intestinal Microbiota During pregnancy, the maternal immune system must adapt to the presence of the fetus. Adaptive changes can influence the response to infection and modulate the course of underlying autoimmune disease. There is a shift from cellular to humoral responses, with downregulation of Th1 and upregulation of Th2 cytokines. Pregnancy modulates natural killer cell cytotoxicity and induces T-regulatory cells that affect the maternal immune response.21,22 Unfortunately, we still do not understand the effects of pregnancy on the mechanisms responsible for autoimmune diseases such as autoimmune hepatitis and Crohn disease well enough to allow us to predict clinical outcomes during pregnancy. The maternal intestinal flora changes during pregnancy, potentially altering the host-microbial interaction in a beneficial fashion.23 Bacteria from the mother colonize the neonate’s gut,

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establishing the microbiota with potential long-lasting health consequences.24 Although the establishment of the human GI microbiota previously was thought to begin at birth, the finding of bacterial products in meconium, placenta, and amniotic fluid suggests that seeding occurs in utero.25,26 

Gallbladder Function Pregnancy causes an alteration in bile composition, including cholesterol supersaturation, decreased chenodeoxycholic acid and increased cholic acid concentrations, and an increase in the size of the bile acid pool.27 These changes are associated with greater residual gallbladder volumes in the fasting as well as fed states. Sex-steroid hormones may inhibit gallbladder contraction in pregnant women, promoting precipitation of cholesterol crystals and stone formation.28,29 

Hepatic Function During pregnancy, maternal blood volume increases progressively until week 30 of gestation when it is 50% greater than normal and remains so until confinement.30 This volume expansion, attributed to the effects of steroid hormones and elevated plasma levels of aldosterone and renin, is responsible for dilution of some blood constituents such as red blood cells (physiologic anemia); thus, total serum protein concentrations diminish 20% by midpregnancy, largely as a result of a reduced serum albumin level. Maternal proteins passively diffuse across the placenta to the fetal circulation.31 Similarly, fetal AFP moves across the placenta from the fetal to the maternal circulation, raising maternal serum levels. Active transport may be involved in the transplacental movement of some macromolecules. Despite increases in maternal blood volume, the levels of many serum proteins measured to assess hepatic injury are unchanged or even increased during gestation. Progesterone causes a proliferation of smooth endoplasmic reticulum, whereas estrogens promote formation of rough endoplasmic reticulum and associated protein synthesis. Pregnant women synthesize the products of the cytochrome P-450 gene superfamily and other proteins at an accelerated rate, including coagulation factors, binding globulins, and ceruloplasmin. Maternal serum alkaline phosphatase levels are normally elevated during the third trimester of pregnancy, largely due to placental production; for this reason, measurement of alkaline phosphatase in pregnant women is only of clinical use early in gestation. Alterations in maternal concentrations of plasma proteins may persist for several months postpartum. Mild leukocytosis and increased erythrocyte sedimentation rates are also common in normal pregnancy. 

DRUG SAFETY IN PREGNANT PATIENTS Patients and physicians tend to avoid treatment with medications during pregnancy because they fear harming the fetus.32,33 Withholding medical intervention, however, may adversely affect the mother’s health and the pregnancy outcome. Having stated this, no medication or other therapeutic intervention can be considered definitely safe during pregnancy. Indeed, the placenta is not a reliable barrier to the passage of most drugs, the distribution of a drug within the fetal compartment cannot be accurately predicted, and data on long-term effects of in utero fetal drug exposure are practically impossible to collect. The necessity of any proposed drug therapy should be discussed with the patient and known and unknown risks of treatments must be carefully evaluated. For this reason, the FDA in 2014 required a change in the content and format of prescription-drug labels required by the Physician Labeling Rule.34 Letter categories (A, B, C, D, X) are no longer used. Instead, the FDA now requires labels to contain a narrative explanation of risk and supporting data. 

ENDOSCOPY DURING PREGNANCY It is estimated that 20,000 pregnant women undergo endoscopy each year.35 Recommendations concerning endoscopy in this setting are largely based on expert opinion and case reports.36 Although the safety of endoscopy during pregnancy has not been completely established, it is performed routinely if there is a clear indication.37 Pregnant women have safely undergone EGD, colonoscopy, sigmoidoscopy, ERCP, and percutaneous gastroscopy.38 Although a recent large Swedish cohort study found endoscopy during pregnancy to be associated with an increased risk of preterm birth or small-for-gestational-age neonates, the authors concluded that the risks were small and likely due to intrafamilial factors or disease activity and not because of endoscopy alone.39 In addition to general contraindications to endoscopic procedures, specific contraindications during pregnancy include imminent or threatened delivery, ruptured membranes, placental abruption, and pregnancy-induced hypertension.40 Several precautions should be observed to avoid complications when performing endoscopy in a pregnant patient.40 Given the extreme sensitivity of the fetus to maternal hypoxia, pregnant women should receive supplemental O2 with continuous saturation monitoring. When the fetus is capable of surviving outside the uterus, usually around 24 weeks of gestation, maternal monitoring for contractions before, during, and after invasive procedures is advisable to enable prompt delivery if fetal distress occurs. In the second and third trimesters, the supine position and external abdominal pressure should be avoided because resulting compression of the vena cava and aorta may cause hypotension and placental hypoperfusion. ERCP should be performed only with therapeutic intent and by expert endoscopists, and every effort should be made to avoid fetal radiation (see later).38 Opioid (narcotic) analgesics cross the placenta, and benefits during endoscopy must be weighed against risks for the mother (see Chapter 42) and the fetus. Sedation with benzodiazepines should be avoided, especially during the first trimester, because diazepam has been reported to cause fetal malformations.41,42 Extensive experience with propofol is lacking, and its high lipid solubility is a reason for concern.43 Lactating patients are advised to avoid breastfeeding and to discard breast milk for 4 hours after a procedure requiring sedation.40 

IMAGING AND RADIATION EXPOSURE DURING PREGNANCY The National Commission on Radiation Protection recommends limiting exposure to ionizing radiation during pregnancy to less than 5cGy.44,45 Well-referenced guidelines for imaging of pregnant women with ionizing radiation have been published by the American College of Radiology Guidelines and Standards Committee46 and by the American College of Obstetricians and Gynecologists Committee on Obstetric Practice.47 The potential for radiation damage to the fetus is determined by dose and gestational age at the time of exposure (Table 40.1). CT should be performed only when its potential benefits clearly outweigh its risks and should be done, if possible, after completion of organogenesis.48 Helical CT may be associated with less fetal radiation exposure than conventional CT. MRI is often a superior alternative to CT; MRI without contrast has not been associated with adverse pregnancy outcomes, and magnetic fields are not considered harmful to living organisms.49 There is a theoretical risk of thermal injury to the fetus from MRI in early pregnancy and thus MRI is not recommended during the first 12 weeks of gestation. Contrast agents may cross the placenta, and their safety in pregnant women has not been formally assessed. Neonatal hypothyroidism has been associated with use of some iodinated agents. Paramagnetic contrast agents used during MRI (e.g., gadolinium) have not been studied in pregnant women.

CHAPTER 40  Gastrointestinal and Hepatic Disorders in the Pregnant Patient

TABLE 40.1  Fetal Effects of Radiation During Gestation* Gestational Age (Days)

Effects of Radiation

0-9

Death

13-50

Teratogenesis Growth restriction

51-280

Growth restriction CNS abnormalities Possible cancer risk

  

*Effects

listed are related to dose of radiation also.

Less than 0.04% of a dose of gadolinium-labeled contrast is excreted in breast milk during the first 24 hours after administration and a negligible amount of this is absorbed from the infant GI tract.50 Therefore, breastfeeding should not be interrupted after imaging with gadolinium. US is widely used and safe during pregnancy. 

GI DISORDERS AND PREGNANCY Nausea, Vomiting, and Hyperemesis Gravidarum (See Chapter 15) In their first trimester, 60% to 70% of pregnant women report having some nausea, and more than 40% report vomiting.51,52 Onset of these symptoms is typically in the 4th to 6th week of gestation, with a peak occurrence in the 8th to 12th week and resolution by week 20. Although nausea and vomiting may vary from mild to severe, most affected individuals are still able to obtain adequate oral nutrition and hydration, in some cases by eating frequent small meals of dry starchy foods. Hp infection in pregnant women may contribute to the development of vomiting.53 Severe persistent vomiting demanding medical intervention, or hyperemesis gravidarum, is less common, occurring in 2% or less of pregnancies.54,55 Hyperemesis is accompanied by fluid, electrolyte, and acid-base imbalances, nutritional deficiency, and weight loss and is defined by the presence of ketonuria and a 5% decrease from pre-pregnancy weight. It may be associated with pyrosis, hematemesis, and hypersalivation (ptyalism).56 Although the prognosis of hyperemesis gravidarum is generally favorable, severe untreated disease may lead to significant maternal and fetal morbidity. Symptoms usually begin at weeks 4 to 5 and improve by weeks 14 to 16 of gestation. In up to 20% of affected patients, however, vomiting persists until delivery.57 Hyperemesis frequently recurs in subsequent pregnancies. Reported risk factors for hyperemesis include a personal or family history of the disorder,58 a female fetus or multiple gestation, gestational trophoblastic disease, fetal trisomy 21, hydrops fetalis, and maternal Hp infection.59 The etiology of hyperemesis gravidarum is likely multifactorial, including contributions by hormonal changes, GI dysmotility, Hp infection, and psychosocial factors. A genetic predisposition is suggested by familial clusters of the disease. Pregnancy-related hormones, specifically HCG and estrogen, have been implicated as important causes of hyperemesis.60 Symptoms worsen during periods of peak HCG concentrations, and conditions associated with higher serum HCG levels, such as multiple gestation, trophoblastic disease, and trisomy 21, are associated with an increased incidence of hyperemesis.61 Elevated serum estrogen concentrations, as seen in obese patients, have also been associated with this disorder.62 Estrogen and progesterone are thought to cause nausea and vomiting by altering gastric motility and slowing GI transit time.63 Other hormones implicated in the pathogenesis of hyperemesis include thyroid hormones and gut-derived hormones, ghrelin, and leptin.64,65 Abnormal thyroid function test results are found in two

595

thirds of patients with hyperemesis gravidarum.66 The alpha subunit of HCG has thyroid-stimulating hormone-like activity that suppresses endogenous thyroid-stimulating hormone release and causes a slight rise in free thyroxine (T4) levels.67 Despite these findings, this transient gestational thyrotoxicosis is not associated with unfavorable pregnancy outcomes and does not usually require treatment. An increased risk of hyperemesis has been found in 2 metaanalyses of Hp infection during pregnancy.68,69 Some authors have documented symptomatic improvement in pregnant patients with vomiting after Hp eradication.70,71 Vomiting in patients with hyperemesis gravidarum is often triggered by olfactory and even auditory and visual stimuli. A pregnancyunique quantification of nausea and emesis (PUQE score) can be used to evaluate the number of hours of nausea and the number of episodes of emesis and retching per day in affected women and is helpful in tailoring therapy.72 Hospital admission for IV fluid and electrolyte replacement and, sometimes, nutritional support is indicated when affected individuals develop hypotension, tachycardia, ketosis, weight loss, or muscle wasting. Abnormal laboratory test results in such patients include hypokalemia, hyponatremia, and ketonuria. Hyperemesis is associated with slight increases in serum aminotransferase and bilirubin levels in 25% to 40% of cases. Hyperamylasemia, seen in a quarter of affected patients, is caused by excessive salivary gland production stimulated by prolonged vomiting.73 Severe hyperemesis gravidarum is associated with poor maternal and fetal outcomes. In a study of more than 150,000 singleton pregnancies, infants born to women with hyperemesis who had gained less than 7 kg of weight during pregnancy were more likely to have low birth weights, be premature and small for gestational age, and to have low Apgar scores.54 These findings were confirmed by a recent meta-analysis.74 Severe, albeit rare, maternal complications of hyperemesis include Mallory-Weiss tears with upper GI bleeding, Boerhaave syndrome, Wernicke encephalopathy with or without Korsakoff psychosis, central pontine myelinolysis, retinal hemorrhage, and spontaneous pneumomediastinum.75 Patients with hyperemesis may have depression and post-traumatic stress disorder during pregnancy and postpartum.76 Lastly, severe depression after elective termination of pregnancy has been reported.77 Given the potential for morbidity and mortality in hyperemesis gravidarum, affected individuals should be treated aggressively. Obstetric management should be overseen, if possible, by physicians qualified in maternal-fetal medicine. The goals of therapy are maintenance of adequate maternal fluid intake and nutrition, as well as symptom control. Patients should be advised to eat multiple small meals as tolerated and to avoid an empty stomach, which may trigger nausea. Also, avoidance of offensive odors, separation of ingestion of solid and liquid foods, and consumption of a high-carbohydrate diet may be helpful.78 Antiemetic and antireflux medications are first-line pharmacologic therapy for outpatients who have failed dietary modifications. Ginger, phenothiazines (chlorpromazine, prochlorperazine), the dopamine antagonist metoclopramide, and pyridoxine (vitamin B6) have proved beneficial in this setting.79,80 Extensive data show lack of teratogenesis and good fetal safety for many of these drugs.81-83 Treatment with ondansetron, a 5-hydroxytryptamine-3 (5-HT3) receptor antagonist, should be considered in patients who do not respond to the above measures. The safety of ondansetron therapy during pregnancy is supported by a recent controlled trial,84 case reports, and widespread clinical experience. Glucocorticoids may benefit individuals with severe symptoms. Failure of oral medical therapy can be managed in the home setting with IV fluid replacement, medications, and multivitamins. It should be noted, however, that as many as 50% of pregnant patients treated through central venous catheters, including those peripherally inserted, have catheter-related complications,85 most likely as a result of the relative hypercoagulable state and increased susceptibility to infections seen in

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pregnant women. Enteral feeding through a nasoenteric tube or surgically placed feeding tube is sometimes required to maintain maternal nutrition.86 

GERD (See Chapter 46) At least as many women experience pyrosis as nausea during pregnancy. By the end of the third trimester, 50% to 80% of pregnant patients have had new, or an exacerbation of preexisting, heartburn.87,88 Pyrosis, however, is rarely accompanied by overt esophagitis or its complications.89 Pregnant women with heartburn may also have regurgitation and, as already mentioned, nausea and vomiting, as well as atypical reflux symptoms, such as persistent cough and wheezing. Symptoms may develop at any time during pregnancy, with a peak incidence in the third trimester,90 may persist until delivery, and may be predictive of recurrent GERD later in life.87 Risk factors for reflux include multiparity, older maternal age, and reflux complicating a prior pregnancy.5,87,91 The contributions of pre-pregnancy BMI and excessive weight gain are controversial.92 The pathogenesis of GERD in pregnant women is related to the effects of gestational hormones on esophageal motility, lower esophageal sphincter tone, and gastric emptying. Compression of the stomach and increased intra-abdominal pressure caused by the enlarging uterus also contribute to development of this disorder. EGD is rarely required for the assessment of pregnant women with symptoms of GERD.93 There are no data assessing the use of 24-hour ambulatory pH monitoring in this setting, and use of a barium esophagogram is undesirable because it entails fetal radiation exposure; thus, evaluation of suspected GERD in a pregnant woman depends on the clinical experience and judgment of the physician and requires due consideration of the patient’s history and all potential, reasonable causes for the patient’s present symptoms. Mild reflux symptoms can often be controlled by modifications of diet and lifestyle. Liquid antacids and sucralfate are prescribed as first-line pharmacologic therapy.94 Magnesium-containing antacids should be avoided during the late third trimester because they theoretically may impair labor. Ranitidine remains the treatment of choice for patients who have persistent heartburn despite liquid antacid therapy.95 PPIs should be reserved for refractory cases. A large population study and 2 meta-analyses have found no significant risk of fetal malformations in babies exposed to PPIs during the first trimester of pregnancy.96,97 Omeprazole, however, has caused fetal toxicity in animals. An association between use of PPIs or H2RAs by pregnant women and development of childhood asthma in their offspring has been noted in a survey of Danish medical registries,98 but the significance of this observation is unclear. The pro-motility agent metoclopramide has not been used extensively to treat GERD during gestation, although it is used during obstetric anesthesia and to treat hyperemesis gravidarum. 

PUD (See Chapter 53) Case studies and retrospective series suggest that the incidence of PUD is lower in pregnant women than in nonpregnant individuals.99,100 This impression, if it is valid, may be related to decreased use of NSAIDs by cautious patients or possibly to increased use of antacid medications to treat nausea or heartburn. It is conceivable, but equally unproved, that gestational steroids promote GI mucosal cytoprotection. PUD is likely underdiagnosed during pregnancy, given the reluctance of physicians to perform diagnostic tests on pregnant women. Gastric acid secretion and the natural history of Hp infection, as far as we know, are not altered by gestation. The dyspeptic symptoms that often accompany pregnancy, especially nausea, vomiting, and heartburn, may make diagnosis

of PUD difficult. Because PUD is exceedingly common in the population as a whole, physicians who care for pregnant women should be vigilant for its occurrence. A trial of empirical acid suppression may be useful in women with suspected PUD and is thought to be safe.101-104 In confusing cases, diagnostic EGD is indicated (see earlier). First-line therapies of PUD in pregnancy include ranitidine and sucralfate, although most PPIs are also effective. Patients with Hp infection may be given antibiotics during pregnancy or after delivery. 

IBD (See Chapters 115 and 116) Physicians who treat patients with IBD are likely to encounter the disorder in pregnant women.105 The majority of cases of IBD in women first present before age 30, the years of peak fertility.106 Some authors report women to have an approximately 30% greater risk than men of developing UC or Crohn disease. There is controversy regarding the effects of IBD on fertility. Pregnancy rates in IBD patients may be spuriously low because of self-image problems that result in sexual avoidance and voluntary childlessness.107 Fear of IBD in offspring and fear of fetal malformation from maternal drug therapy are often cited as major causes of childlessness by affected women.108 Female fertility itself, however, does not appear to be impaired by uncomplicated IBD.109,110 A notable exception is fertility in UC patients treated with total colectomy and ileoanal J-pouch anastomosis.111,112 A meta-analysis found a 3-fold increase in the risk of infertility in IBD patients who had undergone this procedure.112 Infertility in these individuals is most likely caused by pelvic adhesions and fallopian tube scarring. Potential infertility should be discussed with patients of childbearing age who are considering this operation. Fertility in men with IBD is impaired by sulfasalazine treatment, which causes decreased sperm counts, which usually return to normal within 6 months of discontinuing the drug.113 If the initial presentation of IBD is during pregnancy, the disease is often diagnosed during the first trimester.114,115 Cases of this type are no more severe than those in nonpregnant individuals. Likewise, pregnancy does not appear to increase the severity of or morbidity due to preexisting IBD. Evidence suggests that active disease around the time of conception increases the risk of disease relapse during pregnancy; UC patients relapse more often during pregnancy than Crohn disease patients.116 The goals of the treating physician are to minimize IBD symptoms and morbidity prior to conception. Most experts agree that during gestation, affected patients should continue optimized pre-pregnancy therapy to avoid possible flares resulting from medication withdrawal. Exacerbations of IBD that occur during pregnancy should be managed aggressively to avoid complications, including hemorrhage, perforation, sepsis, fetal demise, and premature labor. Treatment of fulminant colitis is the same as in nonpregnant individuals, namely high-dose glucocorticoids, IV antibiotics, cyclosporine, and salvage biological therapies. The indications for bowel surgery likewise are the same as in nonpregnant IBD patients, although bowel surgery is associated with premature labor as well as maternal and fetal mortality.117,118 A colostomy to achieve colonic decompression and fecal diversion may be safer than total colectomy.119 Synchronous cesarean section and subtotal colectomy have been advocated for patients with fulminant colitis after 28 weeks of gestation.120 IBD patients are at increased risk for poor pregnancy outcomes, even if they have mild or inactive disease.121 Major complications include premature birth, low-birth-weight and small-for-gestational-age infants, and increased cesarean section rates.122 The risk of fetal malformations in this setting is unclear.123 Pregnant women with UC may be at increased risk for thromboembolic events.124 The majority of IBD patients require several medications to remain symptom-free. Some safety data are available regarding the teratogenicity of the most commonly used IBD drugs, but

CHAPTER 40  Gastrointestinal and Hepatic Disorders in the Pregnant Patient

there are no long-term studies of their potential adverse effects on the offspring of affected patients. It is important to carefully review the possible risks and known benefits of therapy with patients before conception. Potentially teratogenic drugs should be discontinued before conception, if at all possible. Methotrexate and thalidomide are known teratogens and abortifacients and should be used with caution in patients of childbearing age. The optimum period of abstinence from these medications before conception is unknown; however, a minimum of 6 months is recommended. The 5-aminosalicylates are widely used during pregnancy to treat mild IBD. A prospective study of pregnant patients treated with mesalamine, as well as a large case series, did not show any increased risk of teratogenicity from this therapy.125,126 Azathioprine and its metabolite, 6-mercaptopurine, are among the most studied and widely used immunosuppressant medications in pregnant patients. Their metabolites are found in cord blood and excreted in small quantities in breast milk. Data concerning human use of these agents have failed to confirm the teratogenicity seen in animal studies.127 Many studies of pregnant IBD patients treated with 6-mercaptopurine have not shown an increase in preterm delivery, spontaneous abortion, congenital abnormalities, or childhood neoplasia.128-130 Based on these data and extensive experience with this drug and its metabolites in pregnant women, experts concur that their discontinuation before or during pregnancy is not advisable. Instead, careful monitoring of metabolite levels in the mother are recommended.131 Glucocorticoids have been used for decades to treat pregnant patients with moderate to severe IBD, as well as other more common glucocorticoid-responsive diseases such as asthma. Early reports suggested an increased risk of congenital malformations in the infants of treated mothers.126 Subsequent prospective studies and substantial experience with drugs in this class confirm that the risk of malformations secondary to their use is extremely low. Glucocorticoid treatment during pregnancy is, however, associated with other complications, including maternal glucose intolerance and hypertension (risks factor for preeclampsia), macrosomia, and fetal adrenal suppression.132 Prednisolone is more efficiently metabolized by the placenta than other glucocorticoids and may pose less risk of adrenal suppression.133 Adverse outcomes have not been reported after use of oral budesonide in a small number of pregnant patients.134 Many pregnant organ transplant recipients have been treated with cyclosporine as immunosuppressive therapy, without reports of significant teratogenicity. TNF-α antagonists have been used extensively to treat IBD and other inflammatory diseases. Serum infliximab levels increase, whereas serum adalimumab levels are stable, during pregnancy.135 These immunoglobulins reach the fetal compartment, especially during the third trimester. An exception may be certolizumab, which lacks the Fc fragment required for active transport. The drugs are concentrated in the fetus and are detectable in the infant’s blood for months after birth.114,136 Postmarketing registries of safety data and case series have not identified an increased incidence of fetal malformations or miscarriage in women treated during pregnancy with infliximab or adalimumab.137 Recently published guidelines recommend that TNF-α antagonists be continued throughout pregnancy, unless otherwise indicated.138 Some experts have expressed concerns about potential detrimental effects of fetal exposure to TNF-α antagonists on the development of the neonatal immune system. For this reason, babies exposed in utero to drugs in this class should not receive live vaccines during the first 6 months of life; however, other vaccines are recommended.139 There has been no increase in the short- or long-term incidence of infections in children who have been exposed in utero to TNFα antagonists.140 There is still limited data on the effects of treatment with anti-integrin and anti-IL-12/23 antibodies (vedolizumab or natalizumab and ustekinumab, respectively) during pregnancy.

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Although no problems were identified in one small study of pregnancy outcomes in women exposed to vedolizumab, pregnant women should not be treated with these medications until more safety data become available.141 Vaginal delivery is not contraindicated in IBD patients, but cesarean section is recommended for patients with active perineal disease. Patients with ileoanal pouches are often advised to avoid vaginal delivery in order to avoid anal sphincter injury. 

Appendicitis (See Chapter 120) Suspected acute appendicitis is the most common nonobstetric indication for exploratory laparotomy in pregnant women.142,143 Appendicitis complicates approximately 1 in 1500 pregnancies and may develop at any time during the course of gestation.143 Diagnosis may be difficult because the enlarging uterus displaces the cecum and appendix cephalad, altering the location of pain caused by appendiceal inflammation and resulting in increasingly delayed detection as pregnancy progresses.144 Late diagnosis of an inflamed appendix is responsible for complications that are associated with excess maternal and fetal morbidity and mortality.145 During all 3 trimesters of pregnancy, RLQ pain is the most common presenting symptom of appendicitis.146 In addition to pain, affected individuals frequently complain of nausea, but this symptom is often difficult to interpret during gestation. Graded-compression US of the appendix is the diagnostic test of choice for pregnant patients suspected of having appendicitis.146 Helical CT has also been reported to be helpful in this setting.143 Pregnant patients with appendicitis during any trimester may be treated with laparoscopic appendectomy,147 although potential interference by the gravid uterus may be a relative contraindication to this procedure during the third trimester.148 Appropriate supportive care can prevent fetal loss associated with appendiceal perforation.149 

GALLBLADDER AND PANCREATIC DISORDERS AND PREGNANCY Gallstone Disease (See Chapter 65) Pregnant women tend to form gallstones because of changes in gallbladder function and bile composition (see earlier). Gallstones are frequently noted during gestation when US examination is performed to evaluate the fetus150; the prevalence of gallstones in asymptomatic pregnant women is reported to be between 2.5% and 12%. Despite this high prevalence, the incidence of acute cholecystitis is not increased by pregnancy. When necessary, surgical intervention for gallstone-related disease does not increase the risk of preterm labor or of fetal or maternal mortality.73,151 Endoscopic extraction of bile duct stones with minimal use of fluoroscopy and appropriate maternal shielding is acceptable when necessary to treat choledocholithiasis during pregnancy.152 Endoscopic intervention was found to be associated with fewer hospital admissions and a lower cesarean section rate than conservative treatment in 1 study.153 

Acute Pancreatitis (See Chapter 58) Acute pancreatitis is uncommon during gestation, occurring once in every 1066 to 3300 pregnancies.154,155 Most cases are caused by gallstones and present during the third trimester or the puerperium. The mild hypertriglyceridemia normally seen in pregnant women may be more severe in persons with familial hyperlipidemia, predisposing them to develop pancreatitis on this basis.156 The clinical characteristics of acute pancreatitis during gestation are similar to those in nonpregnant women, although complications of pancreatitis do not develop in the majority of pregnant women with this disorder.157 

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HEPATIC DISORDERS UNIQUE TO PREGNANCY Pregnant women may develop liver diseases that are etiologically related to gestation or its complications.158 As a rule, these disorders become clinically evident during the third trimester or just after delivery. They may be severe, even life threatening, but affected individuals are expected to survive with prompt diagnosis and appropriate management. Liver diseases unique to pregnancy are also associated with increased fetal morbidity and mortality.

Cholestasis of Pregnancy Cholestasis of pregnancy is a form of intrahepatic cholestasis associated with pruritus, elevated serum bile acid levels, and the finding of bland cholestasis on liver biopsy.159,160 This disorder may have a variable course, making it difficult to diagnose; nevertheless, it has serious implications for fetal well-being, and cases must be identified as promptly as possible.161 Cholestasis of pregnancy usually presents in the third trimester, but may be seen earlier in gestation, even in the first trimester. Its first and most characteristic symptom is pruritus, and, as a result, patients may be referred to a dermatologist for initial evaluation. As in other forms of cholestasis, the pruritus of cholestasis of pregnancy is most severe in the skin of the palms and soles and experienced most intensely at night. Only 10% to 25% of affected individuals later develop jaundice. Elevated serum bile acid levels (>10 μmol/L) confirm the presence of cholestasis; some patients with the disorder also have bilirubinuria and even mild hyperbilirubinemia.162 Serum alkaline phosphatase concentrations are modestly increased, but GGTP levels are normal or only marginally elevated.162 The latter pattern of test results is atypical of adult cholestasis but is seen in pediatric patients with progressive familial intrahepatic cholestasis, as in Byler syndrome.163 Serum aminotransferase levels are elevated in affected women, sometimes to values of 1000 U/L or higher, making it difficult, on occasion, to distinguish cholestasis of pregnancy from viral hepatitis. An increased serum autotaxin level has been shown to be a sensitive and specific diagnostic test that can distinguish cholestasis of pregnancy from other pregnancy-related liver diseases.164 Symptoms and laboratory test abnormalities of affected patients may wax and wane. Intense cholestasis is associated with steatorrhea that is usually subclinical but can cause fat-soluble vitamin deficiencies, most notably deficiency of vitamin K. Improvement of symptoms and laboratory test results begins with delivery of the infant, and usually, although not invariably, is prompt and complete. Rare patients experience prolonged cholestasis that may be indicative of underlying biliary tract disease, such as PBC or sclerosing cholangitis.165,166 Women with ordinary cholestasis of pregnancy have no residual hepatic defect after resolution of the disorder, but they are at increased risk for development of gallstones, cholecystitis, and pancreatitis.167 In addition, 60% to 70% of affected individuals develop cholestasis during subsequent pregnancies (although recurrent episodes may be less severe than the initial one) or with use of oral contraceptives. The risk of recurrence with subsequent pregnancies is increased by interval cholecystectomy.168 Cholestasis of pregnancy has serious implications for fetal well being. There are many reports of increased frequencies of fetal distress, unexplained stillbirth, and need for premature delivery of the babies of women with this disorder.169 Fetal hypoxia and meconium staining have been reported at delivery in 19% of Swedish women with cholestasis of pregnancy.170 These complications were shown to correlate with maternal bile acid levels higher than 40 μmol/L.171 Although the risk to the fetus may be reduced by close monitoring of affected mothers, it cannot be eliminated completely.172-175 Planned early elective delivery as soon as the fetal lungs have matured has been recommended for this reason.

As discussed in Chapter 64, a number of the molecular mechanisms of bile formation have been elucidated in recent years, resulting in a more sophisticated understanding of many cholestatic disorders.176,177 Mutations of the MDR3 (ABCB4) gene are likely responsible for approximately 15% of cases of cholestasis of pregnancy.178-181 The MDR3 gene product is a phospholipid flippase that translocates phosphatidylcholine from the inner to the outer leaflet of the canalicular hepatocyte membrane where it is solubilized by bile acids to form mixed micelles. There is, however, no relationship of cholestasis of pregnancy to HLA type.182 Environmental, hormonal, and other factors also likely contribute to the development of cholestasis in pregnant women. In Chile and Scandinavia, where cholestasis of pregnancy is common, the disorder occurs most often during colder months. The incidence of cholestasis of pregnancy in Chile has declined, possibly owing to a fall in mean plasma selenium levels.183 An increased sensitivity to the cholestatic effects of exogenous estrogen has been demonstrated in family members, including male relatives, of patients who develop cholestasis while pregnant.184 Therapeutic or experimental administration of estrogen compounds to susceptible women can precipitate the disorder.185,186 Similarly, progesterone therapy during gestation is associated with development of cholestasis.187,188 The finding that ursodeoxycholic acid alters the metabolism of progesterone may explain its therapeutic effect in this setting.189,190 It is possible that some women with cholestasis of pregnancy have inherited an enhanced sensitivity to estrogen or a variation in the metabolism of progesterone that causes cholestasis in response to a variety of stimuli, including some medications and dietary factors.191 The incidence of cholestasis of pregnancy is significantly higher in women with hepatitis C than in other pregnant women.192 The differential diagnosis of cholestasis of pregnancy includes other cholestatic disorders such as PBC, PSC, benign recurrent intrahepatic cholestasis, cholestatic viral hepatitis, toxic liver injury, and bile duct obstruction. Liver biopsy specimens of affected individuals reveal bland changes typical of cholestasis due to a variety of etiologies, but biopsy is not usually necessary to make the diagnosis. It is important to remember that pregnancy may exacerbate a preexisting subclinical cholestatic disorder. For example, a family of sisters with progressive liver disease who also developed recurrent severe cholestasis of pregnancy was described in 1997.165 Management of cholestasis of pregnancy is primarily palliative.193,194 Ursodeoxycholic acid is helpful in relieving symptoms,190 may reduce fetal complication rates,178 and is well tolerated by mother and fetus.195,196 Studies of treated individuals have demonstrated a change in the bile acid content of maternal serum and amniotic fluid, as well as increased placental bile acid transport.197-199 Mostinvestigators have prescribed a conventional dose (15 mg/kg/day), although one report suggests that a higher dose (20 to 25mg/kg/day) is more effective.186 Treatment with bile-acid binders such as cholestyramine196 and guar gum may alsorelieve symptoms,200 but it is important to keep in mind that therapy with these agents worsens steatorrhea and resultant fat-soluble vitamin deficiencies.201 Administration of S-adenosyl-l-methionine to patients with cholestasis of pregnancy has had mixed therapeutic results202-204; its use in combination with ursodeoxycholic acid may increase its benefit.205 A short course of a glucocorticoid (e.g., oral dexamethasone 12mg/day for 7 days) has been reported to reduce itching and serum bile acid levels in persons with this disorder,206 but was also associated with clinical deterioration in one case.207 Sedatives, such as phenobarbital, may relieve itching in cholestasis patients but may adversely affect the fetus. Exposure to ultraviolet B light has been suggested as therapy in this setting. As in other cholestatic syndromes, no treatment is uniformly effective in women with cholestasis of pregnancy, with the usual exception of delivery. 

CHAPTER 40  Gastrointestinal and Hepatic Disorders in the Pregnant Patient

Preeclampsia Preeclampsia is a multi-system disorder characterized by de novo hypertension associated with endothelial damage and maternal organ dysfunction, possibly including the liver, that may produce severe, even life-threatening, complications and affect pregnancy outcome.208 The placenta is essential to the development of this disorder, and severe cases are associated with pathologic evidence of placental ischemia.209 Preeclampsia complicates 3% to 10% of pregnancies, occurring in the second half of pregnancy or the puerperium and most commonly, but not exclusively, in primiparous women or women with multiple gestations.210 Usual criteria for making the diagnosis include a sustained blood pressure of 140/90 mm Hg or greater after the 20th week of pregnancy in a previously normotensive woman, accompanied by proteinuria (≥300mg/24 hr), which is approximately equivalent to a urine protein concentration of 30 mg/dL (“1+ dipstick”) on random testing.208 Many patients are also hyperreflexic and have edema. Liver disease is recognized as a common and potentially ominous complication of preeclampsia. The HELLP syndrome, first described by Weinstein in 1982,211 is the most usual form of preeclamptic liver disease and may underlie development of hepatic hematoma, rupture, and infarction.212-214 Evidence suggests that there are different preeclampsia phenotypes and that HELLP syndrome may be a distinct genetic and clinical entity.215,216 Although preeclampsia is common in patients with acute fatty liver of pregnancy (AFLP) and may play a role in the pathogenesis of this disorder, AFLP is not usually classified as a preeclamptic liver disease.217 

HELLP Syndrome HELLP is seen in up to 12% of women with severe preeclampsia, occurring in 0.2% to 0.8% of all pregnancies.218-220 In the past, clinicians have relied on 2 major HELLP diagnostic classification systems: the Tennessee classification and the Mississippi TripleClass classification, which further categorizes affected individuals on the basis of the nadir of the maternal platelet count (Box 40.1). More recently, the diagnostic criteria for HELLP syndrome have been standardized by the American College of Obstetricians and Gynecologists Task Force in Hypertension in Pregnancy (Box 40.2).221 In addition to the diagnostic abnormalities of hemolysis, elevated serum aminotransferase levels, and thrombocytopenia in conjunction with hypertension and proteinuria, patients with typical HELLP syndrome frequently have complaints of chest, epigastric, and RUQ abdominal pain (Table 40.2). These symptoms are often accompanied by nausea, vomiting, headache, and blurred vision in varying combinations. Some pregnant patients, however, may present with an asymptomatic fall in the platelet count during observation for preeclampsia, or initially have no hypertension or proteinuria.222 Other women may complain of malaise, suggesting the diagnosis of a viral syndrome.223 Most affected individuals seek treatment after week 27 of gestation, but up to 11% may do so earlier. It is important to note that a delayed presentation of HELLP syndrome after delivery, despite absence of signs of preeclampsia at delivery, occurs in up to 30% of cases.218 The diagnosis of HELLP syndrome is based on an assessment of the clinical circumstances and features of the illness at the time of presentation because there is no single diagnostic test that is specific for the disorder.220,224 Hemolysis in patients with HELLP is mild. Fragmented red blood cells (schistocytes) are seen on smears, and the serum LDH level is elevated. Serum aminotransferase levels are also elevated, sometimes minimally and other times to greater than 1000 U/L in association with laboratory signs of cholestasis.218,225 Serum bilirubin levels can often be mildly elevated, compatible with the finding of hemolysis. Elevated serum levels of glutathione S-transferase alpha,226

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BOX 40.1 The Tennessee and Mississippi Triple-Class Diagnostic Classification Systems of the HELLP Syndrome TENNESSEE CLASSIFICATION 1. Microangiopathic hemolytic anemia with abnormal blood smear, low serum haptoglobin, and elevated serum LDH levels 2. Serum LDH level >600 IU/L or twice the laboratory upper limit of normal and serum AST level >70IU/L or twice the laboratory upper limit of normal, or serum bilirubin level >1.2 mg/dL 3. Platelet count 50,000/mm3 and ≤100,000/mm3 Class III: platelet count nadir >100,000/mm3 and ≤150,000/mm3

BOX 40.2 Recommended Criteria for Diagnosis of HELLP Syndrome (ACOG Task Force in Hypertension in Pregnancy) 1. Hemolysis and at least 2 of the following: a. Schistocytes and burr cells on peripheral smear b. Serum bilirubin ≥1.2 mg/dL c. Low serum haptoglobin d. Severe anemia unrelated to blood loss 2. Elevated liver enzyme levels: a. AST or ALT ≥twice the upper limit of normal b. LDH ≥ twice the upper limit of normal 3. Platelets 34 sec) Elevated serum ammonia levels (>47μmol/L) Elevated serum AST or ALT levels (>42IU/L) Elevated serum bilirubin levels (>14μmol/L or 0.8mg/dL) Elevated serum urate levels (>340μmol/L or 5.7mg/dL) Encephalopathy Hypoglycemia (11,000/mm3) Microvesicular steatosis on liver biopsy Polydipsia/polyuria Renal impairment (creatinine >150μmol/L or 1.7mg/dL) Vomiting

Fig. 40.2  Subcapsular hepatic hematoma in a patient with preeclampsia. This coronal section of a T1-weighted MRI scan demonstrates the subcapsular clot or hemorrhage (horizontal arrows) adjacent to the liver (vertical arrow). (From Barton JR, Sibai BM. Hepatic imaging in HELLP syndrome. Am J Obstet Gynecol 1996; 174:1820-5.)

hepatic rupture tend to be older and to have had multiple previous pregnancies. Diagnosis is made by signs of liver rupture on US, CT, or MRI in conjunction with aspiration of blood on paracentesis.212,269 Imaging studies often show that affected patients have a partially contained subcapsular hematoma (Fig. 40.2).270 In this situation, hepatic artery embolization may be effective in controlling bleeding and limiting morbidity and mortality.271 Management must be aggressive, with rapid delivery of the fetus by the obstetrician and, if embolization is inadequate to control bleeding, repair of the liver by an experienced liver surgeon.272 Postoperatively, patients have a protracted course that may include DIC and hepatic failure. Patients with hepatic rupture have undergone orthotopic liver transplantation after emergent hepatectomy and interval portosystemic shunt as a temporizing measure while a donor graft is sought.265,266,273,274 Survivors of hepatic rupture may have uneventful subsequent pregnancies,275 but recurrence of hematoma and rupture have also been reported.276 Some pregnant women with preeclampsia, HELLP syndrome, and abdominal pain have contained subcapsular hematoma.277 In this circumstance, patients can be observed with serial CT and managed without surgery.212,276 Angiographic embolization of hepatic artery branches supplying blood to the affected portion of the liver may be helpful.271 Hepatic hematoma and rupture complicating preeclampsia presumably result from extravasation of blood from one or several microscopic areas of periportal hemorrhage under Glisson capsule. Periportal hemorrhage is a typical pathologic finding in the livers of patients with preeclampsia and HELLP syndrome.278The capsule is believed to be stretched and torn away from the surface of the liver by the enlarging hematoma. Ultimately, the capsule may rupture, allowing the liver surface to bleed freely into the peritoneal cavity. Hepatic infarcts may also complicate preeclampsia. Affected individuals present with fever, leukocytosis, anemia, and marked elevation of serum aminotransferase levels,212,214,279 and in the most severe cases develop multiorgan failure, including liver failure. Cross-sectional imaging demonstrates confluent hepatic infarcts. Needle aspiration of these areas yields blood and necrotic

aPPT, Activated partial thromboplastin time; PT, prothrombin time. Adapted from Ch’ng CL, Morgan M, Hainsworth I, et al. Prospective study of liver dysfunction in pregnancy in Southwest Wales. Gut 2002; 51:876–80; and Knight M, Nelson-Piercy C, Kurinczuk JJ, et al. A prospective national study of acute fatty liver of pregnancy in the UK. Gut 2008; 57:951–6.

tissue; immediately adjacent liver parenchyma contains periportal hemorrhage and fibrin deposition typical of preeclampsia and HELLP syndrome. Hepatic infarction is sometimes associated with the presence of a hypercoagulable condition, such as factor V Leiden or antiphospholipid antibody.280 

Acute Fatty Liver of Pregnancy AFLP, a form of microvesicular fatty liver disease unique to human gestation, presents late in pregnancy, sometimes as fulminant hepatic failure with sudden onset of coagulopathy and encephalopathy in a woman without a prior history of liver disease.281,282 AFLP is diagnosed on the basis of typical clinical and pathologic manifestations in approximately 1 of 6700 third-trimester pregnancies,283 but it also is recognized that subclinical cases exist.217 A prospective study of more than 1 million pregnant women using the United Kingdom Obstetric Surveillance System and standard diagnostic criteria (Swansea criteria [Box 40.3])284 identified only 57 cases of AFLP.285 The pathophysiologic mechanisms underlying development of this disorder are unknown, although at least some patients with AFLP have an inherited fatty-acid oxidation defect that also affects the fetus.286-290 AFLP presents late in pregnancy, usually between 34 and 37 weeks of gestation, although cases beginning as early as weeks 19 to 20 of gestation have been reported. Rarely, the onset of AFLP is after delivery. Initial symptoms usually include nausea and vomiting, often associated with abdominal pain. Pruritus may be an early complaint; overlap with cholestasis of pregnancy has occurred but is rare.291 Patients with AFLP are frequently confused and have pregnancy-related complications, such as premature labor, vaginal bleeding, and decreased fetal movement. The disorder is most common in primiparous women and in women with multiple gestations.292 Affected individuals have a much greater than expected number of male fetuses. 293 Of note is the fact that preeclampsia, an accompanying diagnosis in 21% to 64% of cases,283,294 is also associated with first pregnancies, twin pregnancies, and male fetuses. On laboratory evaluation, women with AFLP often have prolonged prothrombin times and decreased serum fibrinogen levels, as well as leukocytosis. Their serum aminotransferase levels are usually moderately elevated (≈750U/L) but, rarely, may be

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very high or even normal. Jaundice is common but not invariable. Renal dysfunction with elevations of serum creatinine, blood urea nitrogen, and uric acid levels is often present. The course of AFLP is quite variable. Hypoglycemia and hyperammonemia occur and should be suspected when at-risk patients exhibit signs of altered central nervous system function. Other complications of liver failure, including ascites, pleural effusion, acute pancreatitis, respiratory failure, renal failure, and infection, may develop in patients with AFLP. Vaginal bleeding or post–cesarean section bleeding is also common in these individuals. Transient diabetes insipidus is sometimes seen.295 More rarely, affected patients have myocardial infarction296 or pulmonary fat emboli.297 Diagnosis of AFLP is almost always based on the appearance of typical clinical features of the disorder, including laboratory test results, during the later stages of pregnancy. Hepatic imaging may confirm the presence of hepatic steatosis in patients with suspected AFLP,298 and plays a crucial role in identifying hepatic hematoma, rupture, and infarction. Liver biopsy is usually unnecessary to make the diagnosis, but histologic results may be pathognomonic and, therefore, useful if the obstetrician has reservations about delivery. Trans-vascular sampling of liver tissue, however, may be necessitated by coagulopathy. The histologic hallmark of AFLP is small-droplet fatty infiltration of the liver that is most prominent in hepatocytes surrounding central veins (zone 3) and spares hepatocytes surrounding portal areas (Fig. 40.3). Steatosis of this type has a relatively homogeneous appearance on light microscopy and may be difficult to discern on examination of ordinary H&E-stained specimens. To confirm the diagnosis, special techniques must be used; frozen tissue may be stained for fat with oil-red O, or electron microscopy can be used to examine a glutaraldehyde-fixed specimen. Plans must be made prior to the biopsy for appropriate handling of the liver tissue. Other histologic findings in affected patients can be misleading, including lobular disarray suggestive of viral hepatitis and biliary ductular proliferation, and inflammation suggestive of cholangitis.217,299 Patients with AFLP do not have the periportal hemorrhage and sinusoidal fibrin deposition seen in the livers of individuals with preeclampsia and HELLP syndrome. The differential diagnosis in suspected cases of AFLP includes those causes of acute hepatic failure not associated with pregnancy, as discussed later, especially viral hepatitis and toxic liver injury. Uncommon types of viral hepatitis, such as hepatitis E and herpes simplex hepatitis, may be more severe in pregnant than in non-pregnant individuals.300,301 These viral agents can be identified by appropriate serologic tests. A more difficult problem is

Fig. 40.3  Histopathology of acute fatty liver of pregnancy. The perivenular hepatocytes are pleomorphic and vacuolated, and there is lobular disarray. Large fat droplets are not seen.

distinguishing AFLP from other liver diseases that complicate pregnancy, particularly the preeclamptic liver diseases, namely HELLP syndrome and hemorrhagic or ischemic liver injury. For example, patients with AFLP may develop preeclampsia and DIC with attendant thrombocytopenia, thereby meeting the diagnostic criteria for HELLP syndrome (see Box 40.1). Fortunately, it is not usually necessary to distinguish among these various diagnoses because AFLP, HELLP syndrome, and preeclampsia are treated by expedited delivery of the infant. It is, however, of crucial importance to recognize hepatic hematoma and rupture rapidly (see earlier discussion). The pathogenesis of AFLP has not been elucidated. Initially, AFLP was thought to be caused by exposure to a toxin. For example, microvesicular steatosis of the liver can be caused by treatment with sodium valproate or IV tetracycline. Despite an intensive search, however, no toxin that might be responsible for development of AFLP has been identified. Because of the coincidental occurrence of preeclampsia and AFLP in many patients, the disorder has been considered by some experts to be a severe form of preeclamptic liver disease.217,302,303 Placental oxidative stress, thought to be responsible for development of preeclampsia, is accompanied by release of toxic mediators that may play a role in the pathogenesis of AFLP.304 Arguing against this conclusion are the absence of the usual histologic features of preeclampsia in liver biopsy specimens from patients with AFLP and the absence of the usual clinical features of preeclampsia in many patients with AFLP. There is a well-established association between AFLP and inherited defects in beta oxidation of fatty acids.287-289,305,306 This connection is empirically supported by similar clinical and histologic findings in patients with AFLP and those with Jamaican vomiting sickness, a liver disease caused by a toxin in unripe akee fruit that disables intramitochondrial beta oxidation of fatty acids. Maternal liver disease (HELLP or AFLP) has been reported in 62% of the mothers of infants with defects of fatty-acid oxidation.287 AFLP may develop regardless of maternal genotype if the fetus is deficient in long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) and carries at least 1 allele for the G1528C LCHAD mutation.286,307 Another beta oxidation defect, carnitine palmitoyltransferase-1 deficiency, has also been associated with AFLP.308 Prenatal genetic diagnosis based on chorionic villus sampling has proved to be feasible and accurate in pregnant members of affected families.309,310 Not every investigator, however, has been able to confirm the association between AFLP and beta oxidation defects,311 and other as yet unknown mechanisms may play a role in the pathogenesis of this disorder. Patients with AFLP should be managed in an intensive care setting, preferably by obstetricians qualified in the practice of maternal-fetal medicine, in cooperation with other appropriate specialists. Early diagnosis and prompt delivery of the infant are imperative to minimize maternal and fetal morbidity and mortality. Affected individuals may be very ill postpartum until the physiologic defects responsible for their clinical abnormalities resolve and the livers recover. Supportive care may include infusion of blood products, mechanical ventilation, hemodialysis, and antibiotic therapy. Hepatic encephalopathy is treated as indicated by measures intended to evacuate feces and bacteria from the colon. Infusion of concentrated glucose solution may be required to treat or prevent hypoglycemia. Although many patients with AFLP have DIC and depressed antithrombin III levels, treatment with heparin or antithrombin III is not recommended.312 Patients with diabetes insipidus may be managed with 1-deamino-8-darginine-vasopressin.295 Some individuals with liver failure secondary to AFLP require emergency orthotopic liver transplantation as a potentially life-saving measure.266,313,314 Most affected women, however, recover completely with appropriate supportive care. Persistent or even increasing hyperbilirubinemia and multiple complications after delivery do not necessarily indicate the need for liver transplantation.

CHAPTER 40  Gastrointestinal and Hepatic Disorders in the Pregnant Patient

Survival of patients with AFLP has been reported to be nearly 100% with prompt diagnosis, delivery of the infant, and intensive care.283,294,315,316 Infants of affected women have perinatal mortality rates of less than 7%. Surviving babies may have LCHAD deficiency and develop nonketotic hypoglycemia and obtundation. Recurrence of AFLP has been documented, particularly in women with LCHAD deficiency.317,318 In all cases of AFLP, the mother, father, and child should be tested for the G1528C LCHAD mutation.286 

OTHER HEPATIC DISORDERS AND PREGNANCY Viral Hepatitis Viral hepatitis is the most common form of liver disease worldwide, and frequently affects women of childbearing age, either as an acute infection or as a chronic disease.319,320 Hepatitis A, unless unusually severe, does not appear to alter the normal course of pregnancy, nor does pregnancy appear to influence the natural history of hepatitis A. Acute and chronic viral hepatitis of other types, however, may have implications for maternal and fetal well being.

HEV (See Chapter 82) HEV is an enterically transmitted RNA virus with 4 genotypes and 1 serotype.301,321 Genotypes 1 and 2 only infect humans and usually cause epidemic disease during the monsoon season in central and south Asia and India. Genotypes 3 and 4 infect humans and numerous animal species, particularly swine and chickens and possibly cattle and sheep, as well as rats. These HEV genotypes are responsible for sporadic cases of hepatitis in farmers and may spread to others by consumption of undercooked meat.322 The prevalence of HEV antibody has declined in blood samples collected in the US from 2009 to 2010, as compared to those collected from 1998 to 1994;320 most recently the HEV antibody prevalence was 6% for individuals aged 6 years or above. Two recombinant-protein anti-HEV vaccines have been tested in clinical trials,323 and one of them was approved for use in China by the State Food and Drug Administration in December 2011. Acute hepatitis E during the third trimester of pregnancy is a cause of fulminant hepatic failure and has a mortality rate of up to 20%.301 Maternal HEV infection has also been associated with intrauterine fetal death.324,325 The risks of intrauterine death and abortion in any trimester are greater in pregnant women with hepatitis E than they are in their uninfected counterparts. Maternal-fetal transmission of HEV resulting in symptomatic neonatal hepatitis has occurred,326 and no known therapy prevents vertical transmission of this virus. Pregnant women should avoid traveling to endemic areas during monsoon season and outbreaks of the disease. 

HSV (See Chapter 83) Subclinical hepatitis associated with primary HSV infection is common. In pregnant or immunosuppressed individuals, this virus may cause severe liver disease.327 Infection during pregnancy, particularly the third trimester, can result in fulminant hepatic failure. Affected individuals are obtunded and usually anicteric with elevated serum aminotransferase levels and coagulopathy. They may have subtle oropharyngeal or genital herpetic lesions. Encephalopathy may result from herpes encephalitis. The diagnosis of HSV infection can be confirmed by serologic testing and PCR assay for viral DNA. Liver biopsy specimens from affected patients usually demonstrate characteristic intracytoplasmic inclusion bodies and areas of focal hemorrhage. Treatment with oral acyclovir or valacyclovir is effective and appears to prevent viral transmission to the fetus.328,329 

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HBV and HDV (See Chapters 79 and 81) HBV infection in pregnant women is the most important factor perpetuating the worldwide epidemic of chronic hepatitis B.330-332 Universal HBV screening in pregnant women is recommended.333 Although HBV can be passed from infected mothers to their infants during gestation, at the time of delivery or after birth, most mother-to-infant transmission occurs during delivery, a time when the neonate’s immune system is incapable of clearing the virus. Verticaltransmission of HBV is responsible for most cases of chronic hepatitis B in endemic areas, especially Southeast Asia and Africa.334 Maternal infectivity is proportional to viral load.335 Mothers with a reactive serum test for hepatitis B e antigen have more circulating virus and higher rates of perinatal transmission336 than mothers who have undetectable serum hepatitis B e antigen with a reactive serum test for hepatitis B e antibody,337 although the latter individuals can still be a source of neonatal infection.338 Without treatment, 90% of infants born to hepatitis B e antigen–positive mothers and 10% of infants born to hepatitis B e antigen–negative mothers develop chronic HBV infection. Antiviral therapy beginning in the third trimester is recommended for pregnant women with inactive hepatitis B and serum HBV DNA levels greater than 200,000 IU/mL.339 For pregnant women with active hepatitis B, management should be the same as thatrecommended for nonpregnant women.340 Appropriate therapy during pregnancy significantly reduces the risk of mother-to-infant viral transmission.341 If, however, the risk of transmission is low, antiviral therapy in addition to recommended prophylaxis of the infant offers no advantage.342 Invasive procedures during pregnancy, such as amniocentesis, may pose a risk of HBV transmission from mother to child, especially when the maternal HBV-DNA level is greater than or equal to 7 log copies/mL.343 The infants of mothers with a reactive serum test for hepatitis B surface antigen should receive hepatitis B immunoglobulin and hepatitis B vaccine within 12 hours of delivery.344 This treatment is highly effective, but despite appropriate passive-active immunoprophylaxis immediately after birth, 1% to 2% of treated infants will become chronically infected with HBV.335,345 Breastfeeding by mothers with chronic hepatitis B poses no additional risk of viral transmission as long as the baby has received appropriate immunoprophylaxis.346 Most women of childbearing age with chronic HBV infection are healthy virus carriers with a very low risk of developing disease complications. A flare of hepatitis, however, and in some cases even acute liver failure, may occur in previously asymptomatic individuals during the peripartum period.347,348 In a recent study, approximately 25% of women with chronic hepatitis B had disease flares in the first few months after delivery.349 Investigators have also found an increased incidence of spontaneous preterm birth in association with the presence of HBV DNA in umbilical cord blood.350 For these reasons, pregnant and postpartum patients with hepatitis B should be monitored closely for up to 6 months after delivery.351 The only hepatitis B treatments that have been studied in pregnant women are lamivudine, telbivudine, and tenofovir disoproxil fumarate (TDF). Of these, TDF is preferred because of its reliable efficacy and high barrier to emergence of viral resistance. TDF therapy during the third trimester in pregnant women with high serum levels of HBV DNA has been shown to significantly reduce the incidence of mother-to-child viral transmission.341,352 There was no difference between treated and untreated women in the rates of prematurity, congenital malformations and Apgar scores. Other studies have shown no difference in the incidence of adverse effects between TDF-exposed and -unexposed infants.353-355 Women with chronic hepatitis B are not treated with interferon during pregnancy.356 Vaccination of nonimmune pregnant women against HBV infection is safe and effective.357

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PART IV  Topics Involving Multiple Organs

An accelerated vaccination schedule may be used in women at high risk for exposure to HBV.358 When the indication for hepatitis B therapy is a third-trimester serum HBV DNA level greater than 200,000 IU/mL, stopping treatment at, or within 4 weeks of, delivery is recommended.359 Continued treatment for up to 12 weeks postpartum does not protect the mother from disease flares.360 HDV infection requires simultaneous acute or chronic hepatitis B virus infection. Pregnant patients with hepatitis B who are most likely to have HDV co-infection include those with HIV and immigrants from areas of high HDV endemicity. These individuals should be tested for the presence of anti-HDV antibody, which indicates infection.359 There is no evidence that pregnancy changes the natural course of hepatitis D. Prevention of vertical transmission of HDV is best accomplished by vaccination of the mother against infection with hepatitis B virus, or appropriate therapy of existing maternal hepatitis B prior to pregnancy in conjunction with vaccination and administration of hepatitis B immunoglobulin to the infant. A case report has documented prevention of vertical transmission of hepatitis B and D viruses by this management.361 

HCV (see Chapter 80) Recommendations for the diagnosis and management of hepatitis C in pregnant women (and others) are continually updated by the Hepatitis C Guidance Panel of the AASLD and the Infectious Diseases Society of North America,362 and are available on the internet at https://www.hcvguidelines.org. Although there is currently no recommendation for universal HCV screening of pregnant women, HCV antibody testing is recommended for patients with a risk factor for viral exposure, such as a history of injectiondrug use. Every pregnant woman with HIV infection should be tested for simultaneous HCV co-infection. Patients with reactive antibody tests should have confirmatory HCV nucleic-acid testing.363,364 Mother-to-infant transmission is the principal cause of hepatitis C in children. Between 1% and 2.5% of pregnant women in the US have HCV infection.365 The incidence of HCV vertical transmission is reported to be 5.8% in the children of HCV RNA-positive, HIV-negative women and 10.8% in the children of HCV RNA-positive, HIV-positive women.366,367 Greater serum levels of HCV RNA, as seen in HIV and HCV co-infection, increase the risk of vertical transmission: serum HCV-RNA levels of 106 or greater copies/mL have been associated with vertical transmission in as many as 36% of cases.368 Intrapartum exposure to infected maternal blood, prolonged rupture of membranes, and internal fetal monitoring have also been identified as possible risk factors for neonatal HCV infection.369,370 The incidence of perinatal HCV infection does not seem to be related to whether the baby is delivered vaginally or by cesarean section.368 Although HCV RNA can be detected in breast milk,371 breastfeeding is not considered to be a risk factor for neonatal HCV infection,372 nor are there data that amniocentesis significantly increases the risk of fetal infection. Population-based and case-control studies of the effects of maternal HCV infection on pregnancy outcomes have had inconsistent results. Chronic hepatitis C may be independently associated with development of gestational diabetes, preterm delivery, low birth weight, retarded fetal development, and cholestasis of pregnancy.373-376 Cirrhosis, in particular, is associated with increased maternal and fetal morbidity.377,378 There are no convincing data to suggest that pregnancy alters the natural history of hepatitis C infection, although pregnant women with hepatitis C have a higher incidence of cholestasis of pregnancy than uninfected controls.192 When possible, women of reproductive age with hepatitis C should receive antiviral therapy before becoming pregnant;

direct-acting antiviral agents are not approved for use during pregnancy. No intra- or post-partum intervention has been shown to reduce the risk of vertical HCV transmission, including treatment of the infant with immunoglobulin.379 Patients with hepatitis C are not treated with interferon/ribavirin during pregnancy; ribavirin is a well-established teratogen. Previously infected individuals may have spontaneous HCV-RNA clearance after delivery.380 

Chronic Liver Disease and Portal Hypertension (See Chapters 92 and 94) Women with significant chronic liver disease and cirrhosis often have anovulatory menstrual cycles or are amenorrheic and therefore are unlikely to become pregnant. Only 37 cases of cirrhosis were identified using ICD-9 codes in more than 2 million pregnant women recorded in the California Birth Registry Database between 2005 and 2009.378 Portal hypertension, ascites, and compensatory dilation of submucosal esophageal veins connecting the portal circulation to the azygos vein can occur in pregnant women with noncirrhotic portal hypertension aggravated by physiologic increases in circulating blood volume. Even in the absence of pathologic causes of portal hypertension, these esophageal venous collaterals may become engorged during gestation owing to normal circulatory changes, including increased blood flow and compression of the inferior vena cava by the enlarging uterus, and may be seen on endoscopy. Enlarged veins of the latter type do not bleed spontaneously. Normal pregnancy-associated increases in maternal blood volume appear to aggravate the risk of variceal bleeding in individuals with underlying portal hypertension.381,382 Esophageal variceal bleeding has been reported in 18% to 32% of pregnant women with cirrhosis and as many as 50% of those with known portal hypertension and 78% of those with preexisting varices. In addition to variceal bleeding, women with chronic liver disease and portal hypertension who become pregnant may be at increased risk of death, hepatic decompensation, splenic artery rupture, and uterine hemorrhage, according to reports published between 1950 and 1980.377,381 Cirrhosis appears to significantly increase the risk of preeclampsia, pre-term delivery, low birthweight, and neonatal death.378 Endoscopic band ligation is accepted as the preferred initial therapy of variceal bleeding in pregnant women, although no studies of its safety and efficacy have been done in this setting. Infusion of the somatostatin analog octreotide is also used on the basis of its effectiveness in nonpregnant patients. Vasopressin and octreotide infusions may theoretically cause uterine ischemia and induce premature labor. Despite the risks of associated radiation exposure, placement of a transjugular intrahepatic portosystemic shunt may be indicated when variceal bleeding cannot be controlled by any other means.383-385 The AASLD has recommended that every individual with cirrhosis who does not have a liver stiffness less than 20 kPa (FibroScan) and a platelet count greater than 150,000/mm3 have endoscopic screening for esophageal varices,386 although there are no formal guidelines for prophylactic management of esophageal varices in pregnant women. β-Adrenergic receptor antagonists are tocolytic, but these drugs do not repress normal labor in chronically treated pregnant patients. Use of beta blockers as primary prophylaxis against variceal bleeding in pregnant women has not been formally evaluated. Some authors have suggested prophylactic band ligation, portosystemic shunt procedures, and cesarean section to decrease the risk of bleeding from varices during gestation. Ascites and hepatic encephalopathy in pregnant women with chronic liver disease are managed in the customary manner. The only therapy available for severe hepatic decompensation during pregnancy is liver transplantation. Orthotopic liver

CHAPTER 40  Gastrointestinal and Hepatic Disorders in the Pregnant Patient

transplantation has been performed successfully during pregnancy.387,388 The MELD score can help predict clinical decompensation in a cirrhotic woman during pregnancy. For example, a MELD score of 10 or greater at the time of conception had an 83% sensitivity and an 83% specificity in predicting development of ascites, encephalopathy, or variceal hemorrhage prior to delivery in 1 study.389 

Wilson Disease (See Chapter 76) Wilson disease in women of childbearing age is associated with amenorrhea and infertility. Treatment of affected individuals to remove excess copper may result in resumption of ovulatory cycles and a subsequent pregnancy. Pregnant patients must remain on medication to treat Wilson disease because discontinuation of therapy can cause sudden copper release, hemolysis, acute liver failure, and death.390 d-Penicillamine is potentially teratogenic in humans,391 but has been used safely during pregnancy at doses necessary for copper chelation.392 Similarly, trientine is teratogenic in animals but appears to be safe in humans as treatment for copper overload. Zinc salts such as zinc acetate do not appear to be teratogenic, and some experts favor use of zinc during pregnancy as therapy for Wilson disease for this reason.393 

Autoimmune Liver Diseases (See Chapters 90 and 91) Autoimmune diseases of most types, including autoimmune hepatitis, are more common in women than in men. Autoimmune liver disease has a variety of clinical phenotypes. In women, classic (type-1) autoimmune hepatitis typically presents around the expected time of menarche, but is associated with amenorrhea. When women with autoimmune hepatitis become pregnant, they have a greater-than-expected incidence of spontaneous abortion and preterm delivery.394 Affected patients may also have disease flares during pregnancy and postpartum.395,396 For this reason, treated individuals with autoimmune hepatitis who conceive a child should continue taking immunosuppressive medications during pregnancy. The doses of azathioprine prescribed as part of standard treatment regimens are not thought to be teratogenic. Autoimmune hepatitis patients should be carefully monitored during pregnancy and in the postpartum period. PBC is much more common in postmenopausal women than it is in their fertile counterparts. Women with PBC may experience an exacerbation of pruritus during pregnancy.397 Pruritus can be ameliorated by treatment with ursodeoxycholic acid,398 although the safety of this therapy during pregnancy has not been formally proved. 

Hepatic Tumors and Mass Lesions (See Chapter 96) Mass-like defects of the hepatic parenchyma may be discovered during pregnancy, usually as an incidental finding on US. Benign liver lesions found commonly in women of childbearing age include adenomas, focal nodular hyperplasia, and hemangiomas. Hepatic adenomas are associated with oral contraceptive use and may enlarge during pregnancy; enlarging lesions can bleed and

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rupture into the abdominal cavity. Focal nodular hyperplasia and hemangiomas in pregnant patients have also been reported to hemorrhage. Women known to have a benign hepatic nodular defect should be evaluated with serial US to measure mass size and look for evidence of intralesional bleeding. Hepatocellular carcinoma occurs almost exclusively in persons with chronic liver disease and may present in the absence of cirrhosis in young people with chronic HBV infection. At-risk patients should have standard screening for liver cancer during pregnancy. It must be borne in mind that maternal serum AFP levels are always modestly elevated during normal pregnancy,399 and can increase further in cases of fetal Down syndrome, neuraltube defects, and hydatidiform mole, thereby limiting the positive predictive value for diagnosing hepatocellular carcinoma during pregnancy. Hepatic fibrolamellar carcinoma has been reported to occur in pregnant women.400 Fibrolamellar carcinoma is a slow-growing liver cancer usually found in young adults (median age, 25 years).401 Unlike typical primary liver cancer, this neoplasm has no known association with cirrhosis or chronic liver disease and is not a cause of increased serum AFP levels. It is an aggressive neoplasm with a 5-year survival rate below 50%. Hepatic metastases from other cancers are rare in women of childbearing age. 

Hepatic Vein Thrombosis (Budd-Chiari Syndrome) (See Chapter 85) Pregnancy is a predisposing factor for the development of venous thrombosis. Hepatic vein thrombosis may occur in association with HELLP syndrome402 and with preeclampsia in women who have an antiphospholipid antibody.403 Pregnant women who develop hepatic vein thrombosis should be evaluated for the presence of antiphospholipid antibody and other circulating procoagulants (e.g., factor V Leiden), and also for JAK-2, and possibly other gene mutations.404 

Pregnancy After Liver Transplantation (See Chapter 97) Women of childbearing age may become pregnant after successful orthotopic liver transplantation and deliver normal infants.127,405,406 Delaying pregnancy until the second post-transplant year may be associated with a lower risk of prematurity. Transplant patients must continue immunosuppressive therapy during gestation but may need to have their treatment modified. Mycophenolate mofetil, a part of many post-transplant immunosuppressive regimens, is highly teratogenic407 and must be avoided in women of childbearing age who may become pregnant. Adverse effects of other immunosuppressive medications, including hypertension and hyperglycemia, may increase the incidence of fetal distress and preeclampsia in pregnant liver transplant recipients. In rare instances, pregnancy has been complicated by organ rejection. Full references for this chapter can be found on www.expertconsult.com

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Acute and Chronic Gastrointestinal Side Effects of Radiation Therapy Jarred P. Tanksley, Christopher G. Willett, Brian G. Czito, Manisha Palta

CHAPTER OUTLINE MOLECULAR MECHANISMS OF RADIATION-INDUCED GI DAMAGE ��������������������������������������������������������������������������606 SERIAL VERSUS PARALLEL ORGAN FUNCTION����������������607 SMALL INTESTINE������������������������������������������������������������607 Incidence and Clinical Features��������������������������������������607 Treatment and Prevention����������������������������������������������610 ESOPHAGUS����������������������������������������������������������������������611 Incidence and Clinical Features��������������������������������������611 Treatment and Prevention����������������������������������������������612 STOMACH ������������������������������������������������������������������������613 Incidence and Clinical Features��������������������������������������613 Treatment and Prevention����������������������������������������������614 COLON AND RECTUM��������������������������������������������������������614 Incidence and Clinical Features��������������������������������������614 Treatment and Prevention����������������������������������������������615 ANUS��������������������������������������������������������������������������������616 Incidence and Clinical Features��������������������������������������616 Treatment����������������������������������������������������������������������616 PANCREAS AND LIVER������������������������������������������������������617 Incidence and Clinical Features��������������������������������������617 Treatment����������������������������������������������������������������������617 THERAPEUTIC TECHNIQUES TO REDUCE TOXICITY����������617

Early and late GI organ injury may occur following irradiation of thoracic, abdominal, and pelvic malignancies of GI and nonGI origin. As with all toxicities associated with radiation therapy (RT), GI side effects are categorized broadly into 2 types: early or acute reactions, such as diarrhea and nausea, which can occur during and soon after completion of a treatment course, and late or chronic effects, such as ulceration, stricture formation, and bowel obstruction, which can develop months to years later. Severe acute reactions can lead to treatment breaks and, in turn, a suboptimal treatment course, whereas the concern for chronic toxicity, particularly to the small bowel, is commonly a dose-limiting consideration in the creation of a treatment plan. The incidence and severity of radiation-induced GI morbidity depends on both total dose and fraction size, treatment volumes and techniques, the presence or absence of other treatment modalities such as systemic therapy and surgery, and underlying patient comorbidities. This chapter discusses the early and late toxicities of RT and combined chemoradiation therapy (CRT) regimens to the esophagus, stomach, small intestines, colon, rectum, anus, pancreas, and liver.

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The sections to follow will focus on the various radiation toxicities that can occur in each of the individual organs of the GI tract, as well as the steps radiation oncologists take to reduce the likelihood and severity of said toxicities. Prior to that, we present a brief general discussion of the cellular mechanisms of radiation damage and introduce the concept of an organ that functions in series versus one that functions in parallel, which informs radiation dose constraints. 

MOLECULAR MECHANISMS OF RADIATION-INDUCED GI DAMAGE At the cellular level, both the therapeutic and injurious acute effects of RT are consequences of its ability to induce DNA double-strand breaks through the creation of free radicals. In some cell types, this damage will lead to programmed cell death (apoptosis), which proceeds through a well-defined signaling cascade that is commonly disrupted during the process of oncogenesis. In rapidly dividing cancer cells, generally lacking important components of the normal DNA-damage response system and the apoptotic cascade, RT-induced DNA double-strand breaks can result in lethal chromosomal aberrations that cause cell death when division is attempted, a phenomenon known as mitotic catastrophe. The acute effects of radiation exposure to the normal GI tract have been studied in animal models, where a rapid increase in the rate of apoptosis of intestinal crypt/stem cells can be observed after exposure to low-dose irradiation (1 to 5 cGy). The rate of apoptosis is dose-dependent and reaches a plateau at 1 Gy. Radiation exposure increases expression of the TP53 gene product, p53, in GI epithelium, which induces expression of PUMA (p53 upregulated modulator of apoptosis, also known as BBC3 or Bcl2-binding component 3), a proapoptotic protein that causes cell death via the intrinsic apoptotic pathway. Conversely, the rate of radiation-induced apoptosis in endothelial cells is significantly reduced in animals lacking the proapoptotic bcl-2 multidomain proteins, bax and bak.1,2 It is therefore postulated that p53 promotes apoptosis after irradiation whereas antiapoptotic members of the bcl-2 family protect the normal mucosa. Beyond the acute loss of cells through apoptosis and mitotic catastrophe, radiation injury is the consequence of a complex set of interactions between cells involving multiple cytokines and molecular pathways that can acutely lead to mucosal edema, and chronically to fibrosis and organ dysfunction through excess deposition of extracellular matrix coincident with a reduction in the expression of remodeling enzymes such as matrix metalloproteinases. Radiation-induced fibrosis is, essentially, improper wound healing and, when combined with mucosal stem cell loss, underlies the chronic toxicities associated with RT such as dysmotility, stenosis, and fistula formation.3,4 This process typically begins several months to a year after the conclusion of a course of RT and can progress over the following years. The initial step in this process is the recruitment of immune cells to the site of RT-induced injury, which in turn results in

CHAPTER 41  Acute and Chronic Gastrointestinal Side Effects of Radiation Therapy

the increased local expression of a number of cytokines, including platelet-derived growth factor and transforming growth factor (TGF)-β. Platelet-derived growth factor promotes the migration of fibroblasts to the injured area, whereas TGF-β promotes both the proliferation of fibroblasts and their transdifferentiation into profibrotic myofibroblasts.5,6 Ongoing local expression of active TGF-β is thought to be the primary mediator of radiation-induced fibrosis. In addition to promoting the creation of myofibroblasts, TGF-β promotes the production of extracellular matrix proteins and reduces the expression of matrix metalloproteinases.7,8 Pathologic examination of bowel specimens from patients who underwent surgery for radiation enteropathy showed increased TGF-β in areas with vascular sclerosis and fibrotic areas of the serosa and muscularis propria as compared with patients who had surgery for other causes.9 In rat liver, TGF-β expression was found to be upregulated in a dose-dependent manner in hepatocytes up to 9 months after irradiation.10 Neutralizing antibodies to TGF-β and small molecule inhibitors have been shown to suppress or reverse fibrosis in preclinical models, but this has not been used in clinical practice to date.11-13 The acute to subacute formation of fibrotic tissue and loss of epithelium can in turn lead to chronic and permanent fibrosis, the risk of which is also related to patient comorbidities such as smoking status, nutrition, diabetes, and certain inflammatory diseases.14 The overall picture is thought to be a product of the initial insult and damage response that leads to vascular changes with an end result of tissue ischemia and progressive fibrosis.15 

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Fig. 41.1  Histopathology showing microabscesses and radiationrelated fibroblasts. Submucosal reaction shows large, bizarre radiation fibroblasts that have both cytomegaly and nucleomegaly. Smooth muscle cells also have reactive changes. Microabscesses composed of excess neutrophils infiltrate the stroma. (Courtesy Dr. Robin Amirkahn, Dallas, TX.)

of cancers of the small bowel. Mitigating the risk and severity of radiation enteritis and chronic small bowel injury is commonly the dose-limiting factor in the radiotherapeutic management of most abdominal and pelvic malignancies.

SERIAL VERSUS PARALLEL ORGAN FUNCTION

Incidence and Clinical Features

Through the loss of epithelial stem cells and the formation of scar tissue, RT can cause segments of organs of the GI tract to become less functional. Whether this manifests clinically is partly related to the functional arrangement of the organ, of which there are 2 types: serial and parallel. Organs arranged in series are composed of segments that are reliant on the functionality of the preceding segment such that the loss of any individual segment will make the organ dysfunctional or even nonfunctional downstream, and possibly upstream, from the insult. The prototypical organ with this arrangement is the spinal cord, where significant damage at a single spinal level can cause loss-of-function at every level downstream of the injury. With respect to the GI system, much of the luminal GI tract has this type of organization. Organs with parallel architecture, on the other hand, have some functional redundancy built in such that the loss of segments up to a point may not manifest clinically. The liver has this type of arrangement, although debate continues on exactly how much liver need be preserved to remain fully functional particularly in patients with underlying liver disease. When creating RT plans, consideration of these arrangements informs the types of dose constraints that are used. Organs that function in series are subject to maximum dose constraints, because an ablative dose to a small area can manifest as dysfunction of the entire organ, such as a SBO. Organs with a parallel functional architecture are subject to constraints that allow for the protection of an adequate relative volume of functional tissue. As will be discussed in the case of the liver, it is important to not allow an absolute volume to receive more than a certain dose of radiation. 

The epithelium of the GI tract has a high proliferative rate, with turnover every 3 to 5 days, making it susceptible to radiation and chemotherapy-induced mucositis. Irradiation of intestinal mucosa primarily affects the clonogenic intestinal stem cells within the crypts of Lieberkühn (cells that provide, via self-replication and eventual maturation, replacement cells in the intestinal villi). Stem cell damage, as a result of direct radiation damage or radiationinduced microvascular damage, leads to a decrease in cellular reserves for the intestinal villi. This results in mucosal denudement, shortened villi, a decreased absorptive surface area, and associated intestinal inflammation and edema. Histologic changes are seen within hours of irradiation. Within 2 to 4 weeks, an infiltration of leukocytes with crypt abscess (microabscess) formation can be seen, leading to ulcer formation (Fig. 41.1). This acute injury can result in impaired absorption of fats, carbohydrates, proteins, bile salts, and vitamin B12, with loss of water, electrolytes, and proteins. Impaired ileal bile salt absorption increases loads of conjugated bile salts entering the colon, which are deconjugated by colonic bacteria, causing intraluminal salt and water accumulation and subsequent diarrhea. Furthermore, impaired digestion of lactose may occur following radiation, leading to increased bacterial fermentation with associated flatulence, distention, and diarrhea. There is also evidence of acutely altered gut motility following RT.17 Patients with acute radiation enteritis experience diarrhea, abdominal cramping or pain, nausea and vomiting, anorexia, and malaise. Radiation-induced diarrhea often appears during the third week of a fractionated radiation course, with reported rates of 20% to 70%.18 Acute radiation enteropathy with diarrhea may be seen in some patients after delivery of doses of 18 to 22 Gy using conventional fractionation, which coincides with the start of the third week of therapy, and is seen in most patients by 40 Gy. The symptoms and pathologic findings typically subside 2 to 6 weeks following completion of RT, although evidence suggests that patients who develop acute small intestinal toxicity may be at higher risk for chronic effects.19 Histologic changes of chronic toxicity to the small intestine include progressive occlusive vasculopathy with foam cell

SMALL INTESTINE The first case of radiation injury of the small bowel, or radiation enteropathy, was described in 1897 in the context of irradiating the skin of the abdomen.16 RT can damage the small bowel during the treatment of virtually all GI and gynecologic cancers, while rarely being used as part of the primary treatment

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TABLE 41.1 Clinical Complications of Chronic Radiation Enteritis or Proctitis  

Complication Lesion(s)

Clinical features

Obstruction

Stricture

Constipation, nausea, vomiting, postprandial abdominal pain

Infection

Abscess

Abdominal pain, fever, chills, sepsis, peritonitis

Fistulization

Fistula

Fecal, vaginal, or bladder discharge; pneumaturia

Bleeding

Ulceration

Rectal pain, tenesmus, rectal bleeding, anemia

Malabsorption

Small bowel Diarrhea, steatorrhea, weight loss, damage malnutrition, cachexia

  

Fig. 41.2  Histopathology showing a submucosal arteriole in chronic radiation enteropathy. Radiation-induced changes include thickening of the blood vessel walls, subintimal hydropic change and fibrosis, which results in luminal narrowing and occlusion and subsequent tissue ischemia. (Courtesy Dr. Robin Amirkahn, Dallas, TX.)

Fig. 41.3  Histopathology showing small intestinal submucosal fibrosis following radiation therapy. The patient presented with small intestinal obstruction due to this stricture. (Courtesy Dr. Robin Amirkahn, Dallas, TX.)

invasion of the intima and hyaline thickening of the arteriolar walls, with collagen deposition and fibrosis. The small bowel becomes thickened, with development of telangiectasias, whereas the vessel walls of small arterioles are obliterated, causing ischemia (Fig. 41.2).20 As the vasculopathy progresses, mucosal ulceration, necrosis, and occasionally perforation of the intestinal wall can be seen, leading to fistula and abscess formation. Lymphatic damage contributes to mucosal edema and inflammation. Histologically, the mucosa atrophies, with atypical hyperplastic glands and intestinal wall fibrosis (Fig. 41.3).21 As the ulcers heal, there can be fibrosis and narrowing of the intestinal lumen, with subsequent stricture formation and even obstruction with dilatation of the proximal bowel. Bacterial overgrowth may be an indirect complication arising from stasis in a dilated loop of bowel proximal to the stricture. Although the affected segments of intestine and serosa appear thickened with areas of telangiectasias,22 it should be noted that even if the gut appears normal, patients can still be at risk of spontaneous perforation.23 Chronic radiation enteritis can cause significant morbidity. This complication tends to be progressive, with an onset at least 6 months after radiotherapy. Late radiation injury to the small intestine occurs at a median of 8 to 12 months following RT, although it can appear years later.24 There are many clinical manifestations of the chronic phase of radiation enteritis (Table 41.1). Fibrosis and vasculitis of the bowel may lead to

From Girvent M, Carlson GL, Anderson I, et al. Intestinal failure after surgery for complicated radiation enteritis. Ann R Coll Surg Engl 2000; 82:198-201.   

dysmotility, stricture formation, and malabsorption.25,26 More rapid transit times can occur in the affected bowel, which can cause chronic malnutrition and resultant anemia and hypoalbuminemia. Malabsorption and other complications may require surgical intervention and parenteral alimentation. Patients with severe chronic radiation enteritis have a poor long-term prognosis and a mortality rate of approximately 10%.27-32 The overall incidence of chronic radiation enteritis has not been precisely defined. Retrospective series suggest an incidence of 20%, but these studies often included a large number of patients who were lost to follow-up or died between the end of RT and the completion of the study.33 A review of randomized trials of adjuvant RT for rectal cancer shows severe long-term complications as low as 1.2% and as high as 15%, which is greatly improved in comparison with older trials, suggesting that technical advances have reduced chronic small bowel toxicity rates.34 Certain factors have been found to predispose patients to radiation toxicity to the small intestine. Women, older patients, and thin patients may have a larger amount of small bowel in the pelvic cul-de-sac, which can increase the likelihood of radiation injury in the treatment of pelvic malignancies.35 Patients with a history of pelvic inflammatory disease or endometriosis also appear to be at higher risk of radiation complications.36,37 Patients who have had previous abdominal surgery can develop adhesions that decrease the mobility of the small bowel, allowing it to be consistently exposed to fractionated RT.38,39 In addition, patients with prior pelvic surgery may have an increase in the amount of small bowel within the pelvis. In a series published by Eifel and associates, the risk of small bowel complications was significantly higher in women who had undergone a previous laparotomy.40 Smokers, and patients with diabetes, hypertension, and cardiovascular disease, also have an increased risk of preexisting vascular damage or occlusion.41 These comorbid conditions are compounded by the pathologic changes of chronic radiation injury, which include vasculopathy and ischemia, predisposing the patients to radiation-related small bowel toxicity. Patients with collagen vascular and inflammatory bowel diseases have a higher risk of acute as well as chronic radiation-induced injury. Patients with these diseases may have pathologic changes that include transmural fibrosis, collagen deposition, and inflammatory infiltration of the mucosa. The late effects induced by RT to the small bowel are likely additive to these preexisting changes, and studies have shown that these patients have a lower GI tolerance to RT.42,43 Patients whose IBD or nonmalignant systemic disease is quiescent or well controlled appear to fare better than patients with active disease.

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TABLE 41.2  Pathophysiologic Features of Patients With Chronic (Late) Radiation Enteropathy and Their Clinical Manifestations Clinical Manifestations

Pathophysiologic Feature Mucosal dysfunction

Lactose intolerance Vitamin B12 deficiency Steatorrhea

Stricture or blind loop syndrome with SIBO

Diarrhea

Intestinal dysmotility

Bloating Constipation Diarrhea

Abnormal bile acid recirculation

Cholerheic diarrhea

  

Fig. 41.4  Image from a planning scan performed on a patient with rectal cancer. The patient was positioned prone on a belly board, which allows the small bowel to fall out of the anatomic area to which the prescription dose is planned (illustrated in red).

Studies have also addressed the effect of radiation dose on occurrence of small bowel toxicity. Volume of the treatment field, volume of irradiated small bowel, total dose, fraction size, treatment time, and treatment technique all influence small bowel tolerance. The TD5/5 (dose at which there is a 5% risk of toxicity at 5 years) for small volumes of small bowel has been estimated to be 50 Gy. Patients can generally receive 45 to 50 Gy in 1.8- to 2-Gy daily fractions to a pelvic field without a significant rate of toxicity.44 Retrospective analysis of patients with locally advanced pancreatic cancer treated with CRT found a maximum dose of 55 Gy to 1 mL of the duodenum to be an important metric for preventing long-term toxicity.45 For postoperative patients, radiation to 45 to 50 Gy in 5 weeks is associated with an approximately 5% incidence of SBO requiring surgery, whereas at doses greater than 50 Gy the incidence rises to as high as 25% to 50%.35 Doses greater than 2 Gy per fraction in the postoperative setting also increase the risk of toxicity.46 At radiation doses of 70 Gy or greater, the incidence of toxicity rises precipitously.47 Studies that have analyzed dose-volume parameters associated with acute small bowel toxicity in patients undergoing treatment with 5-fluorouracil (5-FU)–based CRT therapy for rectal cancer found strong correlations between acute toxicity and the amount of small bowel irradiated at each dose level analyzed.48,49 A study of different treatment techniques to minimize the effect of pelvic radiation on the small bowel showed that irradiating smaller volumes of bowel yielded less toxicity.50 In addition, treating patients in the prone position with external compression and bladder distention decreased side effects, likely from exclusion of portions of the small bowel from the radiation field (Fig. 41.4).51 CRT, commonly with concurrent 5-FU or capecitabine, is used in the treatment of GI malignancies and is known to increase the risk of small bowel toxicity. In the French Federation Francophone de Cancerologie Digestive trial, which randomized patients to RT or CRT with 5-FU and leucovorin, the rate of acute toxicity was 2.7% with RT and 14.6% with the addition of chemotherapy to RT.52 A second trial conducted by the European Organization for Research and Treatment of Cancer randomized patients with advanced rectal cancer to preoperative RT or CRT, with or without adjuvant chemotherapy. The addition of chemotherapy resulted in higher grade 3 acute toxicity rates: 13.9% versus 7.4%. Rates of grade 2 diarrhea occurred more frequently in patients receiving concurrent chemotherapy: 37.6% versus 17.3%, with no differences in late toxicity.53 There is ongoing investigation into the integration of novel chemotherapeutic and “targeted” agents with RT in neoadjuvant therapy for GI cancers. Promising results from early phase II studies incorporating oxaliplatin into the neoadjuvant regimen

From Hauer-Jensen M, Wang J, Denham J. Bowel injury: current and evolving management strategies. Semin Radiat Oncol 2003; 13:357-71.   

TABLE 41.3 Therapeutic Options for Patients With Chronic (Late) Radiation Enteropathy Pathophysiologic Feature

Therapeutic Options

Nutritional deficits

Correction of specific deficits Low-fat diet Lactose-free diet Elemental diet TPN

Intestinal dysmotility (increased or decreased)

Loperamide Octreotide Prokinetic agent

Bile acid malabsorption

Bile-salt binding agent

SIBO

Antibiotics

  

From Hauer-Jensen M, Wang J, Denham J. Bowel injury: current and evolving management strategies. Semin Radiat Oncol 2003; 13:357-71.   

were shown later to be more toxic and to offer no disease benefit in subsequent randomized trials.52,54 Data from phase I and phase II trials using novel agents such as irinotecan, VEGF receptor and EGF receptor inhibitors suggest that the addition of these agents may significantly increase grades 3 and 4 GI toxicity rates relative to conventional neoadjuvant chemoradiotherapy (CRT) regimens, further emphasizing the importance of careful radiation planning to maximize normal tissue sparing in these patients. Diagnosis of chronic (late) radiation enteropathy is made clinically (Table 41.2). The cause of symptoms can be variable from patient to patient, and individualization of diagnostic and therapeutic approaches is indicated. Therapeutic options are displayed in Table 41.3. Consultation with the treating radiation oncologist should be requested if the clinical presentation is consistent with radiation enteritis. Review of the patient’s previous radiation treatment record will reveal the total dose, fractionation, volume of treatment, and other radiation parameters. Analysis of the treatment plan may show areas of high dose, especially if the patient had an intracavitary implant or brachytherapy. Lesions encountered at endoscopy or imaging studies are usually localized in the area of high dose. Ulceration of the mucosa, thickening of jejunal folds, and thickening of the intestinal loops are radiologic signs that suggest radiation damage to the small bowel (Fig. 41.5). Faster intestinal transit and reduced bile acid and lactose absorption can be observed in patients with chronic radiation enteritis.55 These effects may be improved after the administration of loperamide. Antibiotics are indicated if there is SIBO syndrome (see Chapter 105).56,57 

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A

C

B

Treatment and Prevention The management of acute radiation small bowel toxicity should be based on the severity of symptoms. Most cases of acute radiation enteritis are self-limited, requiring only supportive treatment. Diarrhea, nausea, vomiting, and abdominal cramping are treated symptomatically. Antidiarrheal medications such as loperamide, diphenoxylate atropine, or opiates can be used. Antiemetic agents may also be effective. A low-fat, lactose-free diet may improve symptoms. A study of oral sucralfate in patients receiving pelvic irradiation showed a decrease in frequency and an improvement in consistency of bowel movements at both early and late time points.58 Cholestyramine to treat diarrhea from bile acid malabsorption has also shown some benefit,59 and treatment with aspirin has been effective.60 Intractable diarrhea during combined-modality treatment (CRT) may require hospital admission for administration of parenteral fluids and electrolyte repletion. Patients who are refractory to conventional antidiarrheal medications may benefit from administration of a synthetic somatostatin analog such as octreotide.61 The management of chronic radiation enteritis remains a major challenge, given the progressive evolution of the pathophysiology, including obstructive endarteritis and fibrosis. The treatment should be conservative, given the diffuse nature of the process and the high morbidity associated with surgery; however, surgical intervention is indicated in intestinal obstruction, perforation, fistulas, and severe bleeding. Chronic effects of diarrhea are managed symptomatically with a low-residue diet. Fiber supplementation (e.g., Metamucil,

Fig. 41.5  Radiologic evidence of radiation injury of the intestine. A, In early injury, bowel and mesenteric edema may cause separation of intestinal loops, lead to thickening and straightening of mucosal folds, and impart a spiked appearance (arrows) to the small bowel mucosa. B, Severe abnormalities of the rectosigmoid colon are evident on this film from a barium enema performed 2 months after the patient underwent radiation therapy for cervical carcinoma. Subacute radiation injury of the colon may present as edematous, occasionally ulcerated mucosa with asymmetrical areas of narrowing suggestive of Crohn colitis or recurrent tumor (arrows). C, Late radiation change in the colon, with stricture formation (arrow) after a cumulative dose of approximately 55 Gy.

Citrucel) has shown benefit in some cases. In the rare setting of malnutrition related to chronic radiation injury, TPN can improve clinical outcome, and methylprednisolone may add to the effects of TPN.36 Despite these interventions, the 5-year survival rate for patients undergoing TPN ranges from 36% to 54%.32,62 It has been estimated that overall mortality rate associated with chronic radiation enteropathy is approximately 10%.63 Endoscopic techniques are sometimes required for diagnosis of bleeding intestinal ulcers. Double-balloon enteroscopy and capsule endoscopy may help facilitate this diagnosis.64 The double-balloon enteroscope method may allow therapeutic intervention in certain situations, including coagulation of small bowel telangiectasias. Significant bleeding refractory to endoscopic intervention may be managed surgically. SBO is generally managed conservatively with bowel rest and tube decompression. In rare situations, the obstruction is severe or chronic enough that bowel resection or lysis of adhesions may be required. It is difficult to perform surgery for chronic radiation enteritis because of the diffuse fibrosis and alterations in the intestine and mesentery, resulting in high rates of surgical morbidity and reoperation.65,66 The risk of anastomotic leak is high if the anastomosis is performed using irradiated bowel.63 The risk of leak can be lowered if at least 1 limb of the anastomosis is previously unirradiated bowel. However, it may be difficult to distinguish between normal and irradiated tissues at time of surgery and even on pathologic evaluation.67 Another method the surgeon can use to circumvent this technical difficulty is to create the anastomosis with unirradiated colon. The accuracy

CHAPTER 41  Acute and Chronic Gastrointestinal Side Effects of Radiation Therapy

in localizing injured bowel may be improved by intraoperative endoscopic examination, which can detect radiation-induced mucosal injury.68 Limited resection of the diseased intestine is the goal, but if the lesion is too diffuse, a bypass procedure may be attempted. If feasible, resection of the affected bowel results in a better outcome than an enteric bypass procedure. However, extensive surgical resection of the diseased intestines may lead to short bowel syndrome (see Chapter 106) and the need for TPN. In selected patients who underwent extensive surgical intestinal resection, 5-year survival was approximately 65%, with two thirds of the patients weaned off of parenteral nutrition.69 Given the progressive evolution of fibrosis, the patient may require additional surgery if extensive surgical resection is not performed. Surgical bypass of the injured bowel may be associated with a blind loop syndrome, and the patient still may be at risk for perforation, bleeding, abscess, and fistulas due to the persistence of the affected bowel. Bypass procedures should be performed when resection is not possible or as temporary management before resection at a later date. Surgery should be performed by an experienced team familiar with the management of radiation enteritis. Perforations and fistulae are best managed surgically. It should be noted that many patients with chronic small bowel radiation toxicity are nutritionally depleted and more susceptible to anastomotic leakage and dehiscence after surgery. The postoperative mortality of these patients may be significant and must be taken into consideration before a decision to proceed with surgery is made. Hyperbaric oxygen has been used in the treatment of chronic radiation enteritis, the rationale being that the creation of an oxygen gradient in hypoxic tissue will stimulate neoangiogensis.70,71 In a retrospective study of 36 patients with severe radiation enteritis refractory to medical management, improvement of clinical symptoms was reported in two thirds of the patients treated with hyperbaric oxygen.72 Hyperbaric oxygen may be helpful in management of bleeding due to chronic radiation enteritis in patients who are not controlled with conservative measures such as formalin and laser therapy (discussed later).73,74 A clinical series of 65 consecutive patients with chronic radiation enteritis (small bowel and rectum), primarily manifested as chronic bleeding, were treated with hyperbaric oxygen. Response rates for rectal and more proximal sites were 65% and 73%, respectively. The response rate for bleeding was 70% and for other symptoms (pain, diarrhea, weight loss, fistula, obstruction) was 58%. The authors concluded that hyperbaric oxygen therapy resulted in clinically significant improvement in two thirds of patients with chronic radiation enteritis.75 Other agents to reduce the incidence of chronic enteritis have been investigated. There is some suggestion that pentoxifylline may abrogate radiation-associated fibrosis through antioxidant effects and inhibition of TGF-β1. In a small study, patients with radiation enteropathy were treated with pentoxifylline and vitamin E, with response assessment by subjective, objective, management, analytic scales. Regression of symptoms by subjective, objective, management, and analytic scales was seen in 40% of patients by 6 months and 80% of patients at 18 months.76 Given that chronic radiation enteritis is complex and rarely curable, prevention is key, and measures to decrease its incidence are imperative. Pancreatic enzymes can exacerbate acute intestinal radiation toxicity, and reducing pancreatic secretion with a synthetic somatostatin receptor analog such as octreotide may reduce early and delayed radiation enteritis in animal studies.77 One of the major risk factors for injury is previous abdominopelvic surgery, which leads to the prolapse of the small intestines into the pelvis and exposure to radiation. Anticipation for the need of radiation and chemotherapy before or after surgery requires close collaboration among surgical, radiation, and medical oncologists. If gross residual tumor is found unexpectedly at surgery, outlining

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the tumor bed with surgical clips to facilitate postoperative treatment planning and surgical techniques to keep the small intestine outside the pelvis (e.g., omentoplasty or polyglycolic mesh) may significantly decrease the rate of complications. Postoperative bowel adhesions may increase the volume of bowel irradiated compared with normal small intestine, which is usually mobile. If RT is anticipated after surgery, attempts should be made at the time of surgery to displace the bowel outside the radiation field.78 One simple technique is the surgical placement of a polyglycolic, biodegradable mesh that moves the intestines out of the pelvis.79,80 This procedure has minimal morbidity and does not significantly increase operating time. It also does not require a second operation to remove the mesh, because it is absorbed 3 to 4 months after surgery. MRI can be used after surgery to verify the position of the mesh, the small bowel, and eventual disappearance of the mesh. A reduction of 50% of the volume of the small bowel exposed to the radiation has been demonstrated with placement of a mesh during surgery, allowing a higher dose of radiation to be given postoperatively where indicated.81,82 Other techniques such as pelvic reconstruction, omentoplasty, and transposition of the colon may also significantly decrease the volume of bowel exposed to RT.82-84 RT technique is critical in reducing the rate of complications. The use of only anterior and posterior fields for pelvic radiation should be avoided if possible because of the high dose and large volume of bowel irradiated. The toxicity of RT correlates with the volume of small bowel irradiated.85 In many patients, treatment in the prone position with a “belly board” allows the displacement of the small intestines out of the radiation field.86,87 Patients should be instructed to maintain a full bladder during the radiation session, which further displaces the intestines out of the pelvis.38 Three-dimensional (3D) treatment planning optimizes the treatment technique by facilitating more accurate dose distributions. A 3D treatment algorithm ensures the sparing of excessive radiation dose to normal tissues by the judicious use of multiple fields to the target volume from multiple geometries.88 In addition, more modern techniques such as intensity-modulated radiotherapy (IMRT) use sophisticated planning techniques to avoid critical structures. Treatment of radiation enteritis is often only partially successful. Management is patient specific and should be as conservative as possible because of the relentless progression of the disease, which can be exacerbated by further injury to the area. A better understanding of the mechanism of fibrosis and the interaction of the molecular events controlling apoptosis and fibrosis may assist in the identification of the patient at risk for radiation complications and in the development of new therapeutic approaches. 

ESOPHAGUS Incidence and Clinical Features Early and late effects of the esophagus often occur following irradiation of thoracic and upper abdominal malignancies (e.g., esophageal/esophagogastric junctional carcinomas, lung carcinomas). Normal esophageal mucosa undergoes continuous renewal. Acute esophageal injury is believed to be primarily related to radiation damage to the basal epithelial layer, manifested histologically by vacuolization, resulting in epithelial thinning followed by denudation (Fig. 41.6). These changes manifest clinically as dysphagia, odynophagia, and substernal discomfort, usually occurring within 2 to 3 weeks following initiation of RT. Patients may describe a sudden, sharp, severe chest pain radiating to the back. As treatment progresses, pain may become constant and may not necessarily be related to swallowing. The symptoms may be confused with Candida esophagitis, which may occur in conjunction with radiation esophagitis. Concurrent chemotherapy exacerbates these toxic effects. Endoscopically, mucositis and

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Fig. 41.6  Histopathology of acute radiation-induced esophageal injury showing esophageal ulceration with abundant fibroblasts.

ulceration may be observed. Perforation and bleeding are rare in the acute phase.89 Shortly after treatment completion, basal proliferation returns and regeneration occurs.90 Chemotherapy administered concurrently with RT, as it commonly is in both lung and esophageal cancer, increases the rates of grade 3 or greater acute esophagitis approximately 5-fold.91 Following recovery from acute injury, late effects such as benign stricture leading to persistent dysphagia, ulceration, and fistula formation may occur months to years following treatment. These effects are believed primarily due to inflammation and scar formation within the esophageal muscle. The connective tissues surrounding the esophagus may also exhibit severe fibrosis over time, and small vessel telangiectasias may be seen endoscopically. Histologic studies of the esophagus in previously irradiated patients have demonstrated epithelial thickening, chronic inflammation, and fibrosis of the submucosa and muscularis propria but rarely chronic ulceration. Complete epithelial recovery from radiation effects may take 3 to 24 months.21 Late effects often manifest as dysphagia due to stricture, as well as altered motility due to fibrosis or muscular damage, possibly with accompanying nerve injury. Fistula formation is unusual and radiation dose dependent. Barium swallow examination may show strictures and disruption of peristalsis at the level of the irradiated esophagus, with repetitive and nonperistaltic waves above and below the irradiated region. Abnormal peristalsis has been reported at 1 to 3 months following treatment completion, whereas most strictures occur 4 to 8 months following treatment completion. Late effects are usually not seen until 3 months following completion of RT, with a median time to onset of 6 months in some series.24,92,93 Development of radiation-related late complications is dose related. Much of the randomized data regarding the dependence of acute radiation esophagitis on different dose-fractionation schemes are from lung cancer trials. The Intergroup 0096 trial of patients with limited stage small cell lung cancer compared CRT regimens of 1.5-Gy fractions delivered twice daily over 3 weeks against 1.8-Gy fractions delivered daily over 5 weeks to the same total dose of 45 Gy. Grade 3 esophagitis was nearly 3 times as likely in the group receiving treatment twice daily.94 In the Radiation Therapy Oncology Group (RTOG) 0617 trial, comparing total doses of 60 Gy versus 74 Gy in the treatment of locally advanced non–small cell lung cancer, a 3-fold increase in grade 3 or greater esophagitis was also noted.95 Historically the TD5/5 (i.e., dose at which 5% of patients will develop complications at 5 years) has been estimated to be 60 Gy when one third of the length of the esophagus is irradiated.96 Cumulatively, it is recommended that the mean esophageal dose be kept less than 34 Gy, while limiting portions of the esophagus treated to no more than 60 Gy.97

Few randomized trials in esophageal cancer have reported late esophageal toxicities. In the RTOG study 0113, which used doses of 50.4 Gy with chemotherapy, the rate of severe late esophageal toxicity was 12% (3% grade 5 toxicity, which is death).98 In RTOG 85-01, a randomized trial comparing definitive radiotherapy to 64 Gy and CRT to 50 Gy, nearly 20% of patients in each arm experienced severe late esophageal toxicity.99 More recent analyses of patients treated with modern planning techniques have found significant reduction in the long-term esophageal sequelae.100 Brachytherapy (the temporary insertion of a radioactive source into or adjacent to a tumor) has also been used as a technique for radiation dose escalation in esophageal cancer. Although some institutions have reported low rates of fistula associated with brachytherapy, Gaspar and colleagues reported the results of a phase I/II study examining the role of brachytherapy in addition to external beam RT in the treatment of esophageal cancer. The 1-year actuarial fistula formation rate was 18%, and the authors recommended caution in the use of this approach, particularly in conjunction with concurrent chemotherapy.101,102 A more contemporary series of 62 patients treated with external beam and brachytherapy resulted in a 16% rate of severe toxicities including ulceration, stricture, esophageal perforation, fistula, and acute esophageal bleeding.102 The intensity of cancer treatment, such as use of concurrent chemotherapy with RT, increases the rate of acute esophagitis.103 Maguire and colleagues evaluated 91 patients treated with RT for non–small cell lung cancer and found that the percentage esophageal volume and surface area treated to greater than 50 Gy predicted late esophageal toxicity. Patients who had preexisting GERD and esophageal erosions secondary to tumor were at increased risk for late toxicity. Hyperfractionation (multiple daily radiation treatments) was also associated with increased acute toxicity.104 Singh and associates studied patients with non–small cell lung cancer who received conformal daily RT with or without concurrent chemotherapy. They found that a maximal esophageal “point” dose of 69 Gy (RT alone) and 58 Gy (with concurrent chemotherapy) predicted significant toxicity. Twenty-six percent of patients receiving concurrent CRT developed grade 3 or higher esophageal toxicity, whereas only 1.3% of patients who received RT alone experienced this degree of toxicity.105 Ahn and colleagues found that the most powerful predictor of late esophageal toxicity in 254 patients treated for non–small cell lung cancer was the severity of acute esophageal toxicity. Severe acute toxicity was predicted by the use of twice-daily radiation, older age, increasing nodal stage, and a variety of dosimetric parameters. The overall incidence of late toxicity was 7%, with a median and maximal time to onset of 5 and 40 months, respectively.92 Wei and coworkers, evaluating 215 patients who received concurrent chemotherapy, found that the relative esophageal volume receiving greater than 20 Gy predicted for grade 3 or greater acute toxicity, and a second series found that when greater than 30% of the esophageal volume received greater than 50 Gy (V50), this resulted in grade 1 or higher acute toxicity.106,107 Based on these and other data, it is clear that the addition of concurrent chemotherapy to RT increases the incidence of both acute and chronic esophageal toxicity. 

Treatment and Prevention The treatment and prevention of radiation-induced esophagitis have come under increased attention with the use of aggressive combination chemotherapy and RT regimens. Treatment interruptions may ease the symptoms of acute esophagitis but may also compromise treatment efficacy and is generally reserved for severe cases. The management of acute esophagitis usually includes symptomatic management such as topical anesthetics (including viscous lidocaine-based regimens), oral analgesics

CHAPTER 41  Acute and Chronic Gastrointestinal Side Effects of Radiation Therapy

(including anti-inflammatory agents and narcotics), gastric antisecretory drugs (histamine blockers, PPIs), promotility agents (e.g., metoclopramide), and treatment of superimposed infection (candidiasis). Dietary modification, including bland foods, pureed or soft foods, and soups, can help patients maintain oral intake. Other modifications include avoidance of smoking, alcohol, coffee, spicy or acidic foods, chips, crackers, and fatty foods. A study of dietary modifications and pharmacologic prophylaxis for radiation-induced esophagitis reported decreased toxicity and fewer treatment interruptions. It was recommended to drink between meals and to eat 6 smaller meals per day, consisting of semisolid food, soup, high-calorie supplements, purees, puddings, milk, and soft breads.108 In addition, ingestion of hot or cold foods should be avoided if possible; instead, foods and liquids should be at room temperature. In severe cases, feeding tube placement may be required. Radioprotective chemical agents have been investigated as a means of mitigating radiation-induced normal tissue toxicity. The best-studied radioprotector, amifostine, is an organic thiophosphate. This agent is a scavenger of free radicals and serves as an alternative target to nucleic acids for alkylating or platinum agents.109 Trials have had conflicting results and are limited by small patient numbers.110-114 In the largest randomized trial, patients treated with chemotherapy and RT for non–small cell lung cancer were randomized to receive amifostine or no drug. Although amifostine did not significantly reduce grade 3 or higher esophagitis, patient self-assessments suggested a significantly lower incidence of acute esophagitis in those who received amifostine. Patients receiving amifostine, however, experienced significantly higher rates of nausea, vomiting, infection, febrile neutropenia, and cardiac events.115 Given this, amifostine is not routinely recommended in the prevention of radiation esophagitis.116 A second radioprotector, glutamine, has generated clinical interest. In hypercatabolic states, such as cancer, glutamine deficiency can develop. A retrospective study in 41 patients with lung cancer demonstrated that glutamine was well tolerated, with supplemented patients experiencing a lower incidence of grade 2 to 3 esophagitis, typically resulting in weight gain during treatment.117 A second analysis from the same institution evaluated 104 patients, 56 of whom received glutamine. Glutamine was associated with less grade 3 esophagitis, treatment breaks, and weight loss, and administration was not associated with differences in time to event end points.118 A pilot study of 75 patients corroborated retrospective data demonstrating no glutamine intolerance or toxicity. Most patients (73%) were treated with sequential chemoradiation, and 49% of those treated with concomitant chemoradiation did not develop esophagitis.119 A recent retrospective analysis of 122 patients with advanced lung cancer noted that patients treated prophylactically with glutamine had significant less acute esophagitis and, consequently, significantly less weight loss.120 Although glutamine is associated with little toxicity, further evaluation of efficacy is needed before its broad incorporation into clinical practice. The management of late esophageal radiation stricture consists of serial endoscopic dilatation for symptomatic improvement. Dilations in advanced stricture can result in esophageal rupture and therefore should be approached cautiously. Long-term use of gastric antisecretory drugs, as well as prokinetic agents such as metoclopramide, has been recommended to decrease gastroesophageal (GE) reflux effects. Uncommonly, tube feedings may be required for patients with significant weight loss who are unable to maintain weight or for those only able to take in liquids. Surgical intervention may be required for patients who develop perforation or fistula. Finally, it is important to note that the clinical symptoms associated with late radiation injury are often difficult to distinguish from those caused by recurrent or new primary

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malignancies. Patients with strictures or ulcerations should also be evaluated to differentiate chronic radiation changes from cancer recurrence. 

STOMACH Incidence and Clinical Features The stomach may be damaged following irradiation of the upper abdomen for cancer, including esophageal-GE junctional, gastric, and pancreatic carcinomas. Radiation to the stomach in animals using a very high single dose results in erosive and ulcerative gastritis. A slightly lower single dose results in gastric dilatation and gastroparesis, with replacement of the normal gastric mucosa by hyperkeratinized squamous epithelium. With even lower doses, gastric obstruction occurring months after irradiation was observed, with an atrophic gastric mucosa and intestinal metaplasia seen in surviving animals.121 Studies in which serial gastric biopsies were obtained following irradiation of patients for PUD noted necrosis of chief and parietal cells, with mucosal thinning, edema, and chronic inflammatory infiltration.24,122 In addition, gastric acid production decreased after relatively low doses of gastric irradiation. In the past, RT had been used to decrease acid production in patients with PUD. Even with a relatively low dose of 18 Gy delivered in 10 fractions, approximately 40% of ulcer patients had a 50% reduction in gastric acid secretion that lasted for a year or more.123 Clinically, radiation-induced gastritis may occur within a week of starting radiotherapy, with microscopic changes including edema, hemorrhage, and exudation. Histologic changes include disappearance of cytoplasmic details and granules in parietal and chief cells as early as 1 week into therapy. Cell damage and subsequent cell death are often seen first in the depths of glands, followed by thinning of the gastric mucosa. Additional mucosal changes include deepening of the glandular pits and proliferation of cells in the glandular neck. Loss of glandular architecture and thickening of the mucosa can be seen by the third week of radiotherapy. Histologic recovery begins approximately 3 weeks after completing radiotherapy. Signs of recovery of early radiation injury to the stomach include re-epithelialization and fibrosis. Symptoms of acute radiation injury of the stomach consist primarily of nausea and vomiting, dyspepsia, anorexia, abdominal pain, and malaise. These are more common with the concurrent administration of chemotherapy. Radiation-induced nausea and vomiting may occur within the first 24 hours following treatment. It is estimated that approximately half of patients receiving upper abdominal radiation will experience emesis within 2 to 3 weeks following radiation initiation.124 Late effects of gastric irradiation have been classified into 4 categories: (1) acute ulceration (occurring shortly after completion of RT); (2) gastritis with smoothened mucosal folds and mucosal atrophy on endoscopy, accompanied by radiographic evidence of antral stenosis (1 to 12 months following irradiation) (see Chapter 52); (3) dyspepsia, consisting of vague gastric symptoms without obvious clinical correlate (6 months to 4 years following irradiation); and (4) late ulceration (averaging 5 months after irradiation).24,125 The TD5/5 for treatment of the entire stomach has been estimated to be 50 Gy.96 Large studies of upper abdominal irradiation have suggested that prior abdominal surgery, as well as using a higher radiation dose per fraction, may increase the risk of late effects.126 Studies from Walter Reed Army Medical Center, delivering abdominal radiation using now-antiquated techniques in testicular cancer patients, have suggested that higher radiation doses lead to an increasing risk of late gastric ulceration and perforation, with ulceration occurring in approximately 6% of patients treated to 45 to 50 Gy, 10% of patients treated to 50 to 60 Gy, and 38% of patients treated to greater than 60 Gy. Perforation rates were 2%

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and 14% after doses less than 50 Gy and 50 Gy or greater, respectively. Symptomatic gastritis occurred approximately 2 months following radiation completion, with ulcer formation occurring at a median of 5 months. Six of 233 patients (3%) required surgery for ulcer hemorrhage or pain related to ulcer disease, almost all of whom had received doses of greater than 50 Gy.24,127 Other studies of patients treated with RT for Hodgkin lymphoma or testicular, gastric, or cervical cancer have established tolerance limits for gastric irradiation.126-129 These studies delivered doses of 40 to 60 Gy. Patients who received doses greater than 50 Gy experienced gastric ulceration and gastric ulcer–associated perforation at rates of 15% and 10%, respectively. If indicated, the dose to the entire stomach with conformal RT is limited to 45 to 50 Gy, with an estimated 5% to 7% risk of severe radiation toxicity, primarily ulceration.130 As in the esophagus, combining chemotherapy with RT decreases the tolerance of the gastric mucosa to RT. 5-FU-based chemotherapy is the most common agent delivered concurrently with RT in the management of GI tumors. This agent can be delivered in the adjuvant or neoadjuvant setting or as “definitive” therapy for GE junction, gastric, peripancreatic, and biliary cancers. 5-FU is a radiation sensitizer but has historically been given safely with RT at doses of 45 to 50 Gy without substantial increases in toxicity. Newer systemic agents have been shown to increase acute gastric toxicity when delivered with radiotherapy, including taxanes, gemcitabine, and EGF receptor inhibitors. A phase I study evaluated 5-FU, gemcitabine, and radiotherapy in locally advanced pancreatic cancer. Of the 7 patients enrolled, 3 experienced gastric or duodenal ulcers with severe bleeding, requiring transfusion.131 These regimens remain the subject of investigation in the treatment of abdominal malignancies. 

Fig. 41.7  Histopathology of acute radiation injury to the rectum with superficial rectal mucosal erosion and focal lamina propria hemorrhage. (Courtesy Dr. Robin Amirkahn, Dallas, TX.)

Treatment and Prevention Acute symptoms of gastric radiation in toxicity are treated with antiemetics (5-hydroxytryptamine-3 [5-HT3] antagonists, phenothiazines, metoclopramide, glucocorticoids, benzodiazepines, antihistamines, or anticholinergics), as well as consumption of a light meal prior to delivery of RT. Randomized trials of prophylactic 5-HT3 inhibitors have shown efficacy compared with placebo in preventing radiation-induced nausea and vomiting.132 A randomized trial of 211 patients receiving upper abdominal radiation compared the 5-HT3 inhibitor ondansetron given twice daily, with or without dexamethasone delivered daily for the first 5 fractions of treatment. Patients receiving dexamethasone showed a trend toward improved complete control of nausea (50% vs. 38%) and significant improvement in complete control over emesis. The authors concluded that the addition of dexamethasone resulted in modest improvement in protection against radiation-induced emesis.133 Narcotic and non-narcotic agents are often used for pain. In addition, it is recommended that patients be placed on acid antisecretory medications, including PPIs. Careful nutritional support along with antiemetic therapy is essential for patients undergoing radiotherapy to the abdomen. Acute symptoms generally resolve within 1 to 2 weeks following completion of RT. Late gastritis-related symptoms are often treated with acid antisecretory drugs, including histamine antagonists and PPIs, and/or sucralfate. These may be used on a long-term basis to avoid late ulceration. With more severe complications of bleeding, ulceration, gastric outlet obstruction, fistula formation, or perforation, patients may require endoscopic therapeutic approaches or rarely surgical intervention with partial gastrectomy. 

COLON AND RECTUM Incidence and Clinical Features The large bowel is less radiosensitive than the small bowel. Nevertheless, the mechanisms underlying acute and chronic

Fig. 41.8  Typical colonoscopic findings of radiation proctitis in a patient treated for prostate cancer. Top panels, Endoscopic view of the rectum reveals the characteristic fine tortuosity and curling of the new vessels. Lower panels, These demonstrate superficial burns from argon plasma coagulation, which was used to stop this patient’s bleeding. It is not necessary to ablate the lesions completely but merely to cause mucosal and submucosal fibrosis, thereby entrapping the vessels in the scarring process. (Courtesy Lawrence J. Brandt, MD, Bronx, New York.)

injuries of the large intestine are similar to those of the small intestine. There is a decrease in the stem cell mitotic rate, resulting in a depletion of precursor cells required to replenish the epithelium as it normally sheds. Acute injury can be accompanied by superficial mucosal erosions and lamina propria hemorrhage. There is also a thickening of the mucosa, with proliferation of fibroblasts (Fig. 41.7).134 Late changes include vascular fibrosis with associated ischemia and formation of telangiectasias, which can be a source of bleeding (Fig. 41.8). Late radiation large bowel changes can lead to fluid and electrolyte malabsorption, obstruction, chronic proctitis, and fistula formation. Ischemic changes also include ulceration (Fig. 41.9), perforation, and fistulae.22 Bowel wall fibrosis may occur, causing decreased motility and compliance, and stricture.135 A decrease in rectal compliance can reduce the ability of the rectum to act as a reservoir, leading to fecal frequency, urgency, and incontinence.

CHAPTER 41  Acute and Chronic Gastrointestinal Side Effects of Radiation Therapy

Fig. 41.9  Histopathology of the rectal mucosa after radiotherapy with residual malformed rectal crypts and flat, regenerating surface mucosa in the region of a radiation-induced rectal ulcer. Note the fibrosis and inflammation of the lamina propria. (Courtesy Dr. Robin Amirkahn, Dallas, TX.)

Acute colitis from RT manifests clinically as diarrhea, cramping, tenesmus, urgency, incontinence, and, less commonly, mucoid or bloody rectal discharge. These symptoms can result from rectal inflammation, edema, and spasm. Symptoms often begin 2 to 3 weeks into treatment and usually resolve within several weeks to 3 months following radiation completion. A relationship between the incidence of acute and chronic radiation injury is uncertain.136,137 Chronic changes appear within 6 months to 2 years and beyond following completion of RT, with symptoms similar to acute injury. Patients may present with tenesmus, bleeding, low-volume diarrhea, rectal pain, and occasionally low-grade obstruction or fistulae (see Table 41.1).138 Patients can develop a pancolitis that mimics IBD. In addition, pelvic irradiation is a risk factor for development of rectal cancer, and there is evidence that those patients who have received prostate-directed RT have a risk for rectal cancer similar to that of having a first-degree relative with rectal cancer.139 The lower radiosensitivity of the colon and rectum than the small intestine may be partially explained by the fact that higher doses of radiation are often delivered to smaller volumes of the rectum compared with small intestine (i.e., focal “collateral” rectal irradiation in prostate and gynecological cancer therapy). The rectum is also a readily accessible organ by endoscopy, allowing early diagnosis and intervention, possibly preventing symptomatic progression. Data suggest that although rectal mucosal changes are present for up to 5 years post treatment, there is often recovery after complications and resolution of mucosal changes.140 Series have reported the risk of serious late rectal complications is 5% or less when less than 80 Gy is delivered.24 Radiation injury of the large intestine occurs most frequently in the rectum, owing to its location adjacent to the prostate, bladder, cervix, uterus, and ovaries, exposing it to a collateral radiation dose with treatment of these organs.21 Acute rectal injury is often self-limited, but the incidence of chronic radiation proctitis is increasing with increased use of pelvic RT and radiation dose escalation.141,142 As is true with other sites, the incidence of large bowel toxicity is associated with radiation dose, volumes treated, and the use of concurrent chemotherapy. The treatment of rectal cancer commonly uses doses of 45 to 54 Gy, whereas treatment of prostate and cervical cancer uses higher doses ranging from 60 to 80 Gy. The incidence of severe rectosigmoid toxicity in cervical cancer patients was 4% or less for patients receiving doses less than 80 Gy and 13% for doses greater than 95 Gy.143 The treatment of prostate cancer with doses of 60 to 70 Gy has been associated

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with an incidence of severe proctitis less than 8%.144 Radiation doses of 60 to 70 Gy for anal cancer yield an incidence of severe rectal toxicity of 5% or less.145-147 Collectively, it is recommended that less than 20% of the rectum should receive doses greater than 70 Gy. This is associated with grade 2 or higher rectal toxicity in the range of 6% to 23%.148 Treatment using conformal radiation, 3-field, and 4-field techniques further decreases the risk of rectal toxicity.143,149 A trial of conformal versus conventional radiation for prostate cancer reported less radiation proctitis (5% vs. 15%, respectively) 150. The use of IMRT may further improve this rate, as demonstrated by an updated analysis of nearly 1000 prostate cancer patients treated to doses greater than 80 Gy. The actuarial rate of grade 2 or higher rectal toxicity at 7 years was 4.4%, and the incidence of late grade 3 toxicity was 0.7%; no patients experienced grade 4 toxicity.151 Even as moderate to severe hypofractionation, including stereotactic body radiotherapy (SBRT), has become more commonly used in the treatment of prostate cancer, late GI toxicities have remained acceptably low with modern planning techniques and image guidance.152,153 Combining chemotherapy with RT increases toxicity rates. A combination of 5-FU and mitomycin C with radiation doses of 40 to 55 Gy in the treatment of anal cancer was associated with a less than 5% risk of severe rectal complications.154 Multiple trials have combined 5-FU–based chemotherapy and RT as neoadjuvant and adjuvant treatment for rectal cancer.155-158 The toxic effect of combined chemotherapy and radiation has varied from no significant increase in toxicity to a 24% incidence of severe diarrhea and a 25% incidence of chronic bowel injury.159 Given the increase in toxicity seen with single or opposed-only radiation fields, the use of conformal and multifield techniques is necessary when using combination therapy. The increasing use of neoadjuvant CRT has also raised the concern of increased postoperative complications in these patients, although a large randomized trial showed a significant reduction in the rates of acute and chronic GI toxicity in patients treated neoadjuvantly.158,160 In contrast to small bowel injury, previous abdominopelvic surgery does not appear to predispose the rectum to radiation injury, likely due to the fact it is not otherwise mobile. Given the similarity of vascular changes seen with small bowel radiation injury, a history of diabetes, hypertension, cardiovascular disease, or peripheral vascular disease may predispose large bowel to radiation toxicity.41-43,161 Patients with collagen vascular disease and IBD also have an increased propensity for large bowel radiation toxicity. 

Treatment and Prevention Management of large bowel radiation toxicity is based on symptom control. Acute toxicity is treated with antimotility agents such as loperamide or diphenoxylate with atropine and a lowresidue diet. Opiates and anticholinergics may also be of benefit. Glucocorticoid-containing suppositories may be helpful in the management of patients with anorectal inflammation. Colonoscopy should be avoided if possible because of the potential risk of perforation associated with friable rectal mucosa during radiation.162 It is recommended that screening colonoscopies be done prior to prostate brachytherapy in order to reduce rectal complications.163 This is also a reasonable approach prior to the initiation of external beam RT. For chronic diarrhea due to decreased rectal compliance, stool softeners or fiber supplements may alleviate symptoms. As in acute proctitis, glucocorticoid suppositories may be beneficial. The benefit of glucocorticoid retention enemas is unclear.164 Short-chain fatty acids and amino acid derivatives, which nourish and protect the colonic mucosa, have been studied in acute radiation proctitis.165 Initial relief of symptoms can be seen, but symptoms recur shortly after stopping treatment.166

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Hyperbaric oxygen has been used to stabilize bleeding related to telangiectasias, but this treatment is not widely available and requires many sessions before any effect is seen.167 Nonetheless, a randomized trial in patients with refractory chronic radiation proctitis reported that hyperbaric oxygen therapy significantly improved healing.168 Treatment of colorectal ulcerations associated with bleeding is initially endoscopic, with the use of coagulation techniques, such as argon plasma coagulation. Bleeding due to radiation proctopathy is usually minor and often controlled endoscopically with conservative measures such as cauterization of the telangiectasias with laser treatment (see Fig. 41.8).169 Application of formalin or colonic irrigation with oral antibiotics may result in long-lasting therapeutic effect.170-174 Sucralfate enemas may alleviate radiation proctopathy by forming a protective complex with the rectal mucosa. It also increases the local levels of fibroblast growth factors and prostaglandins. Sucralfate enemas appear to be helpful in chronic proctopathy, but their benefit is unclear during the acute period.175-177 Short-chain fatty acid enemas may be also helpful for management of chronic hemorrhagic radiation proctopathy by inhibiting the inflammatory response, including the nuclear factor κB pathway.178,179 Strictures can also be endoscopically dilated. For patients who have refractory bleeding, stricture, perforation, or fistulae, surgical management may rarely be necessary. Management of a pelvic fistula (e.g., vaginal or bladder fistula) is complex and requires fecal diversion before corrective surgery. A thorough radiographic investigation with barium enema, small bowel follow-through, or enteroclysis to delineate the extent of the fistula should be performed before surgery. Patients with fistulas may present with additional challenges such as electrolyte imbalance, malnutrition, and infections. Many surgical techniques have been described to repair fistulas, but corrective surgery is best done when the patient is medically stable and enough time has elapsed after surgical diversion. This allows healing and decreased inflammation of the affected tissues.180,181 Prevention of large bowel toxicity from radiation has been studied. Prostaglandins have been investigated as a potential radioprotector. Prostaglandin E2 and prostaglandin analogs display radiation protection in animal studies.182-185 Clinically, misoprostol suppositories also have been shown to reduce symptoms of acute radiation enteritis in patients undergoing RT for prostate cancer. However, a randomized placebo-controlled trial from Germany in patients with prostate cancer undergoing irradiation found that significantly more patients experienced rectal bleeding in the misoprostol group.186,187 Amifostine has been investigated for the prevention of chronic radiation enteritis and has demonstrated protection of the small and large intestines in preclinical studies.188 The drug has also been shown to reduce the incidence of early and delayed radiotherapeutic injuries at several anatomic sites. In a randomized study, the late effects of radiation were significantly reduced in the group receiving parenterally administered amifostine.189 However, the median follow-up was quite short (24 months), and longer follow-up is necessary to confirm the benefits of the medication, given the incidence of late bowel complications increases with time. Another randomized trial evaluated 205 patients with pelvic malignancies who received RT alone or with IV amifostine. Patients receiving amifostine experienced a significantly lower incidence of grades 2 and 3 bladder and lower GI tract toxicity, with no significant difference between the 2 groups in tumor response to treatment.190 There is also evidence to suggest that intrarectal application of amifostine may reduce the risk of proctitis in patients undergoing radiotherapy for prostate cancer.191 In a phase II study of patients receiving prophylactic amifostine with pelvic radiotherapy, sigmoidoscopy was performed prior to initiation, after completion of radiotherapy, and 6 to 9 months later. Patients receiving amifostine were less likely to develop

histologically detectable mucosal lesions. Rates of radiation colitis were 29% in the amifostine arm and 52% in the radiotherapy without amifostine arm.192 A preclinical study showed a possible role for anti-TGF-β1 interventions to reduce delayed radiation fibrosis and enteropathy.193 Many special diets and nutrients such as fiber, elemental diets, short-chain fatty acids, and amino acids such as glutamine may reduce radiation toxicity to the intestine. However, consistent clinical results were not observed.194-198 Preventive therapy must have high efficacy, low toxicity, and low cost and not protect the tumor from RT. Unfortunately, no currently available therapy fulfills all of these objectives. As described previously, careful radiation planning and delivery are of paramount importance. 

ANUS Incidence and Clinical Features The anal canal is typically spared from significant radiation exposure except in treatment of anal, low rectal, and gynecologic cancers. The primary acute toxicity from anal cancer irradiation is diarrhea from large bowel exposure. Damage to the anus itself can occur in the form of acute desquamation or ulceration, with later development of ulcers, strictures, anorectal fistulae, and incontinence.199 The primary data on anal toxicity from RT come from studies using RT or CRT for the treatment of anal cancer. Anal toxicity manifests as mucosal edema and friability.200 These changes are often exacerbated by diarrhea that occurs from rectal toxicity. Chronically, anal fibrotic changes may evolve. Anal toxicity presents initially as a perianal skin reaction that ranges from minimal skin changes and erythema to moist desquamation and diarrhea. These changes are self-limited and usually resolve within a few weeks of treatment completion. Acute toxicity can lead to an interruption of therapy, although this may be less common with modern radiation treatment techniques.200-202 The incidence of acute toxicity is high and is increased with concurrent chemotherapy delivery or use of a large dose per fraction.146,154,203,204 Phase III studies and series of patients treated with combined chemotherapy and RT have noted an incidence of skin toxicity of grade 3 or greater in 26% to 78% of patients using doses of 45 to 60 Gy in 1.8- to 2.25-Gy fractions.154,199,201,205-207 In a multi-institutional experience of anal cancer patients treated with IMRT-based CRT, grade 3 skin toxicity was seen in 38% of patients, with no grade 4 toxicity observed, comparing favorably to the results of previous randomized trials.202 A study comparing IMRT with conventional RT found that patients treated with conventional RT had longer elapsed treatment days with significantly more breaks from treatment with higher rates of grade 2 or greater toxicity.208 Late anal toxicity occurs within months to years following completion of therapy. The most common late complication is anorectal ulceration. Patients also may develop anal stricture or stenosis, incontinence, anal pain, or anorectal fistulae.154,199,206,209 There does not appear to be an increase in the occurrence of chronic anal toxicity with the addition of chemotherapy to RT.201,209,210 Doses of 45 to 60 Gy in fractions of 1.8 to 2 Gy are considered safe, resulting in chronic grade 3 or higher toxicity rates of zero to 22%.145,147,154,204,211,212 Doses greater than 65 Gy or fraction size greater than 2 Gy results in a high incidence of anal toxicity.203 Patients with HIV and anal cancer who are treated with combined chemotherapy and RT have an increased risk of both acute and late anal toxicity.213 

Treatment Treatment of acute toxicity is primarily supportive, including skin care, dietary modifications, pain medications, and topical glucocorticoid medications, with treatment breaks if severe.

CHAPTER 41  Acute and Chronic Gastrointestinal Side Effects of Radiation Therapy

The effects are self-limited and usually resolve within weeks of therapy completion. Treatment for chronic toxicity such as anal stricture and stenosis includes sphincter dilatation. Rarely, patients can require colostomy for severe symptoms. Small studies of hyperbaric oxygen therapy have shown efficacy in treating chronic anorectal ulcers.214 There is also a report of oral vitamin A therapy for treatment of anorectal ulceration, but confirmatory studies are lacking.200 

PANCREAS AND LIVER Incidence and Clinical Features Pancreas A Japanese study that randomized patients with resectable pancreatic adenocarcinoma to surgery versus CRT noted respective 3-year survival rates of 20% and 0%, suggesting that surgery is requisite for long-term survival even in the most favorable patients.215 In turn, the long-term sequelae of irradiation of the pancreas remain poorly defined. Irradiation of the pancreas has a greater impact on exocrine than on endocrine function in animal studies.216 A study that evaluated the early and late effects of intraoperative RT following resection of pancreatic head lesions noted a larger, transient decrement in exocrine function in the immediate postoperative period in the patients who received RT versus those who did not, with this difference resolving on longer follow-up.217 

Liver Radiation-induced liver disease (RILD) is seen in approximately 5% of patients when the whole-liver radiation dose reaches 30 to 35 Gy at 2 Gy per fraction.218 The pathologic lesion in RILD is central vein thrombosis at the lobular level (veno-occlusive disease), which results in marked sinusoidal congestion, leading to lobular hemorrhage and secondary injury to surrounding hepatocytes.219 Fibrin deposition in the central veins is thought to be the cause of the veno-occlusive injury. It is unknown what stimulates the fibrin deposition, but hypotheses suggest that TGF-β is increased in the setting of exposure to radiation, which in turn stimulates fibroblast migration to the site of injury causing fibrin and collagen deposition. Foci of necrosis are found in the affected portion of the lobules.220 Severe acute hepatic toxicity may progress to fibrosis, cirrhosis, and liver failure. Classic RILD is a clinical syndrome consisting of anicteric hepatomegaly, ascites, and elevated liver enzymes. RILD occurs typically between 2 weeks and 4 months after completion of RT. Patients note fatigue, weight gain, increased abdominal girth, and occasionally RUQ pain. Serum alkaline phosphatase levels are elevated out of proportion to other liver enzymes, and initially the total serum bilirubin level is normal. A nonclassic form of RILD consists of markedly abnormal liver enzyme and bilirubin levels and is more likely in patients with underlying liver disease like viral hepatitis or cirrhosis. Abdominal imaging with CT scan or MRI can be used in diagnosis. RILD can progress to a chronic phase in which patients can develop increasing fibrosis and liver failure.221 Given the parallel architecture of the liver, the volume of liver spared from a certain dose of RT, underlying liver function notwithstanding, is an important factor in predicting the likelihood of RILD. Although radiation hepatopathy can occur after doses of 35 to 40 Gy to the entire liver, significantly higher doses can be given with few clinical complications if sufficient normal liver is spared. Studies by Lawrence and colleagues report that if less than 25% of the normal liver is treated with RT, there may be no upper limit on the dose associated with radiation hepatopathy.219 Estimates of the hepatic irradiation doses associated with a

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5% risk of RILD for uniform irradiation of one third, two thirds, and the whole liver are 90 Gy, 47 Gy, and 31 Gy, respectively. Combining chemotherapy and radiation can increase liver damage, particularly if the chemotherapeutic agents are hepatotoxic. Chlorambucil, busulfan, and platinum drugs are used with RT in bone marrow transplantation patients and are potentially hepatotoxic agents. In contrast, fluoropyrimidines do not seem to increase radiation-related hepatotoxicity.218, 222 When considering the appropriateness of liver-directed therapy in a patient, consideration of baseline liver function is important. Patients are presently stratified based upon their Child-Pugh score. Other grading systems exist (e.g., MELD score), but they have not been evaluated in patients receiving RT. Most trials investigating the use of RT in the treatment of HCC have excluded patients with the poorest liver function. Because baseline liver function is typically worse in patients with HCC versus those with cancer that originated outside of the liver, guidelines have suggested adhering to a lower mean liver dose in patients with primary liver cancers.223 Findings extrapolated from trials using SBRT in the treatment of liver metastases have suggested that a volume of 700 mL of normal liver be spared.224 In 3-fraction SBRT regimens this constraint requires that at least 700 mL receive less than 15 Gy over the course of treatment, although it is important to keep in mind that this was in patients without underlying liver disease, in whom the volume to spare may be 800 mL.225 

Treatment Pancreas Exocrine pancreatic insufficiency is a consequence of both pancreatic volume loss and anatomic alteration in patients who have successfully undergone a Whipple procedure, although it is also commonly seen in patients who underwent a distal pancreatectomy. Fat malabsorption is the predominant cause of symptoms, and dietary modification is often the first recommendation. Pancreatic enzyme replacement has shown success in increasing fat absorption and in turn reducing the severity of steatorrhea, but there is no trial evaluating enzyme replacement in postoperative patients.226 Nonetheless, pancreatic enzyme replacement is FDA-approved for this indication and should be used in this population with close attention paid to dosing recommendations, including total dose, timing relative to meals, and whether a PPI or antacid is necessary to optimize efficacy. 

Liver Supportive care is the mainstay of RILD management. A randomized trial comparing a course of pentoxifylline, ursodeoxycholic acid, and low molecular weight heparin versus no treatment in patients receiving interstitial brachytherapy for the treatment of liver metastases noted a significant reduction in radiationinduced liver injury 6 weeks after treatment.227 Unfortunately, RILD is often fatal given the lack of proven effective treatments and, commonly, the patient’s lack of reserve hepatic function. 

THERAPEUTIC TECHNIQUES TO REDUCE TOXICITY GI toxicity is a significant obstacle in the management of many malignancies, resulting in patient morbidity and impeding tumor control by limiting the timely delivery of radiation dose. Maximal avoidance of normal tissue with delivery of adequate therapeutic doses to targets is the primary goal of the radiation oncologist. As discussed, different techniques may be implemented to decrease the volume of nontarget GI tissues treated, including the use of multiple treatment fields to avoid “hot-spots,” treating in the prone position, use of a belly board or false table-top, as well as treating the patient with a full bladder to displace bowel out of the radiation field.

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PART IV  Topics Involving Multiple Organs

In the past, RT plans were based on 2-dimensional (2D) planning in which treatment fields were defined using plain films and known anatomic landmarks. With improvements in imaging and computing capabilities, 3D treatment planning became available in the 1980s. An advanced form of 3D planning, IMRT, has now been implemented in clinical practice.228, 229 As opposed to conventional “static” fields, IMRT uses the principle of multiple “fields-within-fields” that more accurately conform radiation dose to target tissues while sparing normal structures. IMRT requires target tissues and normal organs are accurately defined. Dose constraints are assigned to these organs, along with a desired prescription dose to the target volume(s). “Inverse planning,” whereby computer-searched algorithms establish multiple (and sometimes unconventional) beam or field designs, is then performed, attempting to meet the prescribed target dose and normal tissue dose constraints. Individual fields are treated with multiple, small “beamlets” rather than one uniform beam, and each beam delivers a different dose intensity to the different parts of the target. This allows close conformation of radiation dose to the shape of the target and preferential sparing of nearby normal tissues. Collectively, early clinical results in varying cancers using IMRT-based CRT have shown significant decreases in treatment-related toxicities, with cancer-related outcomes similar to conventional radiotherapy approaches. For example, Mundt

and associates showed a marked improvement in small bowel dosimetry for patients with gynecologic malignancies treated with IMRT compared with conventional 3D planning. An experience of 36 patients with gynecologic malignancies treated with intensity-modulated whole-pelvic radiotherapy were compared with outcomes of 30 patients treated at the same institution with 3D conformal radiotherapy. Patients were well matched with respect to demographic and treatment factors. Significantly lower rates of chronic GI toxicity were seen in the IMRT group, with only 11% of women treated with IMRT experiencing grades 1 to 3 toxicity (0% grade 3) versus 50% in the non-IMRT group.230 In a different series, Salama and colleagues reported on 53 patients with anal carcinoma treated with IMRT-based CRT. The median radiation doses to the pelvis and the primary disease were 45 and 52 Gy, respectively. Fifteen percent of patients experienced acute grade 3 GI toxicity, with no grade 4 toxicity observed, comparing favorably with observed rates of severe GI toxicity in contemporary trials using conventional radiation planning.202 IMRT is now the primary modality used in the treatment of anal canal cancer and is very commonly used in the treatment of esophageal and pancreatic cancer. Full references for this chapter can be found on www.expertconsult.com 

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Preparation for and Complications of Gastrointestinal Endoscopy Aravind Sugumar, John J. Vargo II

CHAPTER OUTLINE COMPLICATIONS OF NEWER ENDOSCOPIC TECHNIQUES���� 619 PREPARATION OF THE PATIENT FOR ENDOSCOPY ����������619 History and Physical Examination ����������������������������������619 Antibiotic Prophylaxis ����������������������������������������������������619 Management of Anticoagulant and Antiplatelet Drugs ����620 Informed Consent����������������������������������������������������������620 SEDATION ������������������������������������������������������������������������620 INFECTIONS����������������������������������������������������������������������621 ELECTROSURGERY�����������������������������������������������������������621 TIMING AND SEVERITY OF COMPLICATIONS��������������������621 EGD ����������������������������������������������������������������������������������621 Cardiopulmonary Events������������������������������������������������621 Topical Anesthesia����������������������������������������������������������621 Perforation ��������������������������������������������������������������������621 Endoscopic Hemostasis��������������������������������������������������621 Enteral Access Procedures ��������������������������������������������622 Mucosal Ablation and Resection ������������������������������������622 Other Therapeutic Procedures����������������������������������������622 SMALL BOWEL ENDOSCOPY��������������������������������������������623 Balloon-Assisted Enteroscopy����������������������������������������623 Capsule Endoscopy��������������������������������������������������������623 COLONOSCOPY ����������������������������������������������������������������623 Perforation ��������������������������������������������������������������������623 Bleeding������������������������������������������������������������������������623 Post-Polypectomy Electrocoagulation Syndrome������������624 Complications Related to Colon Preparation ������������������624 Others����������������������������������������������������������������������������624 ERCP ��������������������������������������������������������������������������������625 Hemorrhage ������������������������������������������������������������������625 Perforation ��������������������������������������������������������������������625 Cholangitis ��������������������������������������������������������������������625 Pancreatitis��������������������������������������������������������������������625 EUS ����������������������������������������������������������������������������������626 NEWER ENDOSCOPIC TECHNIQUES����������������������������������626

and weigh them against the potential benefits. The importance of this process cannot be minimized. Complications are inevitable, but strict attention to the appropriate indications for such procedures by incorporating optimal technical and cognitive abilities can minimize complications. 

PREPARATION OF THE PATIENT FOR ENDOSCOPY History and Physical Examination A thorough and pertinent medical history should be obtained prior to endoscopy. A careful review of previous endoscopic procedures should also be performed. This should include recognition of any adverse events, the targeted level of sedation, and the patient’s satisfaction with the sedation. A list of current medication usage along with relevant allergies should also be obtained. Use of sedatives, analgesics, and alcohol by the patient can predict the need for larger doses of sedatives and analgesics or the use of monitored anesthesia care. A focused physical examination including the airway, heart, lungs, and abdomen should be performed prior to each endoscopy. Assignment of an American Society of Anesthesiology Physical Status (ASA PS) category (Table 42.1) is strongly encouraged because it has been shown to predict adverse cardiopulmonary events.1 

Antibiotic Prophylaxis There are several GI endoscopic procedures in which antibiotic prophylaxis is warranted (Table 42.2).2 The strongest level of evidence for prophylactic administration of antibiotics is prior to percutaneous endoscopic gastrostomy (PEG) placement to reduce the risk of peristomal cellulitis.3 Antibiotic prophylaxis has also been recommended in all liver transplant patients undergoing ERCP, but the necessity of antibiotics in such patients has been questioned.4 Intended or unintended manipulation of sterile pancreatic necrosis or a pancreatic pseudocyst during ERCP or EUS, as well as EUS-guided FNA of cystic structures within and surrounding the GI tract, should receive antibiotic prophylaxis.2 Patients undergoing ERCP with anticipated incomplete drainage of the biliary tree secondary to extensive PSC or hilar tumors should also receive antibiotic prophylaxis.2 Of note, not all patients with cardiac valvular conditions, synthetic vascular grafts, and prosthetic joints should receive antibiotic prophylaxis TABLE 42.1  ASA PS Classification System Used to Assess Risk of GI Endoscopic Procedures ASA PS Category Pre-Procedure Health Status

COMPLICATIONS OF NEWER ENDOSCOPIC TECHNIQUES GI endoscopy plays an integral part in the diagnosis and management of a variety of GI ailments. Risks and benefits are inherent to the performance of any procedure. In recent years, the “scope” of GI endoscopy keeps expanding to include procedures such as peroral endoscopic myotomy (POEM), endoscopic submucosal dissection (ESD) of tumors, and endoscopic bariatric procedures. With such expansion comes the need to understand these risks

1

Healthy (normal)

2

Mild systemic disease

3

Severe systemic disease

4

Severe systemic disease that is a constant threat to life

5

Moribund (not expected to survive without the procedure)

6

Brain death (for organ harvest)

  

ASA PS, American Society of Anesthesiologists Physical Status.

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TABLE 42.2  Conditions and Procedures Requiring Antibiotic Prophylaxis for Endoscopic Procedures Patient Condition

Procedure

Goal of Prophylaxis

Bile duct obstruction without cholangitis

ERCP with anticipated incomplete biliary drainage

Prevention of cholangitis

Sterile pancreatic fluid collections that communicate with the pancreatic duct

ERCP

Prevention of cyst infection

Sterile pancreatic fluid collection

Transmural drainage

Prevention of cyst infection

Cystic lesions along the GI tract, including the mediastinum

EUS-FNA

Prevention of cyst infection

Cirrhosis with acute GI bleeding

All endoscopic procedures

Prevention of infectious complications including SBP

Any condition

Percutaneous endoscopic feeding tube placement

Prevention of peristomal infection (cellulitis)

because there are no data demonstrating a clear link between GI procedures and infectious complications or demonstrating that antibiotic prophylaxis prevents infectious complications after endoscopic procedures.5 When prophylactic antibiotics are given, the choice of antibiotic(s) depends upon the specific GI procedure, clinical scenario, and allergy history of the patient.6 

understanding of the proposed procedure including the potential risks involved and possible alternatives and to have all questions answered. The components of the informed consent should include a discussion of the procedure itself, including the risks, benefits, and alternatives. The frequency and severity of complications should also be reviewed.11 

Management of Anticoagulant and Antiplatelet Drugs

SEDATION

With the advent of newer and novel antiplatelet drugs and anticoagulants, it is important for the practicing gastroenterologist to understand the duration of action such agents to decrease bleeding and thrombotic complications. The management of antithrombotic and antiplatelet drugs should be based on the urgency of the endoscopic procedure and the bleeding risk associated with the procedure if the agent is not discontinued.7 A good framework is required to classify endoscopic procedures as low versus high risk for bleeding and the underlying disease condition as high versus low risk for a thrombotic complication. The ASGE position statement on the management of antithrombotic agents for patients undergoing GI endoscopy is a useful resource.8 For example, procedures such as biliary sphincterotomy, EUS with FNA, percutaneous gastrostomy, and polypectomy have increased risks of bleeding in patients being treated with warfarin.7,8 In high-risk elective procedures, warfarin should be held so that the INR can return to normal; warfarin can usually be restarted within a week after the procedure.9,10 In patients with high-risk conditions such as mechanical heart valves, the use of a low molecular weight heparin “bridge” should be used until 12 hours prior to the endoscopic procedure to minimize the thromboembolic risk. When antithrombotic therapy is temporary, such as in the treatment of venous thromboembolism, elective GI procedures should be delayed if possible until the anticoagulation is no longer indicated.7,8 For procedures such as EGD and colonoscopy with biopsy that carry a low bleeding risk, aspirin, NSAIDs, and clopidogrel may be continued. For procedures with a higher bleeding risk, such as endoscopic sphincterotomy, the decision to continue the antiplatelet agent will relate to the risk of a thromboembolic event. There are limited data currently on optimal management of patients receiving either anticoagulation with newer drugs that have a shorter half-life than warfarin, such as the direct thrombin inhibitor dabigatran or the direct Xa inhibitor rivaroxaban or receiving antiplatelet therapy with a newer P2Y12 ADP receptor inhibitor such as ticagrelor. 

Informed Consent Written informed consent should be obtained by the endoscopist before performance of any endoscopic procedure. The process of obtaining informed consent is a legal requirement as well as a basic ethical obligation. It allows the patient to gain a thorough

Sedation is used for most endoscopic procedures in order to provide a comfortable and safe milieu for the conduct of the procedure. The majority of ambulatory cases including EGD and colonoscopy are performed by targeting a moderate level of sedation. Typically, a combination of a benzodiazepine and opiate is used, although there has been a growth in the application of propofol-mediated sedation over the past decade. Deep sedation or general anesthesia is usually targeted for advanced endoscopic procedures such as ERCP, EUS, ESD, POEM, etc., and in those patients in whom medications used to target moderate sedation could be problematic. This may potentially include patients using narcotic and/or sedative agents as well as those with significant comorbidities who would be at risk for untoward cardiopulmonary events. Patients with hemodynamic instability or respiratory compromise may also benefit from anesthesia-assisted sedation. Unplanned cardiopulmonary events such as hypotension and hypoxemia occur in 0.9% of procedures.1,12 Risk factors for these events include age, ascending ASA PS category (see Table 42.1), inpatient procedures, as well as procedures that are targeted for prolonged deep sedation or general anesthesia, such as ERCP.1 Respiratory complications include hypoxemia and hypoventilation. In ASA PS 1 and 2 patients undergoing ambulatory endoscopy, risk factors for hypoxemia include BMI, advancing age, and higher doses of narcotic analgesics during the procedure.13,14 Use of pulse oximetry allows for early identification of hypoxemia, and routine use of supplemental O2 can prevent hypoxemia in most cases. Alveolar hypoventilation can be due either to central nervous system depression or to relaxation of the hypopharyngeal muscles. The use of capnography to measure effective CO2 elimination significantly decreases the occurrence of apnea in patients undergoing colonoscopy, ERCP, and EUS in which deep sedation is used.15,16 However, there are currently no data supporting routine use of capnography in subjects undergoing EGD or colonoscopy when targeting moderate sedation. Hypotension during endoscopy is usually due to medicationinduced venodilation in patients who are volume depleted and is usually responsive to IV fluid boluses. A vasovagal reaction is the most common cause of arrhythmias seen during endoscopy. This reaction is usually due to a painful stimulus and can usually be remedied by improving endoscope positioning and reducing bowel distention. Occasionally, intravenous atropine and fluid boluses are required. The use of electrocardiographic monitoring should be considered in patients with a history of cardiac disease, in those over the age of 55 years, and in all cases where deep sedation or general anesthesia is targeted. The endoscopist should be

CHAPTER 42  Preparation for and Complications of Gastrointestinal Endoscopy

familiar with the pharmacokinetics and adverse effect profiles of all sedative medications they use, including their reversal agents such as flumazenil for benzodiazepines and naloxone for narcotics. Having a posted placard in the endoscopy suite with this information readily accessible is prudent. In the recovery area, there is a risk of re-sedation once the stimulus of the procedure has been removed. Recovery to baseline vital signs is an important discharge criterion. It should be emphasized that psychomotoric recovery can be delayed even in patients receiving fast-acting agents such as propofol.17 It is therefore advisable to have the patient accompanied by another individual on discharge and to recommend that the patient not drive or operate machinery until the day following the procedure. 

TIMING AND SEVERITY OF COMPLICATIONS

INFECTIONS

EGD

It has been estimated that the rate of transmission infection via GI endoscopy is 1 per 1.8 million in the USA.2,18,19 Infectious adverse events are a consequence of a failure to follow established reprocessing guidelines for endoscopic devices and accessories, failure to follow sterile technique using sedatives such as propofol, or from the procedure itself.2,20,21 Transient bacteremia is not uncommon during endoscopic procedures, but the infectious sequelae from bacteremia, such as endocarditis or seeding of other sites, is so rare that current recommendations from the American Heart Association and the ASGE recommends antibiotic prophylaxis for only very specific situations (see earlier, Antibiotic Prophylaxis, and Table 42.2).5,22 Because the GI tract is not sterile, high-level disinfection of endoscopes between uses is deemed to be sufficient for preventing transmission of infectious organisms between patients.23 This process includes mechanical cleaning of channels and the exterior of the endoscope, followed by soaking in disinfectant solutions such as glutaraldehyde or peracetic acid followed by thorough rinsing and drying of the instruments. The recent outbreak of carbapenem-resistant enterococci infection from duodenoscopes raises the specter of scope designs limitations and the need for meticulous disinfection protocols.24 One outbreak of hepatitis C was linked to improper sterile technique and the use of a vial of sedative on multiple patients.25 It should be emphasized that high-level disinfection kills most pathogens that could contaminate endoscopes, including HBV, HCV, and HIV. Although prions, such as the Jakob-Creutzfeldt agent, are not inactivated by high-level disinfection, prions are not found in saliva, intestinal tissue, feces, and blood, and hence are judged by the WHO as being noninfectious for the purposes of infection control.26 

Cardiopulmonary Events

ELECTROSURGERY The presence of a cardiac pacemaker or implantable cardiac defibrillator (ICD) requires special consideration because electrocautery performed during an endoscopic procedure can inhibit cardiac pacemaker function and can lead to an inappropriate discharge of a defibrillator. It is therefore prudent to place the grounding pad away from the pacemaker on the patient’s thigh or buttock and to use brief bursts of electrosurgical output. Additionally, utilizing a bipolar platform or, in the case of endoscopic hemostasis, a mechanical or thermal device can minimize risk.27 In the case of an ICD, electrosurgery can induce an unwarranted activation of the device. Temporary deactivation of the ICD with an external defibrillator, coupled with continuous cardiac monitoring of the patient’s cardiac rhythm, should be used. It is of extreme importance to understand the operational capabilities of the electrosurgical unit used. This should include understanding the various settings on the device and their correlation with the desired tissue effect. Additionally, the endoscopist should be able to troubleshoot the device, should an error message or a disruption in the circuit be noted.28,29 

621

Endoscopic complications can occur during a procedure or may be delayed. Knowledge of the potential complications is a critical element of the informed consent process (see earlier). Just as important is patient education to allow early recognition of signs and symptoms that may indicate a delayed complication, and availability of a streamlined process for contacting the endoscopist about a potential complication for appropriate management. From a quality-improvement and treatment perspective, it is important to use this standard set of definitions for adverse outcomes, which would include elements of timing, attribution, severity, and ultimate outcome.30 

Cardiopulmonary adverse events related to sedation and analgesia account for 30% to 60% of all adverse events with EGD.1,31,32 Adverse events can include hypoxia, apnea, hypotension/shock, aspiration, respiratory arrest, pneumonia, myocardial infarction, and cerebral vascular accidents. The risk of cardiopulmonary events is related to increasing complexity of the procedure and severity of comorbid conditions.1,12 The ASA PS category (see Table 42.1) correlates with an increased risk of cardiopulmonary adverse events.12 

Topical Anesthesia Topical anesthetic agents such as benzocaine and lidocaine have been associated with serious adverse events including methemoglobinemia and severe anaphylactoid reactions. Methemoglobinemia is manifested by clinical evidence of cyanosis coupled with a low O2 saturation on pulse oximetry despite a normal arterial po2. This potentially fatal condition is diagnosed using a CO-oximeter, usually on an arterial blood sample. Methemoglobinemia can be reversed with the administration of IV methylene blue.33,34 There may also be an increased risk for aspiration with use of topical anesthetics. 

Perforation Perforation of the upper GI tract during diagnostic EGD has been estimated to occur in 1 in 2500 to 1 in 11,000 cases.35,36 The most common site of perforation is the oropharynx or cervical esophagus. As such, patients with proximal esophageal strictures and cancers, as well as those with Zenker diverticula or large anterior cervical osteophytes, are at particular risk for perforation. Development of crepitus with associated neck or chest pain should prompt an urgent evaluation. Typically, either an esophagogram with water soluble contrast or a CT scan of the neck and chest using an oral contrast agent should be considered. When recognized early, most perforations in the neck can be managed conservatively, in concert with the appropriate surgical services, using broad-spectrum antibiotics and nasogastric suctioning. Intrathoracic perforations can also be managed in this manner. In the appropriate setting, an array of endoscopic devices can be used to treat perforations, including metallic clips, over-the-scope tissue apposition devices, stents, and suturing platforms.37-42 

Endoscopic Hemostasis Ulceration following variceal sclerotherapy can occur in up to 78% of patients.43 Significant immediate bleeding with sclerotherapy can occur in up to 6% of patients.44 Other sclerotherapy complications include aspiration, perforation, stricture

42

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PART IV  Topics Involving Multiple Organs

wound infections.56 Bleeding during or following PEG placement is usually minor and self-limited but occasionally can require endoscopic hemostasis. Anticoagulants should be held, and documentation of normalization of coagulation parameters should be documented prior to PEG placement.57 The “buried bumper syndrome” occurs when the external bumper of the PEG remains too tight and causes migration of the internal bumper into the gastric wall.58 Treatment involves removal of the tube and placement of another tube at a different site. Metastasis developing at the PEG insertion site has been described in patients with oropharyngeal and esophageal malignancy. It is unknown whether the metastasis is a result of local or hematogenous spread. In patients with these cancers, an alternative route for enteral nutrition, such as a radiologically assisted tube placement, may be considered.59 Accidental dislodgement of the PEG tube within 1 month of placement can result in peritonitis if a mature fistulous tract has not developed. In the setting of a mature tract and tube dislodgement, a replacement tube should be inserted as soon as possible.60 Contrast injection can be used with fluoroscopy to determine appropriate positioning. Adverse events with percutaneous endoscopic jejunostomy are like those of PEG placement, although the rates of clogging, migration, and unintentional removal may be higher.61 Aspiration pneumonia may develop either due to aspiration of oropharyngeal contents or the tube feedings themselves. Risk factors for aspiration may include neuromuscular or structural problems of the oropharynx, prolonged supine positioning, history of documented aspiration, reduced level of consciousness, or vomiting/regurgitation.62 

Mucosal Ablation and Resection Fig. 42.1  Magnetic resonance enterography showing a migrated, water-filled PEGbumper in the proximal ileum (yellow arrow). The patient presented with a 7-day history of small bowel obstruction. Single balloon enteroscopy was performed; the balloon was deflated with an injection needle, and the bumper was captured with a snare and removed per os, with full recovery.

formation, pericardial and pleural effusions, as well as mediastinitis.45,46 Endoscopic band ligation has the same efficacy as endoscopic variceal sclerotherapy, but is associated with lower rates of adverse events and mortality and has essentially replaced variceal sclerotherapy.45,46 Esophageal ulcer formation with band ligation occurs in up to 15% of patients. Rarer complications of endoscopic hemostasis include aspiration pneumonia, perforation, and peritonitis. The risk of complications increases if a repeat heater probe treatment is used within 24 to 48 hours of the initial session.47,48 Injection hemostasis with agents such as polidocanol and ethanol have been infrequently reported to cause perforation or exacerbation of bleeding.49,50 

Enteral Access Procedures Endoscopy is often used to provide enteral access routes. Endoscopic placement of nasoenteric feeding tubes ensures delivery of the feeding tube into the small intestine and is associated with minor, self-limited complications.51,52 Epistaxis is the most common, occurring in up to 5% of patients. Proximal migration as well as tube dislodgement may also occur. Adverse events with PEG placement can be as high as 10%.53,54 Significant adverse events occur in 2% to 10% of cases and include aspiration, wound infection, bleeding, perforation, necrotizing fasciitis, intestinal obstruction (Fig. 42.1), and injury to other organs.55,56 A single, pre-procedure dose of a cephalosporin or beta lactam significantly reduces the rate of peristomal

In patients with Barrett esophagus (with or without dysplasia) and mucosal carcinoma (see Chapters 47 and 48), thermal electrocoagulation, radiofrequency ablation, cryotherapy, and endoscopic mucosal resection (EMR) have been associated with dysphagia/ odynophagia, chest pain, dyspepsia, ulceration with bleeding, and perforation.63-66 The incidence of serious advents such as perforation and bleeding with EMR in general is between 0.5% and 5%.67 The risk of esophageal stricture formation is heightened in the setting of circumferential EMR. Most of these strictures can be adequately treated with esophageal dilation.68 Endoscopic submucosal dissection in ESD allows for an en bloc resection using a variety of specialized tools and using the submucosal layer as the dissection plane. Adverse events with ESD are similar to EMR, although the incidence of bleeding and perforation may be higher.67,69 

Other Therapeutic Procedures Insertion of an expandable metallic stent is used to treat both malignant and benign refractory strictures. The associated complication rate is up to 12% and can include chest pain, aspiration, improper positioning, respiratory compromise caused by tracheal compression, and perforation.70 GERD can result when the esophagogastric junction is bridged by the stent, making high-dose acid suppressive therapy with a PPI necessary. Late complications of these stents in the setting of malignancy include tumor overgrowth, tracheoesophageal fistula, and stent migration after tumor shrinkage following CRT.71,72 Complications from endoscopic removal of foreign bodies from the upper GI tract include aspiration, perforation, and GI hemorrhage (see Chapter 28). The risk of foreign body aspiration can be reduced using an overtube or endotracheal intubation. Risk factors for perforation include a more than 24-hour delay in endoscopic intervention or the presence of an irregular or sharp object.73-75 

CHAPTER 42  Preparation for and Complications of Gastrointestinal Endoscopy

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SMALL BOWEL ENDOSCOPY

42

Balloon-Assisted Enteroscopy The advent of balloon-assisted enteroscopy has expanded the horizon of diagnostic and therapeutic vistas into the small bowel. Complication rates for diagnostic double-balloon enteroscopy are 0.8% and 4.3% for therapeutic procedures.76 A multicenter survey of double-balloon procedures found bleeding (0.8%), perforation (0.3%), and pancreatitis (0.3%) as the most common complications.76 Virtually all the bleeding complications occurred in therapeutic procedures in which polypectomy was performed. A perforation rate following balloon dilation of 2.9% was also reported. Although the data on single-balloon enteroscopy are not as voluminous, they appear to have a similar complication profile.77,78 

Capsule Endoscopy Contraindications to wireless capsule endoscopy include known or suspected intestinal obstruction, stricture, fistula or extensive Crohn disease, swallowing disorders, and ileus or intestinal pseudo-obstruction (see Chapter 124).79 More relative contraindications include pregnancy, long-standing use of NSAIDs, Zenker diverticulum, gastroparesis, previous pelvic or abdominal surgery or radiation therapy, and the presence of cardiac pacemakers or ICDs and left ventricular assist devices. There is a theoretical risk of electromagnetic interference between these cardiac devices and capsule endoscopes. However, studies of this issue have not demonstrated this to be a clinically significant problem.80-83 Perhaps the most dreaded complication is the retained capsule within the small bowel. Patients at risk for this condition include those with a history of IBD, prior radiation therapy, previous surgery, and use of NSAIDs.79 A capsule retention rate of 1.4% was seen in a large case series. In almost all instances, significant small bowel pathology was identified that necessitated surgical intervention.79 In those individuals with capsule retention, no obstructive symptoms, no indication for immediate surgery, and whose underlying disease is potentially treatable medically or endoscopically, the use of double-balloon enteroscopy can be successful in retrieving the capsule and treating lesions such as diaphragmatic strictures from NSAIDs.84 In patients in whom luminal patency needs to be assessed prior to performing capsule endoscopy, use of a patency capsule system is useful tool in determining whether sufficient luminal narrowing is present to result in capsule retention and subsequent complications.85-87 In patients with dysphagia, an appropriate structural and motility evaluation should be performed prior to capsule endoscopy. In some cases, a barium swallow coupled with a 13-mm barium pill should be obtained before capsule ingestion. Capsule retention at the cricopharyngeus as well as inside a Zenker diverticulum has been described, with successful endoscopic removal.88 Aspiration of the capsule endoscope with successful bronchoscopic retrieval has also been reported.89,90 Endoscopic placement devices are available which can bypass the stomach and lead to a successful capsule examination of the small intestine in the presence of gastroparesis or a postsurgical anatomy that may lead to delayed passage from the stomach.91 

COLONOSCOPY The overall risk of colonoscopic complications is 0.28%.92 Risk factors include patient age, comorbid conditions (e.g., history of stroke, atrial fibrillation, or heart failure), and undergoing a polypectomy.92,93 The main complications of colonoscopy are cardiovascular and pulmonary events (Fig. 42.2), perforation, bleeding, and a post-polypectomy electrocoagulation syndrome.94 As with other

Fig. 42.2  Chest film showing bilateral aspiration pneumonia in a patient who had undergone a colonoscopy with monitored anesthesia care. There was no history of gastroparesis.

endoscopic procedures, the ASA PS category (see Table 42.1) correlates with the risk of procedure-related unplanned cardiovascular events such as hypotension and hypoxemia.1,95,96

Perforation The rate of perforation with colonoscopy varies from 0.05% to 0.3%.95,97,98 Interestingly, the risk of perforation was not increased in patients receiving a colonoscopy with a polypectomy.93 Perforations can be caused by tearing of the antimesenteric border of the colon from excessive pressure on colonic loops, by excessive air/gas pressure (barotrauma), or from injury at the site of electrosurgical application. Colonic tears occur mainly in the sigmoid colon, where looping of the colonoscope is most frequently encountered. Barotrauma is most often encountered in the cecum, where the colonic diameter is the greatest and, therefore, the tension on the colonic wall is the highest. Ablative treatment of angioectasias, particularly in the right colon, is associated with a perforation rate of up to 2.5%.99 There is a 2% risk of perforation with the placement of a colonic decompression tube in patients with pseudo-obstruction.100-102 Balloon dilation of colonic Crohn disease is associated with nearly a 2% risk of perforation.103 Perforation should be considered in patients with abdominal or shoulder pain who have abdominal distention that does not improve. Frequently a perforation can be recognized at the time of colonoscopy (Fig. 42.3A). Defect closure using endoscopic clips in concert with antibiotics and close observation can be effective in many cases (see Fig. 42.3B).104,105 Careful observation by the gastroenterologist in conjunction with a surgeon is advisable in this situation. In cases with larger tears or frank peritonitis, operative intervention should be considered. 

Bleeding The most common cause of immediate or delayed bleeding with colonoscopy is performing a polypectomy. Although the overall rate of hemorrhage associated with colonoscopy ranges from 0.1% to 0.6%, this risk is 0.87% with polypectomy.97 Patient age, cardiovascular comorbidities, and use of antithrombotic and/or antiplatelet agents are associated with increased risk for polypectomy-associated bleeding.93,106-108 Polyp size may be an additional risk factor for post-polypectomy bleeding.106,108,109 Prophylactic clipping of resection sites after endoscopic removal

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A

B Fig. 42.3 A, Colonoscopic view of an ascending colon perforation following polypectomy of a 2-cm sessile polyp. B, Endoscopic closure of the perforation site using metallic clips. The patient was observed for 48 hours on antibiotics, remained asymptomatic, and was discharged.  

Fig. 42.4 A, Colonoscopic view of a polypectomy site in a patient presenting with hematochezia 5 days after colon polypectomy. This polyp stalk was thought to be the cause of the bleeding. B, Although no bleeding was encountered during the second colonoscopy, a hemostatic clip was placed in an effort to reduce the risk of further bleeding.  

A

B

of large (≥2 cm) sessile polyps may reduce the risk of delayed post-polypectomy hemorrhage.110 Acute post-polypectomy hemorrhage is usually amenable to a variety of endoscopic therapeutic measures (Fig. 42.4).111,112 The use of a detachable snare prior to polypectomy has been associated with a significant reduction in bleeding.113 

Post-Polypectomy Electrocoagulation Syndrome Post-polypectomy electrocoagulation syndrome is defined by the constellation of fever, localized abdominal pain with rebound tenderness, and leukocytosis. This syndrome typically occurs 1 to 5 days after colonoscopy with polypectomy. The reported incidence of this complication varies from 0.003% to 0.1%.97 Typically, patients are managed with IV hydration, broad-spectrum parenteral antibiotics, and being NPO until symptoms improve.114 Abdominal CT should also be obtained to rule out the possibility of a localized perforation. CT should also be undertaken if worrisome findings are noted on serial, frequent abdominal examinations. Milder cases of post-polypectomy electrocoagulation syndrome have been treated with oral antibiotics in an outpatient setting.115 

Complications Related to Colon Preparation Polyethylene glycol is generally safer than sodium phosphate preparations in patients with fluid/electrolyte imbalances or with chronic kidney disease, heart failure, and/or liver failure. Medications such as angiotensin-converting enzyme (ACE) inhibitors, NSAIDs, and diuretics can contribute to fluid/electrolyte problems in such patients about to undergo colonoscopy. In general, patients with predisposing conditions for fluid and electrolyte disorders who are taking the aforementioned medications should have a more gradual bowel preparation and be monitored closely, with a baseline serum creatinine level determined.116-119 

Others Rarer complications of colonoscopy include splenic rupture, appendicitis, and chemical colitis after accidental contamination with disinfectant solutions.120-123 Colonoscopy-specific mortality is rare, occurring in 7 per 100,000 procedures. Complications from colonic stent placement include perforation, migration, and stent occlusion. Stricture dilation of malignant colonic strictures before or after stent placement is not recommended owing to the high risk of perforation.124-126

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42

A

B Fig. 42.5 A, Radiologic image showing right perinephric air following a biliary sphincterotomy. The perforation was identified, and a biliary stent was placed (arrow). B, CT showing the retroperitoneal air. The patient was observed for 48 hours on antibiotics and was discharged after an uneventful course.  

Gas explosion has been rarely reported and is thought to be due to combustible levels of methane or hydrogen present in the colonic lumen when electrocautery or argon plasma coagulation is used. Risk factors may include incomplete colonic cleansing and the use of nonabsorbable or (incompletely absorbable) preparations such as sorbitol, lactulose, and mannitol.127-129 EMR and ESD are techniques used for the removal of large colonic polyps, and both bleeding and perforation are associated with either technique. Although the complication rate is higher with ESD (discussed later), most can be managed endoscopically.105,130,131 

ERCP With the advent of EUS and MRCP, ERCP has become almost exclusively a therapeutic technique. Severe complications of therapeutic ERCP are fortunately rare (Fig 42.5; also see Chapters 61 and 70). It is incumbent upon the endoscopist to minimize complications by using less invasive tests whenever possible and to obtain appropriate informed consent.

Hemorrhage Most bleeding complications following ERCP are related to sphincterotomy, which occur in 1% to 2% of cases.132,133 Risk factors for sphincterotomy bleeding include thrombocytopenia, coagulopathy, cholangitis, and initiation of anticoagulant therapy within 3 days after the procedure. Additionally, endoscopists who had performed less than 1 biliary sphincterotomy per week were noted to have a higher bleeding rate following sphincterotomy.132 Treatment of sphincterotomy bleeding can include the injection of dilute epinephrine, thermal methods such as using a BICAP probe, mechanical methods such as using an inflated balloon within the sphincterotomy, use of metallic clips, or placement of covered expandable metallic stents. In instances where the bleeding is not controlled, therapeutic angiography or surgery may be necessary. Care must be taken to avoid damage to the pancreatic sphincter. 

Perforation Perforation occurs in less than 1% of ERCP cases.132-134 Lateral wall duodenal perforations tend to be large and usually require surgical intervention. With the advent of over-the-scope clipping devices, endoscopic closure may be possible.135 Periampullary perforation following biliary sphincterotomy or stone extraction is less likely to require surgical intervention if recognized early (see Fig. 42.5). Endoscopic management can include the placement of plastic or fully covered metal stents.136,137 Perforation of the biliary tree usually occurs as a result of instrumentation with a guidewire or basket near an obstruction. Most of these can be managed conservatively with the placement of a plastic or fully coated metallic stent. In patients with failed closure, delayed access, or clear evidence of retroperitoneal extravasation, surgical intervention should be considered. 

Cholangitis Cholangitis and cholecystitis occur in 1% and less than 0.5% of patients, respectively.132 Risk factors for ascending cholangitis include combined percutaneous/endoscopic procedures, stenting of malignancy, and failed biliary access or drainage.132 Use of additional imaging modalities such as MRCP to further define complex biliary anatomy prior to the ERCP may be useful. Management of these conditions may include a reattempt at endoscopic therapy, a percutaneous approach, or a surgical intervention. Prophylactic antibiotics have not been shown to reduce the risk of cholangitis following ERCP. Current guidelines recommend prophylactic antibiotics in only those patients undergoing ERCP with anticipated incomplete drainage.138 

Pancreatitis Post-ERCP pancreatitis is discussed in Chapter 58. Its incidence varies from 5% to 10%.132,133 Certain risk factors, both procedure- and patient-related, may amplify this risk to over 20%. Both patient and procedural factors have been identified as

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BOX 42.1 Risk Factors for Post-ERCP Pancreatitis (see also Chapter 58) Balloon dilation of an intact sphincter Failed or difficult cannulation History of post-ERCP pancreatitis Normal serum bilirubin level Pancreatic duct injection Pancreatic guidewire placement Pancreatic sphincterotomy Pancreatic tissue sampling Pre-cut sphincterotomy Suspected SOD Young age

risk factors for post-ERCP pancreatitis (Box 42.1) The severity of pancreatitis ranges from mild with a short hospitalization to severe with multiorgan failure and death. Perhaps the most important components of ERCP planning are ensuring that the risk factors listed in Box 42.1 are respected and that the appropriate noninvasive imaging studies are used, in concert with informed consent. Randomized controlled trials and meta-analyses have shown benefit of prophylactic pancreatic stent placement in the prevention of post-ERCP pancreatitis.139,140 Whether particular electrocautery cutting currents influence the risk is controversial.141,142 A recent randomized controlled trial in high-risk patients reported a significant reduction in postERCP pancreatitis using rectal indomethacin.143 Treatment of post-ERCP pancreatitis remains supportive (see Chapter 58), and there is no role for repeat ERCP in this setting. Infection of a pseudocyst, if present, is always a possibility with ERCP. Plans for drainage of the cyst should be considered in concert with the ERCP. In most cases, this can be rendered via an endoscopic cyst gastrostomy or cyst duodenostomy.144 

EUS Esophageal perforation stemming from the passage of an echoendoscope is rare (0.03%).145 Risk factors for esophageal perforation include older patient age, lack of operator experience, and a difficult esophageal intubation.145 In up to one third of patients with esophageal malignancy, there is difficulty or an inability in

passing the echoendoscope. Sequential esophageal bougienage to 16 mm is safe in these patients, allowing completion of the EUS.146,147 FNA of cystic lesions carries an increased risk of fever, infection of the targeted cyst, and sepsis. Evidence favors that prophylactic antibiotics be started before the procedure and continued for up to 48 hours following it.148,149 Additionally, patients undergoing FNA of perirectal lesions should be considered for prophylactic antibiotics. Current data do not support the use of prophylactic antibiotics during FNA of lymph nodes or solid masses. Mild intraluminal GI bleeding may be encountered in up to 4% of FNA cases,150 and extraluminal hemorrhage may occur in 1.3%.151 Pancreatitis, reported in up to 2% of patients, is most likely secondary to passage of the FNA needle through pancreatic tissue.152 

NEWER ENDOSCOPIC TECHNIQUES With the advent of newer endoscopic techniques such as ESD, POEM, and bariatric endoscopic procedures, a thorough understanding of the risks and benefits is imperative. ESD is a technique that is now being increasingly used for removing large neoplastic lesions en bloc. The complication rates of this technique are dependent on the site (rectum vs. cecum). POEM is the most preferred endoscopic treatment of choice for achalasia (see Chapter 44), and complications are lower than those for laparoscopic Heller myotomy. Endoscopic bariatric procedures span the gamut of minimally invasive procedures such as intragastric balloons to endoscopic sleeve gastroplasty (see Chapter 8). The appropriate indications for such procedures are evolving. The use of single operator cholangioscopy to visualize the bile duct has a similar complication profile to ERCP except for an increased risk of cholangitis; A prospective study of the risk of bacteremia in directed cholangioscopic examination of the common bile duct when indicated appears to be as safe as ERCP, even in older patients.153 Endoscopic drainage has become the therapy of choice for the management of complex pancreatic fluid collection and walled off pancreatic necrosis (see Chapter 58). Lumen-opposing metallic stents have an excellent safety profile, with complications requiring intervention that include stent migration (4.2%), infection (3.8%), bleeding (2.4%), and stent occlusion (1.9%).154 Full references for this chapter can be found on www.expertconsult.com

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125. Sebastian S, Johnston S, Geoghegan T, et al. Pooled analysis of the efficacy and safety of self-expanding metal stenting in malignant colorectal obstruction. Am J Gastroenterol 2004;99:2051–7. 126. Baron TH, Wong Keeson LM, Repici A. Role of self-expandable stents for patients with colon cancer (with videos). Gastrointest Endosc 2012;75:653–62. 127. Monahan DW, Peluso FE, Goldner F. Combustible colonic gas levels during flexible sigmoidoscopy and colonoscopy. Gastrointest Endosc 1992;38:40–3. 128. Avgerinos A, Kalantzis N, Rekoumis G, et al. Bowel preparation and the risk of explosion during colonoscopic polypectomy. Gut 1984;25:361–4. 129. Labrooy SJ, Avgerinos A, Fendic CL, et al. Potentially explosive colonic concentrations of hydrogen after bowel preparation with mannitol. Lancet 1981;1:634–6. 130. Kantsevoy SV, Edler DG, Conway JD, et al. Endoscopic mucosal resection and endoscopic submucosal dissection. Gastrointest Endosc 2008;68:11–8. 131. Tanaka S, Oka S, Kaneko I, et al. Endoscopic submucosal dissection for colorectal neoplasia: possibility of standardization. Gastrointest Endosc 2007;66:100–7. 132. Freeman ML, Nelson DB, Sherman S, et al. Complications of endoscopic biliary sphincterotomy. N Engl J Med 1996;335:909–18. 133. Masci E, Toti G, Mariani A, et al. Complications of diagnostic and therapeutic ERCP: a prospective multicenter study. Am J Gastroenterol 2001;96:417–23. 134. Loperfido S, Angelini G, Benedetti G, et al. Major complications from diagnostic and therapeutic ERCP: a prospective multicenter study. Gastrointest Endosc 1998;48:1–10. 135. Voermans RP, LeMoine O, von Renteln D, et al. CLIPPER Study Group. Efficacy of endoscopic closure of acute perforations of the GI tract. Clin Gastroenterol Hepatol 2012;16:26–32. 136. Gostout CJ, Herman L. Hemoclip pair of a sphincterotomy induced duodenal perforation. Gastrointest Endosc 2000;52:566–8. 137. Vezakis A, Fragulidis G, Nasto OS. Closure of a persistent sphincterotomy-related duodenal perforation by placement of a covered self-expandable metallic biliary stent. World J Gastroenterol 2011;17:4539–41. 138. ASGE Standards of Practice Committee. Antibiotic prophylaxis for GI endoscopy. Gastrointest Endosc 2008;67:791–8. 139. Choudhary A, Bechtold ML, Arif M, et al. Pancreatic stents for prophylaxis against post- ERCP pancreatitis: a meta-analysis and systematic review. Gastrointest Endosc 2011;73:275–82. 140. Freeman ML. Pancreatic stents for prevention of post endoscopic retrograde cholangiopancreatography pancreatitis. Clin Gastroenterol Hepatol 2007;5:1354–65. 141. Gorelick A, Cannon M, Barnett J, et al. First cut then blend: an electrocautery technique affecting bleeding at sphincterotomy. Endoscopy 2001;33:976–80. 142. Elta GH, Barnett JL, Wille RT, et al. Pure cut electrocautery current for sphincterotomy causes less post-procedure pancreatitis than blended current. Gastrointest Endosc 1998;47:149–53. 143. Elmunzer BJ, Scheiman JM, Lehman GA, et al. A randomized trial of rectal indomethacin to prevent post-ERCP pancreatitis. N Engl J Med 2012;366:1414–22. 144. Freeman ML, Guda NM. ERCP cannulation: a review of reported techniques. Gastrointest Endosc 2005;61:112–25. 145. Das A, Sivak MV, Chak A. Cervical esophageal perforation during EUS: a national survey. Gastrointest Endosc 2001;53:599–602. 146. Wallace MB, Hawes RH, Sahai AV, et al. Dilation of malignant esophageal stenosis to allow EUS guided fine-needle aspiration: safety and effect on patient management. Gastrointest Endosc 2000;51:309–13. 147. Pfau PR, Ginsberg GG, Lew RJ, et al. Esophageal dilation for endoscopic evaluation of malignant esophageal strictures is safe and effective. Am J Gastroenterol 2000;95:2813–5. 148. Schwartz DA, Harewood GC, Wiersema MJ. EUS for rectal disease. Gastrointest Endosc 2002;56:100–9. 149. Ryan AG, Zamvar V, Roberts SA. Iatrogenic candida infection of a mediastinal foregut cyst following endoscopic ultrasound-guided fine-needle aspiration. Endoscopy 2002;34:838–9. 150. Voss M, Hammel P, Molas G, et al. Value of endoscopic ultrasound-guided fine-needle aspiration biopsy in the diagnosis of solid pancreatic masses. Gut 2000;46:244–9.

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151. Affi A, Vazquez-Sequeiros E, Norton ID, et al. Acute extraluminal hemorrhage associated with EUS-guided fine-needle aspiration: frequency and clinical significance. Gastrointest Endosc 2001;53: 221–5. 152. Gress F, Michael H, Gelrud D, et al. EUS-guided fine-needle aspiration of the pancreas: evaluation of pancreatitis as a complication. Gastrointest Endosc 2002;56:864–7.

153. Bernica J, Elhanafi S, Kalakota N, et al. Cholangioscopy is safe and feasible in elderly patients. Clin Gastroenterol Hepatol 2018;16(8): 1293–9.e2. 154. Hammad T, Khan MA, Alastal Y, et al. Efficacy and safety of lumen-opposing metal stents in management of pancreatic fluid collections:are they better than plastic stents? A systemic review and meta-analysis. Dig Dis Sci 2018;63:289–301. https://doi. org/10.1007/s10620-017-4851-0. Epub 2017.

PART V

43

Esophagus

Anatomy, Histology, Embryology, and Developmental Anomalies of the Esophagus Ryan D. Madanick, Vishal Kaila

CHAPTER OUTLINE ANATOMY AND HISTOLOGY����������������������������������������������627 Musculature������������������������������������������������������������������627 Innervation��������������������������������������������������������������������627 Circulation����������������������������������������������������������������������627 Mucosa��������������������������������������������������������������������������628 Submucosa��������������������������������������������������������������������629 EMBRYOLOGY������������������������������������������������������������������629 DEVELOPMENTAL ANOMALIES����������������������������������������629 Esophageal Atresia and Tracheoesophageal Fistula��������629 Congenital Esophageal Stenosis ������������������������������������633 Esophageal Duplications������������������������������������������������634 Vascular Anomalies��������������������������������������������������������635 Esophageal Rings����������������������������������������������������������635 Esophageal Webs ����������������������������������������������������������636 Heterotopic Gastric Mucosa (Inlet Patch)������������������������637

ANATOMY AND HISTOLOGY The esophagus acts as a conduit for the transport of food from the oral cavity to the stomach. To carry out this task safely and effectively, the esophagus is constructed as an 18- to 26-cm long hollow muscular tube with an inner “skin-like” lining of stratified squamous epithelium (Fig. 43.1). Between swallows the esophagus is collapsed, but the lumen distends up to 2 cm anteroposteriorly and 3 cm laterally to accommodate a swallowed bolus. Structurally, the esophageal wall is composed of 4 layers: innermost mucosa, submucosa, muscularis propria, and outermost adventitia; unlike the remainder of the GI tract, the esophagus has no serosa.1,2 These layers are depicted anatomically and as viewed by EUS in Fig. 43.2.

Musculature The muscularis propria is responsible for carrying out the organ’s motor function. The upper 5% to 33% is composed exclusively of skeletal muscle, and the distal 50% is composed of smooth muscle. In between is a mixture of both types.3 Proximally, the esophagus begins where the inferior pharyngeal constrictor merges with the cricopharyngeus, an area of skeletal muscle known functionally as the upper esophageal sphincter (UES) (Fig. 43.3A). The UES is contracted at rest and, hence, creates a high-pressure zone that prevents inspired air from entering the esophagus. Below the UES, the esophageal wall is composed of inner circular and outer longitudinal layers of muscle (see Fig. 43.2A). The esophageal body lies within the posterior mediastinum behind the trachea and left

mainstem bronchus and swings leftward to pass behind the heart and in front of the aorta.1 At the T10 vertebral level the esophageal body leaves the thorax through a hiatus located within the right crus of the diaphragm (see Fig. 43.1). Within the diaphragmatic hiatus the esophageal body ends in a 2- to 4-cm length of asymmetrically thickened circular smooth muscle known as the lower esophageal sphincter (LES) (see Fig. 43.3B).4 The phrenoesophageal ligament, which originates from the diaphragm’s transversalis fascia and inserts on the lower esophagus, contributes to fixation of the LES within the diaphragmatic hiatus. This positioning is beneficial because it enables diaphragmatic contractions to assist the LES in maintenance of a high-pressure zone during exercise. The LES is contracted at rest, creating a high-pressure zone that prevents gastric contents from entering the esophagus. During swallowing, the LES relaxes to permit the swallowed bolus to be pushed by peristalsis from the esophagus into the stomach. 

Innervation The esophageal wall is innervated by parasympathetic and sympathetic nerves; the parasympathetics regulate peristalsis through the vagus nerve (Fig. 43.4). The cell bodies of the vagus nerve originate in the medulla. Those located within the nucleus ambiguus control skeletal muscle, and those located within the dorsal motor nucleus control smooth muscle. Medullary vagal postganglionic efferent nerves terminate directly on the motor endplate of skeletal muscle in the upper esophagus, whereas vagal preganglionic efferent nerves heading to smooth muscle in the distal esophagus terminate on neurons within Auerbach (myenteric) plexus, located between the circular and longitudinal muscle layers.3 A second neuronal sensory network, Meissner plexus, located within the submucosa, is the site of afferent impulses within the esophageal wall. These are transmitted to the central nervous system through vagal parasympathetic and thoracic sympathetic nerves. Sensory signals transmitted via vagal afferent pathways travel to the nucleus tractus solitarius within the central nervous system (see Fig. 43.4); from there nerves pass to the nucleus ambiguus and dorsal motor nucleus of the vagus nerve, where their signals may influence motor function.5 Pain sensation arising from the esophagus is typically triggered by stimulation of chemoreceptors in the esophageal mucosa or submucosa and/or mechanoreceptors in the esophageal musculature.6 Central perception then occurs when these impulses are transmitted to the brain by sympathetic and vagal afferents. Sympathetic afferents travel through the dorsal root ganglia to the dorsal horn of the spinal cord, and vagal afferents travel through the nodose ganglia to the nucleus tractus solitarius in the medulla. Information from sympathetic/spinal afferents then proceeds via the spinothalamic and spinoreticular pathways to the thalamus and reticular nuclei before transmission to the somatosensory cortex for pain perception and limbic system for pain modulation. Information

627

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PART V  Esophagus Distance from incisors

Stratified squamous Lamina Muscularis epithelium propria mucosae

Mucosa

Longitudinal folds

Cervical esophagus

UES Trachea Submucosa Adventitia

40 cm

Aorta

Submucosal Inner circular layer gland with Outer longitudinal layer duct

A

Muscularis propria

Thoracic esophagus

Right crus of diaphragm LES

Abdominal esophagus

B

Fig.43.1  Anatomy of the esophagus and its relationship to adjacent structure.  The esophagus, approximately 25 cm in length, originates in the neck at the level of the cricoid cartilage, passes through the chest, and ends after passage through the hiatus in the right crus of the diaphragm by joining the stomach below. On barium esophagogram, adjacent structures may indent the esophageal wall, including the aortic arch, left mainstem bronchus, left atrium, and diaphragm. LES, Lower esophageal sphincter; UES, upper esophageal sphincter. (Modified from Liebermann-Meffert D. Anatomy, embryology, and histology. In: Pearson FG, Cooper JD, Deslauriers J, et al, editors. Esophageal surgery. 2nd ed. Philadelphia: Churchill Livingstone; 2002. p 8.)

from vagal afferents in the medulla also travels to the limbic system and frontal cortex for pain modulation. Furthermore, because the esophageal neuroanatomic pathways overlap with those of the heart and respiratory system, in clinical practice it may be difficult to discern the organ of origin for some chest pain syndromes.6 

Circulation The arterial and venous blood supply to the esophagus is segmental. The upper esophagus is supplied by branches of the superior and inferior thyroid arteries, the midesophagus by branches of the bronchial and right intercostal arteries and descending aorta, and the distal esophagus by branches of the left gastric, left inferior phrenic, and splenic arteries.1-3 These vessels anastomose to create a dense network within the submucosa that probably

Fig. 43.2  Cross-sectional and EUS anatomy of the esophagus.  A, The anatomic layers within the wall of the esophagus are depicted. B, An EUS image depicting the pattern of light and dark rings created by echoes from the different layers. (A, Interface between lumen and mucosa; B, mucosa; C, submucosa; D, muscularis propria; E, adventitia.) Note that A, C, and E are hyperechoic, and B and D are hypoechoic. (A, Modified from Neutra MR, Padykula HA. The GI tract. In: Weiss L, editor. Histology, cell and tissue biology. 5th ed. New York: Elsevier Science; 1983. p 664.)

accounts for the rarity of esophageal infarction. The venous drainage of the upper esophagus is through the superior vena cava, the midesophagus through the azygos veins, and the distal esophagus through the portal vein by means of the left and short gastric veins. The submucosal venous anastomotic network of the distal esophagus is important because it is where esophageal varices emerge in patients with portal hypertension.1-3 The lymphatic system of the esophagus is also segmental; the upper esophagus drains to the deep cervical nodes, the midesophagus to the mediastinal nodes, and the distal esophagus to the celiac and gastric nodes. However, these lymphatic systems are also interconnected by numerous channels, accounting for the spread of most esophageal cancers beyond the region at the time of their discovery. 

Mucosa During endoscopic evaluation the normal esophageal mucosa appears smooth and pink. The normal esophagogastric junction appears as an irregular white Z-line (ora serrata) demarcating the interface between the lighter esophageal and the redder gastric mucosa. Histologically the esophageal mucosa is a nonkeratinized, stratified squamous epithelium (Fig. 43.5). This

CHAPTER 43  Anatomy, Histology, Embryology, and Developmental Anomalies of the Esophagus

UES Inferior constrictor

UES

Thyroid cartilage Cricoid cartilage

Cricopharyngeus

629

The esophageal epithelium contains a small number of other cell types including argyrophilic neuroendocrine cells, melanocytes, lymphocytes, Langerhans cells (macrophages), and eosinophils. Neutrophils are not present in healthy epithelium.2 Below the epithelium is the lamina propria, a loose network of connective tissue within which are blood vessels and scattered lymphocytes, macrophages, and plasma cells (see Fig. 43.5). The lamina propria protrudes at intervals into the epithelium to form rete pegs or dermal papillae. Normally these protrude to less than 50% of the epithelium’s thickness; when greater, it also is a recognized marker of GERD.8 The muscularis mucosae is a thin layer of smooth muscle that separates the lamina propria above from the submucosa. Its functions are unclear. 

Submucosa Trachea

Proximal esophagus

A LES Pleura Diaphragm

A ring Phrenoesophageal ligament Sling fibers

Squamocolumnar junction Peritoneum

B Fig. 43.3 A, Anatomic detail of the UES and its relationship to adjacent structures. B, Anatomic detail of the LES and its relationship to the diaphragm, phrenoesophageal ligament, and squamocolumnar junction. (A, Modified from AGA Clinical Teaching Project. Esophageal disorders: Upper esophageal sphincter anatomy, slide 14, American Gastroenterological Association, 1995; B, modified from Kerr RM. Hiatal hernia and mucosal prolapse. In: Castell DO, editor. The esophagus. Boston: Little, Brown & Company; 1992. p 763.)  

multilayered epithelium consists of 3 functionally distinct layers: stratum corneum, stratum spinosum, and stratum germinativum. The most lumen-oriented stratum corneum acts as a permeability barrier between luminal content and blood by having layers of pancake-shaped glycogen-rich cells connected laterally to each other by tight junctions and zonula adherens and having their intercellular spaces filled with a dense matrix of glycoconjugate material.7 The middle layer of stratum spinosum contains metabolically active cells with a spiny shape. The spiny shape is due to the numerous desmosomes connecting cells throughout the layer. Furthermore, this same desmosomal network maintains the structural integrity of the tissue. The basal layers of stratum germinativum contain cuboidal cells that occupy 10% to 15% of the epithelium’s thickness and are uniquely capable of replication.2 Basal cell hyperplasia, defined as basal cells occupying more than 15% of epithelial thickness, reflects an increased rate of tissue repair, as is often seen in GERD (see Chapter 46).2

The submucosa comprises a dense network of connective tissue, within which are blood vessels, lymphatic channels, neurons of Meissner plexus, and esophageal glands (see Fig. 43.2A). These glands, which vary as to number and distribution along the esophagus, consist of cuboidal cells organized as acini.9 They produce and secrete a lubricant, mucus, and factors such as bicarbonate and epidermal growth factor that are important for epithelial defense and repair. The secretions from these glands pass into tortuous collecting ducts that deliver them to the esophageal lumen. 

EMBRYOLOGY A brief review of the embryology of the upper digestive system is presented as a guide to understand the origin of many of the developmental anomalies discussed in this chapter. In the developing fetus, the oropharynx and esophageal components of the GI tract and the larynx, trachea, bronchi, and lungs of the respiratory tract develop from a common tube.3 By gestational week 4, this tube, composed of endoderm, develops a diverticulum on its ventral surface that is destined to become the epithelium and glands of the respiratory tract (Fig. 43.6A to D). This diverticulum subsequently elongates, becomes enveloped by splanchnic mesenchyme (future cartilage, connective tissue, and smooth muscle), and buds off to become the primitive respiratory tract. Concomitantly, the lumen of the dorsal tube, the primitive foregut, fills with proliferating, ciliated-columnar epithelium. By week 10, vacuoles appear and subsequently coalesce within the primitive foregut to reestablish the lumen. By week 16, the columnar epithelium lining the primitive foregut and future esophagus is replaced by stratified squamous epithelium, a process that is complete by birth. 

DEVELOPMENTAL ANOMALIES Congenital anomalies of the esophagus are relatively common and are due to either transmission of genetic defects or intrauterine stress that impedes fetal maturation. Esophageal anomalies are common in premature infants, and 60% have other anomalies, reflected by the term VACTERL (formerly VATER), a mnemonic for the association of anomalies of the vertebral, anal, cardiac, tracheal, esophageal, renal, and limb systems. Common specific defects include patent ductus arteriosus, cardiac septal defects, and imperforate anus.10

Esophageal Atresia and Tracheoesophageal Fistula Esophageal atresia, a loss of continuity between the upper and lower esophagus, and tracheoesophageal fistulas, abnormal connections between the trachea and esophagus, are the most common developmental anomalies of the esophagus (Figs. 43.7 and 43.8). The incidence of esophageal atresia and tracheoesophageal fistula is approximately 1 in 4000.11 The former results from failure of the primitive foregut to recanalize and the latter from failure of the lung bud to separate completely from the foregut.

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PART V  Esophagus

Cortical stimuli

Sensory pathways Motor pathways Nucleus solitarius Dorsal vagal nucleus Nucleus ambiguus Inspiratory center Medulla Phrenic nucleus Phrenic nerve

Pharynx

Vagus nerve

Vagus nerve

+Ach

Esophagus

Myenteric plexus

Crural diaphragm

Phrenic nerve +Ach

Fig. 43.4  Neural pathways of the esophagus.  Extrinsic innervation is provided principally by the vagus nerve. Afferent vagal pathways carry stimuli to the nucleus solitarius, and efferent pathways originating in the dorsal vagal nucleus mediate esophageal peristalsis and LES relaxation. Ach, Acetylcholine; NO, nitric oxide; VIP, vasoactive intestinal peptide. (From Mittal RK, Balaban DH. The esophagogastric junction. N Engl J Med 1997; 336:924.)

–VIP –NO +Ach

Lower esophageal sphincter

Lung bud Primitive common upper digestive and respiratory tract

Foregut

A

B Tracheoesophageal septum Esophagus

Fig. 43.5  Esophageal epithelium.  The human esophagus as shown on this biopsy specimen is lined by nonkeratinized stratified squamous epithelium. The cells of the surface (top) are long and flat and have a small nucleus-to-cytoplasm ratio that contrasts with the cells of the basal layer (bottom), the density, cuboidal shape, and large nucleus-tocytoplasm ratio of which account for their prominence. A subpopulation of these basal layer cells appears to have properties of esophageal stem cells.7 Rete pegs, or dermal papillae containing elements of the lamina propria, normally extend into the epithelium about one half the distance to the lumen. (Courtesy Pamela Jensen, MD, Dallas, TX.)

Although the mechanisms are unclear, esophageal atresia and tracheoesophageal fistulas may result from genetic defects (Table 43.1).12 Proper sonic hedgehog signaling is 1 of the pathways critical to achieve separation of the respiratory tract from the primitive foregut.13 Experimental administration of the anticancer drug, Adriamycin (doxorubicin), into mouse or rat embryos

Trachea Bronchial bud

Lung

C

D

Stomach

Fig. 43.6  Developmental stages in the formation of separate respiratory and digestive systems.  These systems are derived from a common tube of endoderm during embryogenesis. A, Single primitive tube. B, Formation of a lung bud in the fourth week. C, Elongation of the dorsal tube (primitive foregut) and lung bud and formation of a tracheoesophageal septum by 4 to 6 weeks. D, Separation of the primitive foregut from the tracheobronchial tree at 6 weeks.

CHAPTER 43  Anatomy, Histology, Embryology, and Developmental Anomalies of the Esophagus

631

TABLE 43.1  Syndromic Causes and Distinguishing Clinical Features of Tracheoesophageal Fistula and Esophageal Atresia Syndrome

A

B

D

Gene

Anophthalmia/microphthalmia EA/TEF Urogenital anomalies

CHARGE Syndrome

CHD7

 Coloboma of the eye Cardiac anomalies Choanal atresia Intellectual disability Growth retardation Genital anomalies Ear anomalies Hearing loss EA/TEF

Feingold Syndrome

MYCN

Esophageal/duodenal atresias Microcephaly Learning disabilities Syndactyly Cardiac defects

Fanconi Anemia

>20 genes

Bone marrow failure Malignancies Short stature Abnormal skin pigmentation Radial ray defects Eye anomalies Renal anomalies Cardiac defects Abnormal ears Central nervous system anomalies Hearing loss Developmental delay Gastrointestinal anomalies including EA/TEF

VACTERL-H

FANCB

Vertebral anomalies Anal atresia Cardiac malformations TEF Renal anomalies Limb anomalies Hydrocephalus

C

E

Clinical Features

AnophthalmiaSOX2 esophagealgenital syndrome

Fig. 43.7  Esophageal atresia (A) and tracheoesophageal fistulas TEF. In the most common TEF, the trachea communicates with the distal segment of the atretic esophagus (B). The next most common type is the H-type TEF, in which the trachea communicates with an otherwise normal esophagus (C). A TEF in which the trachea communicates with both upper and lower segments of an atretic esophagus (D) or only with the upper segment of an atretic esophagus (E ) is rare. (Modified from The nonneoplastic esophagus. In: Fenoglio-Preiser CM, editor. GI pathology. An atlas and text. 2nd ed. Philadelphia: Lippincott-Raven; 1999. p 31.)

  

EA, Esophageal atresia; TEF, tracheoesophageal fistula. Adapted from Scott DA. Esophageal atresia/tracheoesophageal fistula overview. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle: University of Washington, Seattle; 1993.   

Fig. 43.8  Chest radiograph depicting tracheoesophageal fistula.  A catheter is shown coiled in the esophagus (arrow) at the level of the second thoracic vertebra with air in the stomach. (From Forero Zapata L, Pappagallo M. Esophageal Atresia and Tracheoesophageal Fistula. N Engl J Med. 2018;379(7):e11.)

commonly results in esophageal atresia and tracheoesophageal fistulas, as well as other anomalies that comprise the VACTERL group, by altering sonic hedgehog signaling.14,15 Esophageal atresia occurs as an isolated anomaly in only 7% of cases; the rest are accompanied by a form of tracheoesophageal fistula, most often (89%) a distal-type fistula (see Fig. 43.7B) and rarely (3%) the H-type fistula (see Fig. 43.7C).16 In isolated atresia, the upper esophagus ends in a blind pouch and the lower esophagus connects to the stomach (see Fig. 43.7A). The condition is suspected prenatally by the development of polyhydramnios (due to the inability of the fetus to swallow and so absorb amniotic fluid) and an absent or small stomach bubble.17 The finding of a dilated proximal esophagus with a blind ending, also known as an esophageal pouch, during a prenatal US has high specificity for esophageal atresia, although the sensitivity of this finding is limited.18 A distended fetal hypopharynx during US or MRI is an additional prenatal sign of esophageal atresia and has better sensitivity than an esophageal pouch. Prenatal MRI provides images of the entire length of the esophagus and can be used to assist in the diagnosis of esophageal atresia.19 Additionally, visualization of a lower esophageal lumen during prenatal MRI suggests the presence of a

43

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PART V  Esophagus

tracheoesophageal fistula (Fig. 43.9). At birth the combination of regurgitation of saliva and a scaphoid (gasless) abdomen strongly suggests isolated atresia without a distal tracheoesophageal fistula because no pathway exists for inspired or swallowed air to enter the bowel. At the first feeding, the high complete GI obstruction of esophageal atresia results in the rapid onset of choking, coughing, and regurgitation (Table 43.2). Once suspected, the diagnosis can

Fig. 43.9  Esophageal atresia seen in a sagittal T2-weighted MRI sequence showing the proximal blind pouch (arrow) and the long distal esophagus (arrowhead). (From Cassart M. Fetal Body Imaging: When is MRI Indicated? J Belg Soc Radiol. 2017;101(S1):3.)

be confirmed by failure to pass an NG tube into the stomach and by a concurrent chest radiograph with air contrast in the upper esophageal segment (the air being introduced through a catheter positioned within the upper esophageal segment). In some instances, injection of 1 mL of water-soluble contrast into the obstructed segment helps with the diagnosis. Tracheoesophageal fistula usually accompanies esophageal atresia. The most common type of tracheoesophageal fistula is the distal type associated with esophageal atresia (see Fig. 43.7B).16 In this type, the atretic upper esophagus ends in a blind pouch and the trachea communicates with the distal esophageal segment. The clinical presentation with this configuration is usually similar to isolated esophageal atresia, with the additional risk of aspiration pneumonia from refluxed gastric contents entering the trachea through the fistula (see Table 43.2). Nonetheless, distinction between an isolated atresia and 1 associated with a distal tracheoesophageal fistula is straightforward because the communication between the trachea and the esophagus results in a gasfilled abdomen, as shown on plain radiographs (see Fig. 43.8). In some instances, confirmation of the type of configuration is obtained by esophagography with or without bronchoscopy. The 3 less common types of tracheoesophageal fistula occur when (1) the atretic upper esophagus communicates with the trachea, (2) both upper and lower segments of the atretic esophagus communicate with the trachea, and (3) an H-type fistula communicates with the trachea in a nonatretic esophagus (see Figs. 43.7E, D, and C, respectively). Because these types have in common the communication between upper esophagus and trachea, they all manifest clinically with signs and symptoms of recurrent (aspiration) pneumonia (see Table 43.2). Distinguishing among types, however, should not be difficult. Esophageal atresia accompanied by proximal tracheoesophageal fistula presents in infancy as recurrent pneumonia, and the presence or absence of bowel gas on a plain radiograph indicates whether an accompanying distal tracheoesophageal fistula exists. In contrast, in those with an H-type tracheoesophageal fistula without esophageal atresia, the diagnosis can be delayed until childhood or, at times, adulthood. Diagnosis of a suspected H-type fistula is usually made by esophagography, but this may be difficult owing to the small size of some communications.20 In such cases, detection

TABLE 43.2  Clinical Aspects of Esophageal Developmental Anomalies Anomaly

Age at Presentation

Predominant Symptoms

Diagnosis

Treatment

Isolated atresia

Newborns

Regurgitation of feedings Aspiration

Esophagogram* Plain film: gasless abdomen

Surgery

Atresia + distal TEF

Newborns

Regurgitation of feedings Aspiration

Esophagogram* Plain film: gas-filled abdomen

Surgery

H-type TEF

Infants to adults

Recurrent pneumonia Bronchiectasis

Esophagogram* Bronchoscopy†

Surgery

Esophageal stenosis

Infants to adults

Dysphagia Food impaction

Esophagogram* Endoscopy†

Dilation‡ Surgery§

Esophageal duplication cyst

Infants to adults

Dyspnea, stridor, cough (infants) Dysphagia, chest pain (adults)

EUS* MRI/CT†

Surgery

Vascular anomaly

Infants to adults

Dyspnea, stridor, cough (infants) Dysphagia (adults)

Esophagogram* Angiography† MRI/CT/EUS

Dietary modification‡ Surgery§

Esophageal ring

Children to adults

Dysphagia

Esophagogram* Endoscopy†

Dilation‡ Endoscopic incision§

Esophageal web

Children to adults

Dysphagia

Esophagogram* Endoscopy†

Bougienage

  

*Diagnostic test of choice. †Confirmatory test. ‡Primary therapeutic approach. §Secondary therapeutic approach. TEF, Tracheoesophageal fistula.

  

CHAPTER 43  Anatomy, Histology, Embryology, and Developmental Anomalies of the Esophagus

may be improved by ingestion of methylene blue and searching by bronchoscopy for the blue-stained fistula site. Treatment of esophageal atresia and tracheoesophageal fistulas is surgical. Patients should be evaluated preoperatively for other VACTERL anomalies, particularly for cardiac abnormalities.21 The choice of surgical procedure depends on the distance between the upper and lower esophageal segments. Short gaps (gaps of fewer than 3 vertebral bodies) permit end-to-end anastomosis, as do some long gaps after lengthening of the upper segment by either bougienage or intraoperative myotomy.16Magnetic compression anastomosis, or magnamosis, has been used in the repair of some patients with esophageal atresia.22 If approximation of the 2 segments is not possible, primary reconstruction is undertaken. The colon can be interposed between the proximal esophageal remnant and the stomach, or the stomach can be pulled proximal and anastomosed to the esophageal remnant. The results of surgical correction of esophageal atresia are excellent when it exists as an isolated anomaly, with overall outcome determined principally by the severity of concomitant cardiac anomalies and by the birth weight of the infant.23,24 Survival after successful repair of isolated esophageal atresia has steadily increased over the years and now approaches 100% in the absence of other major malformations.25 Despite dramatically improved survival rates over the last several decades, long-term complications are still common. In long-term follow-up, gastroesophageal reflux without esophagitis develops in 57% of patients.26 GERD with esophagitis occurs in 40% of patients, with a 6.4% prevalence of Barrett esophagus.27 The development of GERD is likely related to abnormalities of esophageal motility and impaired acid clearance following surgical repair.28 Approximately 20% to 35% of patients will require fundoplication for GERD at some point during their lives. Unfortunately, 20% to 30% of fundoplication procedures in these patients will fail.29 Dysphagia occurs in 50% patients who survive to adulthood.26 Anastomotic strictures can be found in 30% to 56% of patients. Although several cases of esophageal cancer (both adenocarcinoma and squamous cell carcinoma) have been reported in adults who have undergone repair of esophageal atresia, registry studies from Finland and Sweden do not necessarily show a statistically significant increased cancer risk in these patients.28,30 

Fig. 43.10  Barium esophagograms in 2 patients with congenital esophageal stenosis.  A, Barium esophagogram with a tapered narrowing in the distal esophagus and dilatation of the proximal esophagus. B, Barium esophagogram with an abrupt narrowing in the mid-esophagus (large arrows). The small arrow indicates the site of a previous repair for esophageal atresia. (A and B, From Usui N, Kamata S, Kawahara H, et al. Usefulness of endoscopic ultrasonography in the diagnosis of congenital esophageal stenosis. J Pediatr Surg 2002; 37:1744.)

A

633

Congenital Esophageal Stenosis Esophageal stenosis is a rare anomaly, occurring in only 1 in every 25,000 to 50,000 live births.31 The stenotic segment varies from 2 to 20 cm in length and is usually located within the middle or lower third of the esophagus (Fig. 43.10A). The precise cause of the congenital stenosis is not entirely clear. Some patients (17% to 33%) have other associated anomalies, the most common being esophageal atresia (see Fig. 43.10B) and tracheoesophageal fistula.32 Three types of stenosis are recognized, based on histology: (1) ectopic tracheobronchial remnants (TBRs), which are sequestered respiratory tissue (hyaline cartilage, respiratory epithelium), suggesting its origin is incomplete separation of lung bud from primitive foregut33; (2) fibromuscular hypertrophy, associated with damage to the myenteric plexus with loss of the muscle-relaxing nitrinergic neural elements; and (3) membranous diaphragm, which is limited to the mucosa and does not involve the muscle layers.34 A systematic review showed that congenital esophageal stenosis secondary to fibromuscular hypertrophy makes up 54% of cases; 30% of cases occur secondary to TBRs and 16% are secondary to membranous diaphragms.35 Membranous diaphragms are typically found in the upper and middle esophagus, fibromuscular hypertrophy in the middle, and lower esophagus and TBRs are primarily encountered in the lower third of the esophagus.35 Roughly a quarter of cases are associated with esophageal atresia and tracheoesophageal fistula.36 Although tight stenoses are symptomatic in infancy, most stenoses present with dysphagia and regurgitation in childhood when more solid food is ingested (see Table 43.2). The stenosis is best demonstrated by esophagography, which may reveal either an abrupt or tapered stricture. Dilatation of the esophagus proximal to the stenosis is commonly noted (see Fig. 43.10). Endoscopy may be of value by demonstrating normal mucosa in the stenotic region, helping to exclude an acquired cause for the stenosis (e.g., GERD). EUS with a high-frequency mini-probe can show hyperechoic lesions with acoustic shadowing, which indicates the presence of cartilaginous structures in patients whose stenoses result from TBRs.37 Some patients improve after endoscopic-guided bougienage or balloon dilation, although endoscopists should approach

B

43

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PART V  Esophagus

A

C a

A

S

B Fig. 43.11 Imaging studies showing an esophageal duplication cyst. A, Barium esophagogram showing extrinsic compression of the wall of the esophagus. B, EUS image showing the distortion of the esophageal wall created by the hypoechoic cyst (C) and the cyst’s relationship to other hypoechoic areas created by the aorta (A), azygos vein (a), and spine (S). (A, Courtesy David Ott, MD, Winston-Salem, N.C.; B, from Kimmey MB, Vilman P. Endoscopic ultrasonography. In: Yamada T, editor. Atlas of gastroenterology. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2003. p 1044.)  

esophageal dilation carefully in these patients because chest pain and mucosal tears commonly occur. Perforation rates of 10% to 44% following dilation have been reported.38-40 Problematic stenoses require surgical resection of the involved segment. One novel surgical approach to this lesion is circular myectomy, a technique that involves stripping of the esophageal muscle layers containing the TBRs, with preservation of the mucosal layer. This has the advantage of avoiding many of the potential complications associated with primary repair and end-to-end esophageal anastomosis.41 The stenotic segment in cases secondary to fibromuscular hypertrophy can be amenable to longitudinal myotomy.42 

Esophageal Duplications Congenital duplications of the esophagus occur in 1 in 8000 live births and represent roughly 20% of alimentary tract duplications.2,43 The pathogenesis of esophageal duplications is uncertain, although they may develop as a result of aberrant vacuolization during organogenesis. Duplications are composed of both epithelial lining and a well-developed smooth muscular layer, and maintain an attachment to the esophagus. Duplications can be either cystic, tubular, or diverticular in morphology. Cysts account for 80% of the duplications and are usually single fluid-filled structures that typically do not communicate with the esophagus.2 Most duplication cysts occur in the lower esophagus and are located within the posterior mediastinum, although intra-abdominal esophageal duplication cysts have been reported.44 The majority of esophageal duplication cysts are diagnosed in childhood, with ∼7% of cases presenting as symptomatic cysts in adulthood.45 Some cysts are discovered while asymptomatic, manifesting as a

 

mediastinal mass on a chest radiograph or a submucosal lesion on an esophagogram (Fig. 43.11A). Others manifest with symptoms from compression of structures adjacent to the tracheobronchial tree (cough, stridor, tachypnea, cyanosis, wheezing, or chest pain) and of structures adjacent to the esophageal wall (dysphagia, chest pain, or regurgitation) (see Table 43.2).46 The diagnosis of an esophageal duplication cyst is supported by the demonstration of a cystic mass on CT, MRI, or EUS (see Fig. 43.11B).47 Duplication cysts appear as lesions that cause extrinsic compression of the true esophageal lumen with normal appearing mucosa. On EUS, duplication cysts can appear as homogenous anechoic or hypoechoic masses with well-defined margins.48 Peristalsis seen within a cyst is very specific (and is considered a diagnostic feature) of esophageal duplication cyst.49 EUS-guided FNA of duplication cysts for pathologic diagnosis is controversial due to the significant risk of procedure-related infection.48 Surgical removal is the preferred treatment of choice for confirmed cases of both symptomatic and asymptomatic duplication cysts.48 Rarely, large duplication cysts can manifest with acute life-threatening respiratory symptoms. In this circumstance, emergent decompression can be achieved by radiologic- or endoscopically guided needle aspiration. The tubular esophageal duplication is far less common than its cystic counterpart (20% of cases), and the diverticular type is rarely observed. The tubular type is usually located within the esophageal wall, parallels the true esophageal lumen, and, in contrast to duplication cysts, communicates with the true lumen at either or both ends of the tube.46 Tubular duplications usually cause chest pain, dysphagia, or regurgitation in infancy, and the diagnosis is established by esophagography or endoscopy.

CHAPTER 43  Anatomy, Histology, Embryology, and Developmental Anomalies of the Esophagus

Right common carotid artery

635

Esophagus Left common carotid artery

43

Left subclavian artery

Lusorian artery

Ascending aorta

Trachea Descending aorta

A Fig. 43.12  Dysphagia lusoria.  A, Anatomic configuration of an aberrant right subclavian artery (lusorian artery) as it courses behind the esophagus from the aortic arch toward the right shoulder. B, Barium esophagogram showing the characteristic diagonal indentation of the esophageal wall at the level of the third and fourth thoracic vertebrae. C, CT with 3D reconstruction. (A, From Janssen M, Baggen MG, Veen HF, et al. Dysphagia lusoria: Clinical aspects, manometric findings, diagnosis, and therapy. Am J Gastroenterol 2000; 95:1411; B, courtesy David Ott, MD, Winston-Salem, NC; C, From (1) Hudzik B, Gąsior M. Dysphagia Lusoria. N Engl J Med. 2016;375(4):e4.)

B

C

Although some cases can be managed endoscopically, reconstructive surgery is indicated for most patients who are symptomatic.46,50,51 

Vascular Anomalies Intrathoracic vascular anomalies are present in 2% to 3% of the population. Only rarely do they produce symptoms of esophageal obstruction despite evident vascular compression on an esophagogram. In infancy, most intrathoracic vascular anomalies manifest as respiratory symptoms from compression of the tracheobronchial tree. Later in childhood or adulthood, however, these same abnormalities can produce dysphagia and regurgitation, owing to esophageal compression (see Table 43.2). Dysphagia lusoria is the term given for symptoms arising from vascular compression of the esophagus by an aberrant right subclavian artery (Fig. 43.12).52 This condition results from defective development of the right-sided pharyngeal arch, which under normal circumstances transforms into the right subclavian artery. The right subclavian artery in dysphagia lusoria arises from the left side of the aortic arch and courses from the lower left to the upper right posterior to the esophagus. In 20% of cases the artery courses anterior to the esophagus.53 It is estimated that arteria lusoria is present in 0.7% of the general population on the basis of autopsy studies. Typically the diagnosis is established by barium

esophagogram, which shows the characteristic pencil-like indentation at the level of the third and fourth thoracic vertebrae (see Fig. 43.12B).52 Confirmation is by CT, MRI, arteriography, or EUS(see Fig. 43.12C).53 Given the considerable frequency with which such lesions are asymptomatic, endoscopy or esophageal manometry may be desirable to exclude other causes of dysphagia. During endoscopy the right radial pulse may diminish or disappear from instrumental compression of the right subclavian artery. Esophageal manometry has demonstrated a pulsatile highpressure zone at the location of the aberrant artery.54 Symptoms usually respond to simple modification of the diet to meals of soft consistency and small size. When necessary, surgery relieves the obstruction by anastomosing the aberrant artery to the ascending aorta (see Fig. 43.12A).54 

Esophageal Rings The distal esophagus may contain 2 “rings,” the A and B (Schatzki) ring, that demarcate anatomically the proximal and distal borders of the esophageal vestibule. The A (muscular) ring is located at the proximal border (see Fig. 43.3). It is a broad (4 to 5 mm) symmetrical band of hypertrophied muscle that constricts the tubular esophageal lumen at its junction with the vestibule. In this location the A ring, which is covered by squamous epithelium, corresponds to the upper end of the LES.55 The A ring is rare, and because it varies in

636

PART V  Esophagus

A

B

Fig. 43.13  Imaging studies showing an esophageal B (Schatzki) ring.  A, Barium esophagogram showing the ring of mucosa localized to the squamocolumnar junction. Below the B ring is a hiatal hernia. The hernia is visualized as a small sac between the B ring above and the diaphragm below. B, Endoscopic view of the ring. (A, Courtesy David Ott, MD, and Winston-Salem, NC; B, courtesy John D. Long, MD, and Winston-Salem, NC.)

caliber on esophagography depending on the degree of esophageal distention, it is generally asymptomatic. Occasionally an A ring is found in association with dysphagia for solids and liquids (see Table 43.2).55 Symptomatic A rings can be treated by passage of a large-caliber mercury-weighted esophageal dilator, injection of botulinum toxin, or by peroral endoscopic myotomy.56,57 The B ring, otherwise known as the mucosal or Schatzki ring, is very common, and found in 6% to 14% of subjects having a routine upper GI series.58 A recent review of more than 10,000 upper endoscopies found a Schatzki ring in 4% of cases.59 On barium study it is always found in association with a hiatal hernia and is recognized as a thin (2-mm) membrane that constricts the esophageal lumen at the junction of the vestibule and gastric cardia (Fig. 43.13A). The Schatzki ring has squamous epithelium on its upper surface and columnar epithelium on its lower surface and so demarcates the squamocolumnar junction. The ring itself is composed of only mucosa and submucosa; there is no muscularis propria. Schatzki rings can be congenital or acquired, and a relationship to GERD is likely (see Chapter 46).58 Most B rings are asymptomatic, yet when the diameter of the esophageal lumen is narrowed to 13 mm or less, rings commonly are the cause of intermittent dysphagia for solids or unheralded acute solid-food impactions (see Table 43.2).60 It is usually not difficult to identify symptomatic rings on esophagography (see Fig. 43.13A) or endoscopy (see Fig. 43.13B), although attention should be paid to adequately distend the distal esophagus.58 In some instances, the obstructing ring is best demonstrated radiographically by its ability to trap a swallowed marshmallow or a barium tablet, techniques that can also assist in determining the diameter of the ring. Asymptomatic B rings require no treatment, and those producing dysphagia are effectively treated by passage of either a single, large (symptomatic mercury-weighted dilator or a series of such

dilators of progressively larger diameter.61 Early studies reported that 32% of patients required repeat dilation after 1 year.58 More recent studies report much lower redilation rates (13%), perhaps due to the more routine use of both larger dilators and a course of postdilation antireflux therapy.62 In 1 randomized placebocontrolled study of 44 patients with symptomatic Schatzki rings, maintenance therapy with omeprazole resulted in a 40% reduction in the need for redilation after a mean follow-up of 35 months.63 A recent observational study demonstrated that complete Schatzki ring excision using 4 quadrant jumbo cold biopsy forceps was safe and effective in preventing recurrence.64 Symptomatic rings that are refractory to dilation have been successfully treated by endoscopic means using electrocautery incision.65 A randomized controlled trial of standard bougie dilation versus electrocautery incision for symptomatic Schatzki rings has demonstrated that the 2 therapies have comparable initial success rates but that endoscopic incision had a longer duration of symptom resolution.66 

Esophageal Webs Esophageal webs are developmental anomalies characterized by 1 or more thin horizontal membranes of stratified squamous epithelium within the upper (cervical) esophagus and midesophagus. Unlike rings, these anomalies rarely encircle the lumen but instead protrude from the anterior wall, extending laterally but not to the posterior wall (Fig. 43.14A and B). Webs are common in the cervical esophagus and are best demonstrated on an esophagogram with the lateral view. In up to 5% of cases they are identified in an asymptomatic state, but when they are symptomatic they cause dysphagia for solids (see Table 43.2).67 Webs are fragile membranes and so respond well to esophageal bougienage with mercury-weighted dilators.

CHAPTER 43  Anatomy, Histology, Embryology, and Developmental Anomalies of the Esophagus

637

43

Fig. 43.14  Imaging studies of esophageal webs.  A, Barium esophagogram of a cervical esophageal web seen on the lateral view as a thin membrane protruding from the anterior esophageal wall. Webs, unlike rings, often incompletely encircle the esophageal lumen. B, Endoscopic view of a cervical esophageal web. (A, Courtesy David Ott, MD, and Winston-Salem, NC; B, courtesy John D. Long, MD, and WinstonSalem, NC.)

A

A

B

B Fig. 43.15  Endoscopic images of an inlet patch.  A, Endoscopic view of heterotopic gastric mucosa in the cervical esophagus (“inlet patch”). B, Photomicrograph view of an inlet patch showing glandular epithelium with parietal cells (right) adjacent to normal esophageal squamous epithelium (left). (A, From Avidan B, Sonnenberg A, Chejfec G, et al. Is there a link between cervical inlet patch and Barrett’s esophagus? GastrointestEndosc 2001; 53:717; B, courtesy Pamela Jensen, MD, Dallas, TX.)

As discussed in Chapter 37, an association in adults of cervical esophageal webs, dysphagia, and iron deficiency anemia has been described as the Plummer-Vinson or Paterson-Kelly syndrome.67 The syndrome, although uncommon, occurs primarily in women. There may be an association between Plummer-Vinson syndrome and celiac disease.68 The syndrome identifies a group of patients at increased risk for squamous carcinoma of the pharynx and esophagus.67 Correction of iron deficiency in Plummer-Vinson syndrome may result in resolution of the associated dysphagia as well as disappearance of the web(s).67 

Heterotopic Gastric Mucosa (Inlet Patch) The inlet patch refers to the appearance on endoscopy of a small (0.5 to 2 cm) distinctive, velvety red island of heterotopic gastric mucosa amid a lighter pink squamous mucosa, generally localized immediately below the UES (Fig. 43.15A). When sought, an inlet patch is found in up to 10% of endoscopies, and biopsy

specimens reveal gastric fundic- or antral-type mucosa (see Fig. 43.15B).69,70 The fundic-type mucosa contains chief and parietal cells and, thus, in some specimens retains the capacity for acid secretion.71 Similar to gastric mucosa in the stomach, the inlet patch may be infected with Hp.72 However, inlet patches are usually asymptomatic and unassociated with disease and thus require no treatment. A possible association with globus pharyngeus was suggested in a study in which this symptom was improved after ablation of inlet patches using argon plasma coagulation.73 In rare instances, an inlet patch is found in association with an esophageal web or stricture74 or ulcer, the latter resulting in bleeding or perforation.69 Adenocarcinoma arising in an inlet patch is a rare complication, although there is a statistically significant association between inlet patches and proximal esophageal adenocarcinomas.69,75 The necessity of surveillance endoscopy is controversial and a formal consensus has not been reached. Full references for this chapter can be found on www.expertconsult.com

.

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56. Song G, Ko W, Kim W, et al. Peroral endoscopic myotomy for esophageal muscular ring. Endoscopy 2015;47(S 01):E387–8. 57. Varadarajulu S, Noone T. Symptomatic lower esophageal muscular ring: response to Botox. Dig Dis Sci 2003;48:2132–4. 58. Jalil S, Castell DO. Schatzki’s ring. A benign cause of dysphagia in adults. J Clin Gastroenterol 2002;35:295–8. 59. Mitre MC, Katzka DA, Brensinger CM, et al. Schatzki ring and Barrett’s esophagus: do they occur together? Dig Dis Sci 2003;49:770–3. 60. Byrne KR, Panagiotakis PH, Hilden K, et al. Retrospective analysis of esophageal food impaction: differences in etiology by age and gender. Dig Dis Sci 2006;52:717–21. 61. Mann NS. Single dilation of symptomatic Schatzki ring with a large dilator is safe and effective. Am J Gastroenterol 2001;96:3448–9. 62. Scolapio JS, Pasha TM, Gostout CJ, et al. A randomized prospective study comparing rigid to balloon dilators for benign esophageal strictures and rings. Gastrointest Endosc 1999;50:13–7. 63. Sgouros SN, Vlachogiannakos J, Karamanolis G, et al. Long-term acid suppressive therapy may prevent the relapse of lower esophageal (Schatzki’s) rings: a prospective, randomized, placebo-controlled study. Am J Gastroenterol 2005;100:1929–34. 64. Gonzalez A, Sullivan MF, Bonder A, et al. Obliteration of symptomatic Schatzki rings with jumbo biopsy forceps (with video). Dis Esophagus 2014;27(7):607–10. 65. DiSario JA, Pedersen PJ, Bichis-Canoutas C, et al. Incision of recurrent distal esophageal (Schatzki) ring after dilation. Gastrointest Endosc 2002;56:244–8. 66. Wills JC, Hilden K, DiSario JA, et al. A randomized, prospective trial of electrosurgical incision followed by rabeprazole versus bougie dilation followed by rabeprazole of symptomatic esophageal (Schatzki’s) rings. Gastrointest Endosc 2008;67:808–13.

67. Atmatzidis K, Papaziogas B, Pavlidis T, et al. Plummer-Vinson syndrome. Dis Esophagus 2003;16:154–7. 68. Jessner W, Vogelsang H, Puspok A, et al. Plummer-Vinson syndrome associated with celiac disease and complicated by postcricoid carcinoma and carcinoma of the tongue. Am J Gastroenterol 2003;98:1208–9. 69. Von Rahden BHA, Stein HJ, Becker K, et al. Heterotopic gastric mucosa of the esophagus: literature review and proposal of a clinicopathologic classification. Am J Gastroenterol 2004;99:543–51. 70. López-Colombo A, Jiménez-Toxqui M, Gogeascoechea-Guillén PD, et al. Prevalence of esophageal inlet patch and clinical characteristics of the patients. Rev Gastroenterol Mex 2018 Oct 11. 71. Galan AR, Katzka DA, Castell DO. Acid secretion from an esophageal inlet patch demonstrated by ambulatory pH monitoring. Gastroenterology 1998;115:1574–6. 72. Gutierrez O, Akamatsu T, Cardona H, et al. Helicobacter pylori and heterotopic gastric mucosa in the upper esophagus (the inlet patch). Am J Gastroenterol 2003;98:1266–70. 73. Meining A, Bajbouj M, Preeg M, et al. Argon plasma ablation of gastric inlet patches in the cervical esophagus may alleviate globus sensation: a pilot trial. Endoscopy 2006;38:566–70. 74. Ward EM, Achem SR. Gastric heterotopia in the proximal esophagus complicated by stricture. Gastrointest Endosc 2003;57:131–3. 75. Orosey M, Amin M, Cappell MS. A 14-year study of 398 esophageal adenocarcinomas diagnosed among 156,256 EGDs performed at two large hospitals: an inlet patch is proposed as a significant risk factor for proximal esophageal adenocarcinoma. Dig Dis Sci 2018;63(2):452–65.

44

Esophageal Neuromuscular Function and Motility Disorders John E. Pandolfino, Peter J. Kahrilas

CHAPTER OUTLINE MOTOR AND SENSORY FUNCTION������������������������������������638 Oropharynx and Upper Esophageal Sphincter ����������������638 The Pharyngeal Swallow������������������������������������������������639 Esophagus ��������������������������������������������������������������������640 Esophagogastric Junction (EJG)��������������������������������������642 Esophageal Sensation����������������������������������������������������644 ESOPHAGEAL MOTILITY DISORDERS ������������������������������645 Epidemiology ����������������������������������������������������������������646 Pathogenesis������������������������������������������������������������������646 Clinical Features������������������������������������������������������������650 Differential Diagnosis ����������������������������������������������������651 Diagnostic Methods��������������������������������������������������������652 Treatment����������������������������������������������������������������������656

The esophagus is a muscular tube with a sphincter at each end joining the hypopharynx to the stomach with the simple function of transporting food, fluid, and gas between these endpoints. As such, the esophagus encompasses the anatomic and physiologic transition from the striated muscle oropharynx and the smooth muscle gut. Neurologically, the oropharynx is controlled by the cerebral cortex and medulla and capable of precise tactile sensation; the distal esophagus is composed entirely of smooth muscle, controlled by the vagus nerve and enteric nervous system, and comparatively insensitive. Although there is a gradual transition between these endpoints, motor function in the oropharynx and esophageal body are quite distinct. With that in mind, the ensuing discussion includes selected aspects of pharyngeal, gastric, and diaphragmatic function that are inextricably entwined with esophageal function.

MOTOR AND SENSORY FUNCTION Oropharynx and Upper Esophageal Sphincter Within the oral cavity, the lips, teeth, hard palate, soft palate, mandible, floor of the mouth, and tongue serve to form and contain food into a bolus suitable for transfer to the pharynx. The pharynx is divided into 3 segments: nasopharynx, oropharynx, and hypopharynx (Fig. 44.1). The nasopharynx extends from the base of the skull to the distal edge of the soft palate. Muscles in the nasopharynx elevate the soft palate during swallowing, seal the nasopharynx, and prevent nasopharyngeal regurgitation. The oropharynx extends from the soft palate to the base of the tongue. The inferior margin of the oropharynx is demarcated by the valleculae anteriorly and the mobile tip of the epiglottis posteriorly. The hypopharynx extends from the valleculae to the inferior margin of the cricoid cartilage and includes the upper esophageal sphincter (UES). Musculature of the soft palate, tongue, and pharynx all participate during swallowing to collapse and shorten the pharyngeal lumen and then expel its contents into the esophagus.

638

Additionally, extrinsic muscles elevate and pull the pharynx forward, thereby sealing the airway and opening the UES. The intrinsic muscles of the pharynx, the superior, middle, and inferior pharyngeal constrictors (see Fig. 44.1), overlap and insert into a collagenous sheet, the buccopharyngeal aponeurosis. The inferior constrictor is composed of the thyropharyngeus (superior part) and the cricopharyngeus (inferior part). The thyropharyngeus arises from the thyroid cartilage, passes posteromedially, and inserts in the median raphe. The cricopharyngeus has superior and inferior components, each of which arise bilaterally from the sides of the cricoid lamina; the superior fibers course posteromedially to the median raphe whereas the inferior fibers loop around the esophageal inlet without a median raphe. Killian triangle, a triangular area of thin muscle, is formed posteriorly between these components and is the most common site of origin for pharyngeal pulsion diverticula. The pharynx also contains 5 single or paired cartilages (see Fig. 44.1). The spaces formed between the lateral insertion of the inferior constrictor and the lateral walls of the thyroid cartilage are the pyriform sinuses that end inferiorly at the cricopharyngeus muscle, separating the pharynx from the esophagus. The larynx and trachea are suspended in the neck between the hyoid bone superiorly and the sternum inferiorly. A number of muscles, categorized as the laryngeal strap muscles, contribute to this suspension and, together with the intrinsic elasticity of the trachea, permit the larynx to be raised and lowered. The hyoid bone also serves as the base for the tongue that rests upon it. Laryngeal movement is crucial to the swallow response as the laryngeal inlet is both closed and physically removed from the bolus path in the course of a swallow. Failure to achieve this synchronized laryngeal movement can result in aspiration. The pharyngeal muscles are densely innervated with motor fibers coming from nuclei of the trigeminal, facial, glossopharyngeal, and hypoglossal nuclei, as well as the nucleus ambiguus of the vagus and spinal segments C1 to C3. All motor neurons within nucleus ambiguus participate in swallowing, with those innervating the striated muscle esophagus situated rostrally and those innervating the pharynx and larynx more caudally.1 The muscular components of the UES are the cricopharyngeus, adjacent esophagus, and adjacent inferior constrictor with the cricopharyngeus contributing the 1 cm zone of maximal pressure.2 The closed sphincter has a slit-like configuration, with the cricoid lamina anterior and the cricopharyngeus lateral and posterior. Neural input via vagal trunks originating in the nucleus ambiguus maintains UES pressure and vagal transection abolishes this contractile activity. Manometric evaluation of UES function is difficult because it is a short, complex anatomic zone that moves briskly during swallowing. Furthermore, UES pressure is heavily influenced by recording methodology, owing both to its marked asymmetry and to its reflexive contraction to pharyngeal and esophageal stimulation. Thus, it is not possible to define a meaningful normal range of UES pressure.3 UES relaxation during swallowing also poses substantial recording challenges, making for great variability in technique and interpretation. However, HRM using solid-state technology permits accurate tracking of UES relaxation and intrabolus pressure changes during swallowing (Fig. 44.2).

CHAPTER 44  Esophageal Neuromuscular Function and Motility Disorders

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44

Soft palate Hard palate

Lateral pterygoid plate

Oral cavity Tongue

Mylohyoid Thyrohyoid membrane Vocal cord Transverse arytenoid Cricothyroid membrane Cricoid cartilage

Oral pharynx Buccinator Valleculae Digastric (ant. belly) Hyoid bone Epiglottis Laryngeal pharynx (hypopharynx) Mylohyoid Stylohyoid Esophagus Hyoid bone Thyroid cartilage Cricothyroid membrane Cricoid cartilage

A

Digastric (post. belly) Superior constrictor Styloid process Styloglossus Stylohyoid ligament Glossopharyngeus Stylopharyngeus Middle constrictor Hyoglossus Thyrohyoid membrane Inferior constrictor Cricopharyngeus Esophagus

B Fig. 44.1  Anatomy of the pharynx. A, Sagittal view of the pharynx showing the musculoskeletal structures involved in swallowing. Note that the esophagus is collapsed and empty at rest. In the course of a swallow, the laryngeal inlet will be sealed and the mouth of the esophagus will be opened by highly coordinated muscular activity. B, Cutaway view of the musculature of the pharynx. Note that the hyoid bone is positioned as a fulcrum and is instrumental in directing anterior, superior traction forces critical to closing the larynx and opening the esophageal inlet during a swallow. ant., anterior; post., posterior. (Reprinted from Kahrilas PJ, Frost F. Disorders of swallowing and bowel motility. In: Green D, editor. Medical problems of the chronically disabled. Rockville, MD: Aspen Publishers; 1990. p 11-37.)

The UES maintains closure of the proximal end of the esophagus unless opening is required, necessitated for swallowing or belching. It also constitutes an additional barrier to refluxed material entering the pharynx from the esophagus and prevents air from entering the esophagus by contracting in synchrony with inspiration. Inspiratory augmentation is most evident during periods of low UES pressure and can be exaggerated in individuals experiencing globus sensation.4 Balloon distension of the esophagus stimulates UES contraction,5 with the effect being more pronounced with proximal balloon positions. However, when the distension pattern of gas reflux is simulated using a cylindrical bag or rapid air injection into the esophagus, UES relaxation rather than contraction occurs.2 Belch-induced UES relaxation is also associated with glottic closure. Stress augments UES pressure, whereas anesthesia or sleep6 virtually eliminates it. Neither experimental acid perfusion of the esophagus nor spontaneous gastroesophageal acid reflux alters continuously recorded UES pressure in either normal volunteers or in individuals with peptic esophagitis. 

The Pharyngeal Swallow Disorders of the oral phase of swallowing occur with many conditions characterized by global neurologic dysfunction, such as traumatic brain injury, brain tumors, or chorea (see Chapter 37). Detailed discussion of these conditions can be found in texts on swallow evaluation and therapy.7 The pharyngeal swallow is the largely subconscious coordinated contraction that transfers oral contents into the esophagus. Afferent sensory fibers capable of triggering the pharyngeal swallow travel centrally via the internal branch of the superior laryngeal nerve (from the larynx) and the glossopharyngeal nerve (from the pharynx). These sensory fibers converge before terminating in the medullary swallow center.

Although understood physiologically as the patterned activation of motor neurons and their corresponding motor units, swallowing is clinically evaluated in mechanical terms and best evaluated by videofluoroscopic or cineradiographic analysis. The pharyngeal swallow rapidly reconfigures pharyngeal structures from a respiratory to an alimentary pathway and then reverses this reconfiguration within 1 second. The pharyngeal swallow response can be dissected into several closely coordinated actions: (1) nasopharyngeal closure by elevation and retraction of the soft palate, (2) UES opening, (3) laryngeal closure, (4) tongue loading (ramping), (5) tongue pulsion, and (6) pharyngeal clearance. Precise coordination of these actions is an obvious imperative, and to some degree the relative timing of these events is affected either by volition or by the volume of the swallowed bolus (see Fig. 44.2). The most fundamental anatomic reconfiguration required to transform the oropharynx from a respiratory to a swallow pathway is to open the inlet to the esophagus and seal the inlet to the larynx. These events occur in close synchrony, facilitated by laryngeal elevation and anterior traction via the hyoid axis. It is critical to recognize the distinction between UES relaxation and UES opening. UES relaxation is due to cessation of excitatory neural input while the larynx is elevating. Once the larynx is elevated, UES opening results from traction on the anterior sphincter wall caused by contraction of the supra- and infrahyoid musculature that also results in a characteristic pattern of hyoid displacement. Bolus transport out of the oropharynx is facilitated by the tongue and pharyngeal constrictors. Tongue motion adapts to varied swallow conditions and propels most of the bolus into the esophagus prior to the onset of the pharyngeal contraction. On the other hand, the pharyngeal contraction is more stereotyped, functioning to strip the last residue from the pharyngeal walls. UES closure coincides with passage of the pharyngeal contraction.

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1

2

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7

mm Hg 150

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50 30

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Glossopalatal junction opening 0.1 sec

Velopharyngeal junction closure Laryngeal vestibule closure UES opening

Fig. 44.2  Fluoroscopy combined with high-resolution manometry (HRM). The fluoroscopic images (top) are depicted at specific times demarcated on the HRM (color panel by pink arrows). The time line illustrates the coordination and timing of events within the pharyngeal swallow on fluoroscopy. Each horizontal bar depicts the period during which one of the oropharyngeal valves is in its swallow configuration, as opposed to its configuration during respiration, and is correlated with the images on fluoroscopy: (1) baseline anatomy with bolus in the mouth; (2) glossopalatal opening occurring in synchrony with UES relaxation, which is typically to less than 10 mm Hg; (3) velopharyngeal junction closure, sealing off the nasopharynx to prevent regurgitation (note the elevation depicted by the white arrow); (4) laryngeal vestibule closure and UES opening occurring as the epiglottis inverts, closing the laryngeal vestibule as the bolus, led by air, is rapidly pushed through the UES; (5) continued bolus transit with the onset of the pharyngeal stripping wave; (6) bolus transfer to the esophagus is completed as the pharyngeal stripping wave traverses the UES while the laryngeal vestibule remains closed; (7) return of the pharynx to a respiratory configuration, with the laryngeal vestibule opened and the epiglottis back in its upright configuration. The black dots on the topography (HRM) plot represent the location of the proximal aspect of the UES at each time point. (With permission from the Esophageal Center at Northwestern.)

However, the contractile activity of the sphincter has an added dimension as well, exhibiting augmented contractility during laryngeal descent, resulting in a grabbing effect such that the sphincter and laryngeal descent complement each other to clear residue from the hypopharynx.8 This clearing function probably acts to minimize the risk of postswallow aspiration by preventing residual material from adhering to the laryngeal inlet when respiration resumes. 

Esophagus The esophagus is a 20- to 22-cm tube composed of skeletal and smooth muscle. The proportion of each muscle type is species dependent, but in humans, the proximal 5% is striated, the middle 35% to 40% is mixed with an increasing proportion of smooth muscle distally, and the distal 50% to 60% is entirely smooth muscle. The outer longitudinal muscle arises from the

cricoid cartilage with slips from the cricopharyngeus passing dorsolaterally to fuse posteriorly about 3 cm distal to the cricoid cartilage. This results in a posterior triangular area devoid of longitudinal muscle, Laimer triangle. Distal to Laimer triangle, the longitudinal muscles form a continuous sheath of uniform thickness around the esophagus. The adjacent, inner muscle layer is formed of circular or, more precisely, helical muscle also forming a sheath of uniform thickness along the length of the esophagus. There is a decreasing degree of helicity moving distally ranging from 60 degrees in the proximal esophagus to nearly 0 degrees at the lower esophageal sphincter (LES).9 Unlike the distal GI tract, there is no serosal layer to the esophagus. The extrinsic innervation of the esophagus is via the vagus nerve with motor neurons in nucleus ambiguus (striated muscle portion) and the dorsal motor nucleus of the vagus (smooth muscle portion). Efferent vagal fibers reach the cervical esophagus by the pharyngoesophageal nerve, and synapse directly on striated

641

CHAPTER 44  Esophageal Neuromuscular Function and Motility Disorders (A) Segmental Architecture

(B) Landmarks of Propagation

44

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UES

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mm Hg 150

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Length along the esophagus (cm)

10

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15

Segment 2 M

20

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50

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30

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D

CDP 30 EGJ

0

EGJ relaxation

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Time (sec)

Fig. 44.3  Topographic depiction of esophageal peristalsis using HRM showing the segmental architecture of peristalsis and landmarks of contractile propagation. A, The 30-mm Hg isobaric contour plot (black lines) demonstrates that progression through the esophagus is not seamless. The proximal striated segment 1 and the distal smooth muscle esophageal contractile segments 2 and 3 are separated by a transition zone (P). The distal esophagus is also divided into 2 distinct contractile segments (2 and 3), separated by a pressure trough (M). The region of the EGJ is also distinguished by a distinct contractile segment that is separated from the adjacent esophagus by another pressure trough (D). B, Same depiction with the topographic landmarks of peristalsis represented. The pink circle located within segment 3 localizes the CDP, the point along the contractile wavefront at which velocity slows, demarcating the transition from peristalsis to sphincter reconstitution. The DL, which is a manifestation of deglutitive inhibition, is measured from UES relaxation to the CDP. Contractile front velocity is measured by taking the best-fit tangent from the CDP to the transition zone, P. Of interest is the concept of concurrent esophageal contraction illustrated by the vertical dashed arrows. The length of the esophagus concurrently contracting, between the onset of the contractile front and the offset of contraction proximally, is, on average, 10 cm and maximizes in close approximation to the CDP. Following the CDP, the length of concurrent contraction lessens as the “rear” catches up with the slowed contraction front. (With permission from the Esophageal Center at Northwestern.)

muscle neuromuscular junctions. The vagus also provide sensory innervation; in the cervical esophagus, this is via the superior laryngeal nerve with cell bodies in the nodose ganglion, whereas in the remainder of the esophagus, sensory fibers travel via the recurrent laryngeal nerve or, in the most distal esophagus, via the esophageal branches of the vagus. Vagal afferents are strongly stimulated by esophageal distension. The esophagus also contains an autonomic nerve network, the myenteric plexus, located between the longitudinal and circular muscle layers. Myenteric plexus neurons are sparse in the proximal esophagus, and their function is unclear because the striated muscle is directly controlled by nucleus ambiguus motor neurons. On the other hand, in the smooth muscle esophagus preganglionic neurons in the dorsal motor nucleus of the vagus synapse on relay neurons in the myenteric plexus ganglia. A second nerve network, the submucosal or Meissner plexus, is situated between the muscularis mucosa and the circular muscle layer, but this is sparse in the human esophagus.

Esophageal Peristalsis The esophagus is normally atonic and its intraluminal pressure closely reflects pleural pressure, becoming negative during inspiration. However, swallowing or focal distention initiates peristalsis. Primary peristalsis is initiated by a swallow and traverses the entire length of the esophagus; secondary peristalsis can be elicited in response to focal esophageal distention with air, fluid, or a balloon, beginning at the locus of distention. The mechanical correlate of peristalsis is of a stripping wave that milks the esophagus clean from its proximal to distal end. The propagation of the stripping wave corresponds closely with that of the manometrically recorded contraction such that the point of luminal closure seen fluoroscopically at each esophageal locus corresponds with the upstroke of the pressure wave on line tracings or the contractile wavefront on esophageal pressure topography (EPT) (Fig. 44.3). The likelihood of achieving complete esophageal emptying from the distal esophagus is inversely related to peristaltic amplitude,

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such that emptying becomes progressively impaired with peristaltic amplitudes of 30 mm Hg or less.10 However, emptying is also modified by the pressure gradient across the esophagogastric junction (EGJ), and this interaction can have significant influence on both bolus transit and peristaltic contractility. Another essential feature of peristalsis is deglutitive inhibition. A second swallow initiated while an earlier peristaltic contraction is still progressing in the proximal esophagus completely inhibits the contraction induced by the first swallow. Deglutitive inhibition in the distal esophagus is attributable to hyperpolarization of the circular smooth muscle and is mediated via inhibitory ganglionic neurons in the myenteric plexus. Deglutitive inhibition can be demonstrated experimentally in the esophagus by distending an intraluminal balloon, which stimulates esophageal contraction.11 Once the high-pressure zone is established, deglutitive inhibition is evident after swallowing while recording intraluminal pressure between the balloon and the esophageal wall. The physiologic control mechanisms governing the striated and smooth muscle esophagus differ. The striated muscle receives exclusively excitatory vagal innervation, and its peristaltic contraction results from sequential activation of the musculature. These vagal fibers release acetylcholine (ACh) and stimulate nicotinic cholinergic receptors on the striated muscle cells. Striated muscle peristalsis is programmed by the medullary swallowing center in much the same way as is the pharyngeal swallow. The vagus nerves also exhibit control of primary peristalsis in the smooth muscle esophagus, but the mechanism of vagal control is more complex than that of the striated muscle because vagal fibers synapse on myenteric plexus neurons rather than directly on muscle cells. However, the myenteric plexus can also orchestrate peristalsis independently of vagal activation; secondary peristalsis can be elicited anywhere along the smooth muscle esophagus despite extrinsic denervation. In contrast, transection across the striated muscle esophagus does not inhibit peristaltic progression across the transection site or distally. Regardless of central or ganglionic control, esophageal smooth muscle contraction is ultimately elicited by ganglionic cholinergic neurons. Less clear are the control mechanisms for the direction and velocity of peristalsis. Nerve conduction studies indicate that neural stimuli initiated by swallowing reach the ganglionic neurons along the length of the esophagus essentially simultaneously. However, the latency between the arrival of the vagal stimulus and muscle contraction progressively increases, moving aborally. In humans, the latent period is 2 seconds in the proximal smooth muscle esophagus and 5 to 7 seconds just proximal to the LES. The current hypothesis is that peristaltic direction and velocity result from a neural gradient along the esophagus, wherein excitatory ganglionic neurons dominate proximally and inhibitory ganglionic neurons dominate distally (Fig. 44.4). This organization is consistent with the demonstration of 2 subsegments within the smooth muscle segment with pressure topography plotting, the first of which is strongly reactive to cholinergic drugs.12 The primary inhibitory neurotransmitter is nitric oxide (NO), produced from l-arginine by the enzyme NO synthase in myenteric neurons.13 There is also evidence for a role of vasoactive intestinal polypeptide (VIP)-containing neurons mediating inhibition.14 High-resolution EPT allows for the imaging of esophageal contractility as a continuum not only in time, but also along the length of the esophagus. Clouse and colleagues pioneered this technology, noting that peristalsis was not a seamless wave of pressurization, but rather a coordinated sequence of 4 contiguous contractile segments (see Fig. 44.3). A transition zone exists between the first and second segments, characterized by the nadir peristaltic amplitude, slightly delayed progression, and occasional failed transmission. The topographic analysis also reveals a segmental characteristic of peristaltic progression within the smooth muscle esophagus, with 2 contractile segments separated by a

pressure trough, followed by the LES, which contracts with vigor and persistence quite dissimilar to the adjacent smooth muscle esophagus.15 More recently, a distinct landmark along the wavefront was recognized localized in the third segment, at which point contractile propagation slows dramatically (see Fig. 44.3).16 This landmark, defined as the contractile deceleration point (CDP), has pathophysiologic significance because it is localized at the proximal aspect of the LES, and it is hypothesized that this represents the locus of termination of peristalsis.17 Contraction beyond this point is more consistent with reconstitution of the LES that was relaxed, elongated, and effaced during peristalsis to form the phrenic ampulla. 

Longitudinal Muscle The longitudinal muscle of the esophagus also contracts during peristalsis, with the net effect of transiently shortening the structure by 2 to 2.5 cm. Similar to the pattern of circular muscle contraction, longitudinal muscle contraction is propagated distally as an active segment at a rate of 2 to 4 cm/s.18 Central mechanisms control longitudinal muscle contraction during peristalsis with progressively increasing latency moving distally, similar to that seen with the circular smooth muscle. However, unlike the circular muscle, nerve stimulation studies suggest the longitudinal muscle to be free of inhibitory neural control. 

Esophagogastric Junction (EJG) The anatomy of the EGJ is complex (see also Chapter 43). The distal end of the esophagus is anchored to the diaphragm by the phrenoesophageal ligament that inserts circumferentially into the esophageal musculature close to the squamocolumnar junction (SCJ). The esophagus then traverses the diaphragmatic hiatus and joins the stomach almost tangentially. Thus, there are 3 contributors to the EGJ high-pressure zone: the LES, the crural diaphragm, and the musculature of the gastric cardia that constitutes the distal aspect of the EGJ. The LES is a 3- to 4-cm segment of tonically contracted smooth muscle at the distal extreme of the esophagus. Surrounding the LES at the level of the SCJ is the crural diaphragm, most commonly bundles of the right diaphragmatic crus forming a teardrop-shaped canal about 2 cm long on its major axis (Fig. 44.5).19 The component of the EGJ high-pressure zone distal to the SCJ is largely attributable to the opposing sling and clasp fibers of the middle layer of gastric cardia musculature.20 In this region, the lateral wall of the esophagus meets the medial aspect of the dome of the stomach at an acute angle, defined as the angle of His. Viewed intraluminally, this region extends within the gastric lumen, appearing as a fold that has been conceptually referred to as a “flap valve” because increased intragastric pressure forces it closed, sealing off the entry to the esophagus. Physiologically, the EGJ high-pressure zone is attributable to a composite of both the LES and the surrounding crural diaphragm extending 1 to 1.5 cm proximal to the SCJ and about 2 cm distal to it.21 Resting LES tone ranges from 10 to 30 mm Hg relative to intragastric pressure, with considerable temporal fluctuation. With HRM, this is quantified as the EGJ contractile integral, and the normal value ranges from 28 to 125 mm Hg/cm.22 The mechanism of LES tonic contraction is likely both myogenic and neurogenic, consistent with the observation that pressure within the sphincter persists after elimination of neural activity with tetrodotoxin. Myogenic LES tone varies directly with membrane potential that leads to an influx of Ca2+. Apart from myogenic factors, LES pressure is also modulated by intra-abdominal pressure, gastric distention, peptides, hormones, foods, and many medications. Large increases in LES pressure occur with the migrating motor complex; during phase III of the migrating motor complex, the LES pressure may exceed 80 mm Hg.

CHAPTER 44  Esophageal Neuromuscular Function and Motility Disorders

A

B

C

643

D

44

UES Striated muscle

Smooth 8 cm muscle 3 cm

LES

200 mm Hg

8 cm

0 mm Hg 200 mm Hg

3 cm

0 mm Hg

Fig. 44.4  Alterations in the balance and gradient of excitatory (cholinergic) and inhibitory (nitrergic) neurons in the distal esophagus as a pathophysiologic mechanism of esophageal motor disorders. The upper panel depicts the ganglionic constituents in the esophagus, and the lower panel illustrates manometric tracings at 3 and 8 cm above the LES. The blue circles represent excitatory neurons, and the red circles represent inhibitory neurons. A, In normal subjects, cholinergic neurons are most dense proximally, becoming increasingly sparse distally. Conversely, inhibitory neurons are more prominent distally and relatively sparse proximally. This inverse neural gradient causes increasing latency of the contraction as it progresses distally. With simultaneous vagal stimulation of ganglia along the length of the esophagus, contraction first occurs proximally and propagates distally only as the effects of increasingly dense inhibition wear off. Thus, pharmacologic manipulation can alter both contractile vigor and timing of propagation. Conceptually, esophageal motor pathophysiology can be explained by alterations in these neural gradients. B, Patients with hypercontractility and normal (or fast) propagation may have a relative increase in excitatory neurons. C, Patients with loss of inhibitory neurons will lose deglutitive inhibition, and contractions will occur simultaneously and prematurely. D, Patients with loss of both excitatory and inhibitory neurons may present with absent or weak peristalsis that does not propagate. (Modified from Goyal R, Shaker R, GI Motility Online.)

Lesser fluctuations occur throughout the day, with pressure decreasing in the postprandial state and increasing during sleep.23 Superimposed on the myogenic LES contraction, input from vagal, adrenergic, hormonal, and mechanical influences will alter LES pressure. Vagal influence is similar to that of the esophageal body, with vagal stimulation activating both excitatory and inhibitory myenteric neurons. Thus, the LES pressure at any instant reflects the balance between excitatory (cholinergic) and inhibitory (nitrergic) neural input, and altering the pattern of vagal discharge results in LES relaxation. The crural diaphragm is also a major contributor to EGJ pressure. Even after esophagogastrectomy, with consequent removal of the smooth muscle LES, a persistent EGJ pressure of about 6 mm Hg can be demonstrated during expiration. During inspiration, there is substantial augmentation of EGJ pressure attributable to crural diaphragm contraction. Crural diaphragm contraction is also augmented during abdominal compression, straining, or coughing.24 On the other hand, during esophageal distension, vomiting, and belching, electrical activity in the crural diaphragm is selectively inhibited despite continued respiration, demonstrating a control mechanism independent of the costal diaphragm. This reflex inhibition of crural activity is eliminated with vagotomy.

LES Relaxation LES relaxation can be triggered by distention from either side of the EGJ or swallowing. Relaxation induced by esophageal distention is an intramural process, unaffected by vagotomy. Relaxation is, however, antagonized by tetrodotoxin, proving that it is mediated by postganglionic nerves. Deglutitive LES relaxation is mediated by the vagus nerve, which synapses with inhibitory neurons in the myenteric plexus. NO, produced by NO synthase from the precursor amino acid l-arginine, is the main neurotransmitter in the postganglionic neurons responsible for LES relaxation. NO is released with neural stimulation in the esophagus, LES, and stomach, and NO synthase inhibitors block neurally mediated LES relaxation.13,25 However, NO may not work alone. VIP-containing neurons have been demonstrated in the submucosal plexus and VIP relaxes the LES by direct muscle action. It is thought that VIP acts on NO synthase–containing neural terminals as a prejunctional neurotransmitter, facilitating the release of NO and on gastric muscle cells to stimulate production of NO by the muscle.26 Another contributor to intraluminal pressure during bolus transit through the LES is the bolus itself. The LES relaxes

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PART V  Esophagus

Esophagus

Aorta L1

Right crus of diaphragm

Left crus of diaphragm

Fig. 44.5  Anatomy of the diaphragmatic hiatus as viewed from below. The most common anatomy, in which the muscular elements of the crural diaphragm derive from the right diaphragmatic crus, is shown. The right crus arises from the anterior longitudinal ligament overlying the lumbar vertebrae. Once muscular elements emerge from the tendon, 2 flat muscular bands form that cross each other in scissor-like fashion forming the walls of the hiatus and then merging with each other anterior to the esophagus. L1, first lumbar vertebrae. (Modified from Jaffee BM. Surgery of the esophagus. In: Orlando RC, editor. Atlas of esophageal diseases. 2nd ed. Philadelphia: Current Medicine, Inc.; 2002. p 221-42.)

during the initial phase of the swallow, but it does not actually open until the bolus enters the sphincter, thereby implicating intrabolus pressure. Hence, EGJ opening is dependent on the balance of forces acting to open it (intrabolus pressure generated by peristalsis) and the forces resisting opening (LES tone and the mechanical properties of the esophageal wall and crural canal). Although each of these factors may dominate in a particular physiologic scenario, it is difficult to tease them apart with conventional manometric recordings. HRM with EPT has improved on this, and the current assessment of EGJ relaxation during swallowing uses an electronic sleeve or “eSleeve” to ascertain the lowest average postdeglutitive pressure for a 4-second time period, skipping inspiratory crural contractions if necessary (Fig. 44.6). This measurement provides an integrated assessment of the pressure dynamics through the EGJ that is sensitive to both pathologic conditions resisting opening, such as impaired LES relaxation with achalasia, and mechanical obstruction at the EGJ related to a structural cause (stricture, tumor, LES hypertrophy). 

Transient LES Relaxations During rest, the EGJ must prevent gastroesophageal reflux, but also must transiently relax to selectively permit gas venting of the stomach. These functions are accomplished by prolonged LES relaxations that occur without swallowing or peristalsis. These transient LES relaxations (tLESRs) are an important mechanism in GERD pathogenesis and are the most frequent mechanism for reflux during periods of normal LES pressure (see Chapter 46). tLESRs are distinguishable from swallow-induced relaxation in several ways: (1) they are prolonged (>10 seconds) and independent of pharyngeal swallowing; (2) they are associated with contraction of the distal esophageal longitudinal muscle, causing

esophageal shortening; (3) there is no synchronized esophageal peristalsis; and (4) they are associated with crural diaphragm inhibition, which is not the case with swallow-induced relaxation (Fig. 44.7).27,28 tLESRs occur most frequently in the postprandial state during gastric distention. In the setting of the completely relaxed EGJ during tLESRs, even the minimal gastroesophageal pressure gradients observed with gastric distention (3 to 4 mm Hg) are sufficient to facilitate gas venting of the stomach. Thus, tLESRs are the physiologic mechanism of belching. Proximal gastric distention is the major stimulus for tLESR. Distention stimulates mechanoreceptors (intraganglionic lamellar endings) in the proximal stomach, activating vagal afferent fibers projecting to the nucleus of the solitary tract. The efferent limb of both swallow and nonswallow LES relaxations lies in the preganglionic vagal inhibitory pathway to the LES. Both types of relaxation can be blocked by bilateral cervical vagotomy, cervical vagal cooling, or NO synthase inhibitors. tLESRs triggered by gastric distention likely use NO and CCK as neurotransmitters, evident by increased tLESR frequency after IV CCK infusion and blockade by either NO synthase inhibitors or CCK-A antagonists. Finally, GABA-B agonists, such as baclofen, inhibit tLESRs, acting on both peripheral receptors and receptors located in the dorsal motor nucleus of the vagus.29,30 

Esophageal Sensation The human esophagus can sense mechanical, electrical, chemical, and thermal stimuli, perceived as chest pressure, warmth, or pain, with substantial overlap in perception among stimuli.31 Esophageal sensation is carried via both the vagal and spinal afferent nerves. The associated vagal neurons are located in the nodose and jugular ganglia, whereas the corresponding spinal neurons are located in thoracic and cervical dorsal root ganglia. Vagal afferents predominantly mediate homeostatic and secretory functions, whereas spinal afferents project centrally in a pattern characterized by overlap among spinal segments and convergence with somatic afferents. Consequently, esophageal pain tends to be poorly localized, accompanied by referred somatic pain and subject to viscerovisceral hyperalgesia.32 Esophageal sensations are usually perceived substernally; in the instance of pain, radiation to the midline of the back, shoulders, and jaw is very analogous to cardiac pain. These similarities are likely due to convergence of sensory afferent fibers from the heart and esophagus in the same spinal pathways, even to the same dorsal horn neurons in some cases. Esophageal afferents are predominantly activated by wall stretch, temperature, and acidity. When accompanied by mucosal injury, inflammatory mediators (prostaglandins, bradykinins, etc.) augment the response. The proximal esophagus is more sensitive than the distal esophagus, consistent with the observation that proximal stimuli such as reflux are more likely to be perceived.33 Excessive proximal sensitivity has been associated with esophageal hypersensitivity and functional heartburn.34 With sensory endings concentrated deeply within the muscularis propria beneath a relatively impermeable mucosa, it seems unlikely that intraluminal acid can directly stimulate them. However, these afferents easily respond to mucosally applied bile or capsaicin (a derivative of chili pepper), suggesting that these chemicals induce the release of an endogenous substance that in turn excites the afferents. These responses are thought to be mediated by transient receptor potential vanilloid 1 (TRPV1) receptors and/or acid-sensing ion channels.35,36 Consistent with this, current evidence suggests that chronic esophagitis increases mRNA expression of purinergic receptors accompanied by upregulation of TRPV1 and neurotrophic factors mediating sensitization of the inflamed human esophagus.37 Owing to its significance in the pathogenesis of GERD, there has been substantial interest in modulating the tLESR reflex (see Chapter 44). The current concept is that vagal afferent endings

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CHAPTER 44  Esophageal Neuromuscular Function and Motility Disorders 0

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5

mm Hg 100

10

Length along the esophagus (cm)

80 15

60

2 sec

20

40

20

25

0 30 1.6 mm Hg 35

30

eSleeve

1.6 mm Hg

mm Hg 0

Gastric 2 sec

15 mm Hg 0

Fig. 44.6 EGJ relaxation and bolus transit during swallowing. The IRP provides a pressure topography metric of the pressure dynamics across the EGJ during swallowing. The IRP is a complex metric because it involves accurately localizing the margins of the EGJ, demarcating the time window following deglutitive upper sphincter relaxation within which to anticipate EGJ relaxation, and then applying an eSleeve measurement within that 10-sec time box (delineated by the black brackets). The eSleeve is referenced to gastric pressure and provides a measure of the greatest pressure across the axial domain of the EGJ at each time point and is plotted as a line tracing. The IRP is the mean value of the 4 sec during which the eSleeve value is the lowest. The time intervals contributing to the IRP are indicated by the white boxes on the plot and by the shaded red area on the red line eSleeve tracing. In this example, the IRP is 1.6 mm Hg, which is normal. The EGJ is closed, and no flow occurs at the beginning of the swallow because the intrabolus pressure is insufficient to overcome EGJ pressure (left fluoroscopic image). Bolus transit occurs when the intrabolus pressure ahead of the contractile wave front overcomes the resisting forces at the EGJ (right fluoroscopic image).  

terminating in intraganglionic lamellar endings located in the proximal stomach are primarily responsible for initiating the reflex, which is then mediated through the medulla and back to the esophagus and diaphragm via vagal efferents and the phrenic nerves. Pharmacologic and physiologic studies have demonstrated that the mechanotransduction properties of tension-sensitive vagal afferent fibers can be attenuated by the GABA-B receptor agonist baclofen, thereby reducing the frequency of tLESR. Glutamate receptors are also present in vagal and spinal sensory afferent fibers, and metabotropic glutamate receptor antagonists (especially mGluR5 antagonists) have also been shown to inhibit tLESR.38 Recent investigations have also explored functional brain imaging, mainly functional magnetic resonance imaging, as a noninvasive assessment of brain function in visceral sensation and pain.39 Although the results thus far are quite variable among research groups, the brain regions most consistently activated by esophageal stimuli are the anterior and posterior insula, cingulate cortex, primary sensory cortex, prefrontal cortex, and thalamus. Preliminary studies also suggest

differences in functional magnetic resonance imaging activation patterns among subgroups of GERD patients and normal controls.40 

ESOPHAGEAL MOTILITY DISORDERS A working, albeit restrictive, definition of an esophageal motility disorder is: an esophageal disease attributable to neuromuscular dysfunction that causes symptoms referable to the esophagus, most commonly dysphagia, chest pain, or heartburn. Using this definition, there are only 3 firmly established primary esophageal motility disorders: achalasia, distal esophageal spasm (DES), and GERD. GERD is clearly the most prevalent among the group and, fittingly, it is addressed in detail elsewhere in this text (see Chapter 46). Esophageal motility disorders can also be secondary phenomena, in which case esophageal dysfunction is part of a more global disease, such as in pseudoachalasia, Chagas disease, and PSS (scleroderma). Dysphagia due to pharyngeal or UES dysfunction can also be included in a discussion of esophageal motor

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UES relaxation

Length along the esophagus

5 10

Pressure (mm Hg) 30

Gastroesophageal common cavity

20

15 Proximal esophageal clip

20 25 30 35

10 5.0 cm

7.0 cm

0

SCJ clip Abdominal Onset of strain tLESR 4490

4495

9.5 cm

4500

4505

4510

–10 4515

Time (sec) Fig. 44.7  Esophageal shortening during a tLESR. Fluoroscopic visualization of movement of endoclips (one placed at the SCJ and one 10 cm proximal to the SCJ) during a tLESR is recorded in a high-resolution EPT format. The manometric recording spans the pharynx to the stomach and, in this instance, the tLESR is associated with an abdominal strain and a “microburp” evident by the brief UES relaxation and abrupt depressurization of the esophagus with gas venting. When the clip data are imported into the isobaric contour plot, it is evident that the SCJ clip excursion mirrors movement of the EGJ high-pressure band. Esophageal shortening is most prominent in the distal portion of the 10-cm segment isolated by the endoscopic clips, as seen from the approximately 7-cm movement of the distal SCJ clip concurrent with minimal movement of the proximal clip. Note also the absence of crural diaphragm contractions for the duration of the tLESR.

disorders, but this is usually as a manifestation of a more global neuromuscular disease process. The major focus of this chapter will be on the primary motility disorders, particularly achalasia. However, mention will be made of the secondary motility disorders and proximal pharyngoesophageal dysfunction when important unique features exist.

Epidemiology Estimates of the prevalence of dysphagia among individuals older than 50 years range from 16% to 22%, with most of this related to oropharyngeal dysfunction. Most oropharyngeal dysphagia is related to neuromuscular disease; the prevalence of the most common anatomic etiology, Zenker diverticulum, is estimated to range from a meager 0.01% to 0.11% of the population in the USA, with peak incidence in men between the 7th and 9th decades.41 The consequences of oropharyngeal dysphagia are severe: dehydration, malnutrition, aspiration, choking, pneumonia, and death. Within health care institutions, it is estimated that up to 13% of hospitalized patients and 60% of nursing home residents have feeding problems and, again, most are attributed to oropharyngeal dysfunction as opposed to esophageal dysfunction. Mortality of nursing residents with dysphagia and aspiration can be as high as 45% over 1 year. As the U.S. population continues to age, oropharyngeal dysphagia will become an increasing problem associated with complex medical and ethical issues. Achalasia is the most easily recognized and best-defined motor disorder of the esophagus. Modern estimates of the incidence of achalasia are about 2.9 per 100,000 population in the USA42 and 2.6 per 100,000 in south Australia,43 affecting both genders equally and usually presenting between 25 and 60 years of age.44 Because achalasia is a chronic condition, its prevalence greatly exceeds its incidence; a recent estimate of achalasia prevalence in Chicago concluded that it may be as high as 76 per 100,000 population, given that the average age of diagnosis was 56 with an expected

average survival of 26 years after diagnosis.42 Reports of familial clustering of achalasia raise the possibility of genetic predisposition. However, arguing against a strong genetic determinant, a survey of 1012 first-degree relatives of 159 achalasics identified no affected relatives. There is a rare genetic achalasia syndrome associated with adrenal insufficiency and alacrima. This syndrome is inherited as an autosomal recessive disease and manifests with the childhood onset of autonomic nervous system dysfunction including achalasia, alacrima, sinoatrial dysfunction, abnormal pupillary responses to light, and delayed gastric emptying.45 It is caused by mutations in AAAS, which encodes a protein known as ALADIN. There are no population-based studies on the incidence or prevalence of esophageal motility disorders other than achalasia. Thus, the only way to estimate the incidence or prevalence of spastic disorders is to examine data on populations at risk and reference the observed frequency of spastic disorders to the incidence of achalasia, which, as detailed earlier, is about 2.75 per 100,000 population. Doing so, the prevalence of DES is much lower than that if modern restrictive diagnostic criteria are used. Populations at risk for motility disorders are patients with chest pain and/or dysphagia, so it is among these patients that extensive manometric data have been collected. Manometric abnormalities are prevalent among these groups, but in most cases the manometric findings are of unclear significance.46 

Pathogenesis Oropharyngeal Dysphagia Obstructing lesions of the oral cavity, head, and neck can cause dysphagia. Structural abnormalities may result from trauma, surgery, tumors, caustic injury, congenital anomalies, or acquired deformities. The most common structural abnormalities of the hypopharynx associated with dysphagia are hypopharyngeal diverticula and cricopharyngeal bars.

CHAPTER 44  Esophageal Neuromuscular Function and Motility Disorders

TABLE 44.1  Mechanical Events of the Oropharyngeal Swallow, Evidence of Dysfunction, and Disease Association(s) in Patients with Oropharyngeal Dysphagia Mechanical Event

Evidence of Dysfunction

Disease Association(s)

Nasopharyngeal closure

Nasopharyngeal regurgitation Nasal voice

Laryngeal closure

Aspiration during bolus Stroke transit Traumatic brain injury

UES opening

Dysphagia Postswallow residue/ aspiration Diverticulum formation

Cricopharyngeal bar Parkinson disease

Sluggish misdirected bolus

Parkinson disease Surgical defects Cerebral palsy

Pharyngeal clearance Postswallow residue in hypopharynx/ aspiration

Polio or post-polio syndrome Oculopharyngeal dystrophy Stroke

Tongue loading and bolus propulsion

Myasthenia gravis

If the etiology of oropharyngeal dysphagia is not readily apparent after an initial evaluation for anatomic disorders, evidence of functional abnormalities should be sought. Primary neurologic or muscular diseases involving the oropharynx are often associated with dysphagia. Whereas esophageal dysphagia usually results from esophageal diseases, oropharyngeal dysphagia frequently results from neurologic or muscular diseases, with oropharyngeal dysfunction being just one pathologic manifestation. Although the disease specifics vary, the net effect on swallowing can be analyzed according to the mechanical description of the swallow outlined earlier. Table 44.1 summarizes the mechanical elements of the swallow, the manifestation and consequence of dysfunction, and representative pathologic conditions in which they are likely encountered. Neurologic examination may indicate cranial nerve dysfunction, neuromuscular disease, cerebellar dysfunction, or an underlying movement disorder. Functional abnormalities can be due to dysfunction of intrinsic musculature, peripheral nerves, or central nervous system control mechanisms. Of note, contrary to popular belief, the gag reflex is not predictive of pharyngeal swallowing efficiency or aspiration risk. The gag reflex is absent in 20% to 40% of normal adults.47 Evident in Table 44.1, oropharyngeal dysphagia is frequently the result of neurologic or muscular diseases. Neurologic diseases can damage the neural structures requisite for either the afferent or efferent limbs of the oropharyngeal swallow. Virtually any neuromuscular disease can potentially cause dysphagia (see Chapter 37). As there is nothing unique to neurons controlling swallowing, their involvement in disease processes is usually random. Furthermore, in most instances, functions mediated by adjacent neuronal structures are concurrently involved. The following discussion will focus on neuromuscular pathologic processes most commonly encountered. 

Stroke Aspiration pneumonia has been estimated to inflict a 20% death rate in the first year after a stroke, and 10% to 15% each year thereafter. It is usually not the first episode of aspiration pneumonia, but the subsequent recurrences over the years that eventually cause death. The ultimate cause of aspiration pneumonia is dysphagia leading to aspiration that can occur by a number of mechanisms: absence or severe delay in triggering the swallow, reduced lingual control, or weakened laryngo-pharyngeal musculature.7 Conceptually, these etiologies can involve motor

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or sensory impairments. Cortical infarcts are less likely to result in severe dysphagia than brainstem strokes. Cortical infarcts are also more likely to demonstrate recovery from dysphagia. Of 86 consecutive patients who sustained an acute cerebral infarct, 37 (43%) experienced dysphagia when evaluated within 4 days of the event. However, 86% of these patients were able to swallow normally 2 weeks later, with recovery resulting from contralateral areas taking over the lost function.48 Failure to recover was more likely among patients incurring larger infarcts or patients who had prior infarcts. 

Amyotrophic Lateral Sclerosis Amyotrophic lateral sclerosis is a progressive neurologic disease characterized by degeneration of motor neurons in the brain, brainstem, and spinal cord. Specific symptoms are dependent upon the locations of affected motor neurons and the relative severity of involvement. When the degenerative process involves the cranial nerve nuclei, swallowing difficulties ensue. Oropharyngeal dysfunction characteristically begins with the tongue and progresses to involve the pharyngeal and laryngeal musculature. Patients experience choking attacks, become volume depleted or malnourished, and incur aspiration pneumonia. The decline in swallowing function is progressive and predictable, invariably leading to gastrostomy feeding. Patients often die as a consequence of their swallowing dysfunction in conjunction with respiratory depression.49 

Parkinson Disease Although only 15% to 20% of patients with Parkinson disease complain of swallowing problems, more than 95% have demonstrable defects when studied videofluoroscopically.50 This disparity suggests that patients compensate in the early stages of the disease and complain of dysphagia only when it becomes severe. Abnormalities include repetitive lingual pumping prior to initiation of a pharyngeal swallow, piecemeal swallowing, and oral residue after the swallow. Patients may also exhibit a delayed swallow response and a weak pharyngeal contraction, resulting in vallecular and pyriform sinus residue. Recent data suggest this to be related to the combination of incomplete UES relaxation and a weakened pharyngeal contraction.50 

Vagus Nerve Disorders Unilateral lesions of the vagus can result in hemiparesis of the soft palate and pharyngeal constrictors, as well as of the laryngeal musculature. The recurrent laryngeal nerves can be injured as a result of thyroid surgery, aortic aneurysms, pneumonectomy, primary mediastinal malignancies, or metastatic lesions to the mediastinum. Owing to its more extensive loop in the chest, the left recurrent laryngeal nerve is more vulnerable to involvement by mediastinal malignancy than the right laryngeal nerve. Unilateral recurrent laryngeal nerve injury results in unilateral adductor paralysis of the vocal cord. This defect can result in aspiration during swallowing because of impaired laryngeal closure. It is, however, rare to have any primary pharyngeal dysfunction resultant from recurrent laryngeal nerve injury. 

Oculopharyngeal Muscular Dystrophy Oculopharyngeal muscular dystrophy is a syndrome characterized by ptosis and progressive dysphagia. In the past, afflicted patients reaching age 50 typically died of starvation resulting from pharyngeal paralysis. The disease is now known to be a form of muscular dystrophy and is inherited as an autosomal dominant disorder, with occurrences clustered in families of FrenchCanadian descent. Genetic studies of an afflicted family indicate linkage to chromosome 14, perhaps involving the region coding

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for cardiac alpha or beta myosin heavy chains. Oculopharyngeal dystrophy affects the striated pharyngeal muscles and the levator palpebrae. Although other forms of muscular dystrophy occasionally affect the pharyngeal constrictors, this is rarely a dominant manifestation. The first symptom of oculopharyngeal dystrophy is usually ptosis that slowly progresses and eventually dominates the patient’s appearance. Dysphagia may begin after, concomitant with, or even before ptosis. The dominant functional abnormalities are of a weak or absent pharyngeal contraction, reduced cricopharyngeal opening, and hypopharyngeal stasis.51 Dysphagia is slowly progressive, but may ultimately lead to starvation, aspiration pneumonia, or asphyxia. 

Zenker diverticulum

Myasthenia Gravis Myasthenia gravis is a progressive autoimmune disease characterized by high circulating levels of ACh receptor antibody and destruction of ACh receptors at neuromuscular junctions. Musculature controlled by the cranial nerves is almost always involved, particularly the ocular muscles. Dysphagia is prominent in more than a third of patients with myasthenia gravis and, in unusual instances, can be the initial and dominant manifestation of the disease. In mild cases, dysphagia may not be evident until after 15 to 20 minutes of eating. Classically, manometric studies reveal a progressive deterioration in the amplitude of pharyngeal contractions with repeated swallows. Peristaltic amplitude recovers with rest or following the administration of 10 mg edrophonium chloride, an acetylcholinesterase inhibitor. In more advanced cases, the dysphagia can be profound and associated with nasopharyngeal regurgitation and nasality of the voice, even to the extent of being confused with bulbar amyotrophic lateral sclerosis or brainstem stroke.52 

Cricopharyngeus

Fig. 44.8  Film from a barium swallow study showing a small Zenker diverticulum. Although the point of herniation is midline posterior at Killian dehiscence, the diverticulum migrates laterally in the neck as it enlarges, because there is no potential space between the posterior pharyngeal wall and the vertebral column.

Hypopharyngeal (Zenker) Diverticula and Cricopharyngeal Bar Hypopharyngeal diverticula and cricopharyngeal bars are closely related disease entities in that it is a cricopharyngeal bar that can result in diverticulum formation. The most common type, Zenker diverticulum (Fig. 44.8), originates in the midline posteriorly at Killian dehiscence, a point of pharyngeal wall weakness between the oblique fibers of the inferior pharyngeal constrictor and the transverse cricopharyngeus muscle. Other locations of acquired pharyngeal diverticula include: (1) the lateral slit separating the cricopharyngeus muscle from the fibers of the proximal end of the esophagus, through which the recurrent laryngeal nerve and its accompanying vessels run to supply the larynx; (2) at the penetration of the inferior thyroid artery into the hypopharynx; (3) and at the junction of the middle and inferior constrictor muscles. The unifying theme of these locations is that they are sites of potential weakness of the muscular lining of the hypopharynx through which the mucosa herniates, leading to a “false” diverticulum. The best-substantiated explanation for the development of diverticula is that they form as a result of a restrictive myopathy associated with diminished compliance of the cricopharyngeus muscle. Surgical specimens of cricopharyngeus muscle strips from patients with hypopharyngeal diverticula demonstrated structural changes that would decrease UES compliance and opening.53 The cricopharyngeus samples from these patients had “fibro-adipose tissue replacement and (muscle) fiber degeneration.” Thus, although the muscle relaxes normally during a swallow, it cannot distend normally, resulting in the appearance of a cricopharyngeal indentation, or bar, during a barium swallow (Fig. 44.9). Diminished sphincter compliance necessitates increased hypopharyngeal intrabolus pressure to maintain trans-sphincteric flow through the smaller UES opening. The increased stress on the hypopharynx from the increased intrabolus pressure may ultimately result in diverticulum formation. 

Cricopharyngeus

Esophagus

Trachea

Fig. 44.9  Film from a barium swallow study showing a cricopharyngeal bar in a patient with oropharyngeal dysphagia. The posterior indentation of the barium column is caused by a noncompliant cricopharyngeus muscle. (Courtesy Dr. Richard Gore, Evanston, IL.)

Achalasia Achalasia is characterized by impaired LES relaxation with swallowing and aperistalsis in the smooth muscle esophagus. If there are premature, spastic contractions in the esophageal body, the disease is referred to as spastic (type III) achalasia.54

CHAPTER 44  Esophageal Neuromuscular Function and Motility Disorders

These physiologic alterations result from damage to the innervation of the smooth muscle segment of the esophagus (including the LES) with loss of ganglion cells within the myenteric (Auerbach) plexus. Several observers report fewer ganglion cells and ganglion cells surrounded by mononuclear inflammatory cells in the smooth muscle esophagus of achalasics.55 The degree of ganglion cell loss parallels the duration of disease, likely progressing from EGJ outflow obstruction to type II achalasia, to type I achalasia, to end-stage achalasia.55,56 Type III achalasia seems to have a unique pathogenesis, characterized by myenteric plexus inflammation and altered function, but not destruction.55 Physiologic studies in achalasics suggest dysfunction consistent with postganglionic denervation of esophageal smooth muscle potentially affect excitatory ganglion neurons (cholinergic), inhibitory ganglion neurons (NO ± VIP), or both (see Fig. 44.4). Muscle strips from the circular layer of the esophageal body of achalasics contract when directly stimulated by ACh but fail to respond to ganglionic stimulation by nicotine, indicating a postganglionic excitatory defect. However, partial preservation of the postganglionic cholinergic pathway is suggested by the observations that in some cases, an achalasic’s LES pressure increases after administration of the AChE inhibitor edrophonium and decreases after administration of the muscarinic antagonist atropine, crucial observations for understanding why botulinum toxin may have some therapeutic benefit (see section on treatment). Regardless of excitatory ganglion neuron impairment, it is clear that inhibitory ganglion neuron dysfunction is as an early manifestation of achalasia. These neurons mediate deglutitive inhibition (including LES relaxation) and the sequenced propagation of esophageal peristalsis; their absence offers a unifying hypothesis for the key physiologic abnormalities of achalasia: impaired LES relaxation and aperistalsis. Achalasics have been shown to lack NO synthase and have a marked reduction of VIP-staining neurons in the gastroesophageal junction. There is substantial evidence of impaired esophageal postganglionic inhibitory innervation in achalasics. Muscle strips from the LES do not relax in response to ganglionic stimulation by nicotine as they do in normal controls. Furthermore, CCK, which normally stimulates the inhibitory ganglion neurons and thus reduces LES pressure, paradoxically increases LES pressure in achalasics.57 Impaired inhibitory innervation of the smooth muscle esophagus above the LES has been more difficult to demonstrate because of the absence of resting tone in this region. However, in a clever experiment, Sifrim and coworkers used an intraesophageal balloon to create a high-pressure zone in the tubular esophagus that then relaxed with the onset of deglutitive inhibition. This deglutitive relaxation in the esophageal body was absent in early, nondilated cases of achalasia.58 The ultimate cause of ganglion cell degeneration in idiopathic achalasia is gradually being unraveled, with increasing evidence pointing toward an autoimmune process in genetically susceptible individuals.59 Analysis of the myenteric plexus infiltrate in achalasia patients revealed that the majority of inflammatory cells are either resting or activated cytotoxic T cells. Antibodies against myenteric neurons have been detected in sera of achalasia patients, especially in patients with specific HLA alleles. The trigger for initiating the autoimmune response leading to the development of achalasia remains controversial, but is suspected to be a chronic or latent human herpes virus 1 (HSV-1) infection.59 Interestingly, HSV-1 was also detected in LES tissue from nonachalasic organ donors, suggesting that the development of achalasia is dependent on both the virus and a genetic predisposition. 

Distal Esophageal Spasm (DES) Although the diagnosis of DES is often invoked as a cause of esophageal chest pain, the entity is actually exceedingly rare with

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most cases of esophageal chest pain attributable to reflux disease or achalasia. Historically, the manometric criteria for diagnosing DES have been nonspecific, leading to over-diagnosis of the entity. This has been clarified somewhat with the Chicago Classification of high-resolution manometry and the adoption of reduced distal latency (DL) of peristalsis as the cardinal abnormality in DES.60 Although DES is clearly a disorder of peristalsis, the majority of afflicted patients exhibit normal peristaltic contractions most of the time. The neuromuscular pathology responsible for DES is unknown and there are no known risk factors. The most striking reported pathologic change is of diffuse muscular hypertrophy or hyperplasia in the distal esophagus with thickening of up to 2 cm. However, there are other well-documented cases in which esophageal muscular thickening was not found at thoracotomy, and still other instances of patients with muscular thickening not associated with DES symptoms. Despite the absence of defined histopathology, physiologic evidence implicates myenteric plexus neuronal dysfunction in spasm because the latency of contraction along the smooth muscle esophagus is a function of postganglionic myenteric plexus neurons. Swallow-induced vagal impulses reach the entire smooth muscle segment of the esophagus simultaneously, and it is the balance of excitatory and inhibitory ganglionic neurons within the myenteric plexus that determine the timing of contraction at each esophageal locus. Furthermore, experimental evidence suggests heterogeneity among spasm patients, such that some primarily exhibit reduced inhibitory interneuron function, whereas in others the defect is of excess excitation. Defining DES based on the latency of the postdeglutitive contraction puts it in a pathophysiologic continuum with achalasia, consistent with documented case reports of patients undergoing this evolution.61 Furthermore, there are marked similarities between spastic achalasia and DES because both are characterized by rapidly propagated contractions in the distal esophagus. The differentiating features of vigorous achalasia are involvement of the LES and the absence of any normal peristalsis. 

Hypercontractile (Jackhammer) Esophagus Vigorous esophageal contractions with normal DL, defined as esophageal hypercontractility or jackhammer esophagus in the Chicago Classification, can be associated with both dysphagia and chest pain. Hypercontractility is thought to be a manifestation of either excessive excitatory drive or a reactive compensation for outflow obstruction leading to myocyte hypertrophy.62 Consistent with this, patients with hypercontractility demonstrate heightened sensitivity to cholinergic agonists such as edrophonium. Data supporting obstruction as an etiology of hypercontractility come from physiologic studies using an inflatable pressure cuff implanted around the distal esophagus of cats.63 Small cuff inflation volumes augmented the amplitude of peristalsis, but with larger volumes there was complete disruption of the peristalsis. From a clinical perspective, the summary metric for quantifying distal esophageal contractility in HRM is the distal contractile integral (DCI). DCI values greater than 8000 mm Hg•cm•sec represent an extreme pattern of hypercontractility, often associated with repetitive contractions, rarely seen in normal subjects and almost always associated with chest pain and dysphagia. The current version of the Chicago Classification labels this condition “jackhammer esophagus” when 2 such contractions occur in a manometric study.64,65 

Absent Peristalsis Impaired peristalsis ranges from weak contractions to absent contractility as can be seen in achalasia and scleroderma. Although absent contractility is often idiopathic, achalasia and scleroderma

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serve as models that shed some light on its pathogenesis— aganglionosis in achalasia (see Fig. 44.4) and myogenic disruption in scleroderma. Ultrastructure studies in scleroderma patients have reported thickening of capillary basement membranes and atrophy or fibrosis of the esophageal smooth muscle. Hence, weak peristalsis and absent contractility can be related to either myogenic or neurogenic processes, similar to elsewhere in the GI tract. 

Clinical Features Dysphagia is a fundamental symptom of esophageal motility disorders. Esophageal (as opposed to oropharyngeal) dysphagia is suggested by the absence of associated aspiration, cough, nasopharyngeal regurgitation, drooling, pharyngeal residue following swallow, or co-occurring neuromuscular dysfunction (e.g., weakness, paresthesia, slurred speech). On the other hand, the associated conditions of heartburn, regurgitation, chest pain, odynophagia, or intermittent esophageal obstruction suggest esophageal dysphagia. An important limitation of the patient history in esophageal dysphagia is that a patient’s identification of the location of obstruction is of limited accuracy. Specifically, a distal esophageal obstruction caused by an esophageal ring, stricture, or achalasia will often be perceived as cervical dysphagia, and patients can correctly localize distal dysfunction only 60% of the time. Because of this subjective difficulty in distinguishing proximal from distal lesions within the esophagus, an evaluation for cervical dysphagia should encompass the entire length of the esophagus. Another important consideration in patient management is that esophageal motility disorders are much less common than mechanical or inflammatory etiologies of dysphagia, such as tumors, strictures, rings, or esophagitis, be that peptic, pillinduced, eosinophilic, or infectious. Historical points suggestive of a motor disorder are difficulty with both solids and liquids, as opposed to only with solids, which is more suggestive of mechanical obstruction. However, the functional consequences of mechanical or inflammatory disorders can exactly mimic those of primary motility disorders. Thus, as with the evaluation of oropharyngeal dysphagia, a motility disorder should be considered as an etiology for esophageal dysphagia only after exclusion of more common diagnoses by endoscopic, histologic, and/or radiographic examination.

Achalasia Clinical manifestations of achalasia may include dysphagia, regurgitation, chest pain, hiccups, halitosis, weight loss, and aspiration pneumonia. All patients have solid food dysphagia; the majority of patients also have variable degrees of liquid dysphagia. The onset of dysphagia is usually gradual, and often present for years at the time of presentation. The severity of dysphagia fluctuates but eventually plateaus. With long-standing disease, there is progressive esophageal dilatation, and regurgitation becomes frequent with recumbency. The regurgitant is often recognized as food that has been eaten hours, or even days, previously. It tends to be nonbilious, nonacid, and mixed with copious amounts of saliva. Patients often fail to recognize the slimy mucoid regurgitant as saliva, being unfamiliar with its visual consistency. Chest pain is a complaint early in the course of achalasia in approximately two thirds of patients. Its etiology is unknown, but is thought to be related to the occurrence of esophageal spasm (more recently, proposed to be spasm of longitudinal muscle). Treatment of achalasia is less effective in relieving chest pain than it is in relieving dysphagia or regurgitation. However, unlike dysphagia or regurgitation, chest pain may spontaneously improve or disappear over time.

With advanced achalasia, up to 10% of cases have bronchopulmonary complications as a result of regurgitation and aspiration; in some instances, it is these complications rather than dysphagia that prompts them to seek medical care. Another interesting, but fortunately rare, symptom of achalasia is airway compromise and stridor as a result of the dilated esophagus compressing the membranous trachea in the neck. This is hypothesized to occur because the neuromuscular apparatus facilitating UES relaxation as part of the belch reflex is compromised.66 It is paradoxical that many achalasics complain of heartburn even after the onset of dysphagia. Although reflux may be a common sequela of the treatments for achalasia, it seems physiologically inconsistent to simultaneously have dysphagia from impaired LES relaxation and reflux from excessive LES relaxation. In support of this skepticism, ambulatory 24-hour esophageal pH studies of achalasics have only shown periods of esophageal acidification caused by the bacterial fermentation of retained food in the esophagus, rather than discrete gastroesophageal reflux events.67 Furthermore, it is highly unusual for an achalasic to have a tLESR. Rather, they usually exhibit incomplete tLESRs with crural inhibition, esophageal shortening, and a profound after-contraction, but devoid of the LES relaxation element.68 

Distal Esophageal Spasm The major symptoms of DES are dysphagia and chest pain. Weight loss is rare. Dysphagia is usually intermittent and sometimes related to swallowing specific substances such as red wine or liquids at extreme hot or cold temperature. In some instances, patients experience episodes of esophageal obstruction while eating that persists until relieved by emesis. Esophageal chest pain is very similar in character to angina, often described as crushing or squeezing in character, radiating to the neck, jaw, arms, or midline of the back. Pain episodes may last from minutes to hours, but continued swallowing is not always impaired. The mechanism producing esophageal pain is poorly understood. High-frequency intraluminal ultrasound data suggest that it may be related to sustained contraction of esophageal longitudinal muscle.69 Chest pain is also prevalent in patients subsequently found to have manometric abnormalities that are insufficient to establish a diagnosis of achalasia or DES. Among such individuals, there is a high prevalence of reflux and of psychiatric diagnoses, particularly anxiety and depression.46 

Hypercontractile Esophagus The hypercontractile disorders also typically present with chest pain and dysphagia, although the dysphagia is less likely to involve impaired bolus transit. By definition, contractile latency is normal with hypercontractility; hence, peristaltic progression and bolus transit are normal. However, the jackhammer pattern is associated with prolonged repetitive contractions that can persist long after bolus transit (Fig. 44.10B). The natural history of hypercontractility is unknown, but it is clear that at least in some cases jackhammer patients can have a prolonged and difficult clinical course. 

Absent Contractility Patients with absent peristalsis can present with dysphagia or symptoms suggestive of severe GERD, such as heartburn, regurgitation, and chest pain. The severity of the presentation is to some degree dependent on the function of the EGJ; GERD symptoms are much worse when absent peristalsis is accompanied by gross EGJ incompetence. Alternatively, with an intact EGJ, absent peristalsis may be difficult to distinguish from achalasia, owing to the similar symptomatology and physiologic findings. 

CHAPTER 44  Esophageal Neuromuscular Function and Motility Disorders (A) Normal

651

(B) Hypercontractile—Jackhammer

44

1 mm Hg Length along the esophagus (cm)

5 10

DCI= 3212 mm Hg;sec;cm DCI= 6508 mm Hg;sec;cm

150 DCI= 20,452 mm Hg;sec;cm 100

15 20

50 25

30

30 10 sec

35

0 10 sec

Time (sec)

Time (sec)

Fig. 44.10  Normal and abnormal contractile vigor. A, A normal swallow with a distal contractile interval (DCI) of 3212 mm Hg•sec•cm, normal propagation, and a single uniform contraction. B, Swallow with an extremely high DCI. This swallow exhibits repetitive contractions without evidence of an EGJ outflow obstruction. This is a hypercontractile or “jackhammer” pattern in the Chicago Classification (see Table 44.2). (With permission from the Esophageal Center at Northwestern.)

Differential Diagnosis

Chagas Disease

The patient history is crucial in the evaluation of dysphagia. Major objectives of the history are to differentiate oropharyngeal dysphagia from esophageal dysphagia, xerostomia (hyposalivation), or globus sensation. All are frequently confused with each other. Globus sensation, in particular, is frequently confused with dysphagia. Unlike dysphagia, which occurs only during swallowing, globus sensation is prominent between swallows. Patients relate the nearly constant sensation of having a lump in their throat or feeling a foreign object caught in their throat. In some instances globus is associated with reflux symptoms, and in others with substantial anxiety. It is the linkage with anxiety that led to the older nomenclature “globus hystericus.” Unfortunately, studies have failed to define an objective anatomic or physiologic cause for globus, and we are left with the crucial data being in the history; globus sensation persists regardless of the act of swallowing.

Esophageal involvement in Chagas disease, which is endemic in areas of central Brazil, Venezuela, and northern Argentina, can be indistinguishable from idiopathic achalasia. An estimated 20 million South Americans are infected. Due to immigration, about 500,000 people in the USA are believed infected. Chagas disease is spread by the bite of a reduvid (kissing) bug that transmits the parasitic protozoan, Trypanosoma cruzi. An acute septicemic phase of the illness follows that varies in severity from going unnoticed to being fatal. The chronic phase of the disease develops up to 20 years after infection and results from destruction of autonomic ganglion cells throughout the body, including the heart, gut, urinary tract, and respiratory tract. Chronic cardiomyopathy with conduction system disturbances and arrhythmias is the most common cause of death. Within the digestive tract, the organs most commonly affected are the esophagus, duodenum, and colon. The severity of esophageal dysfunction is directly proportional to the degree of intramural ganglion cell loss; abnormal peristalsis is first detectable after 50% of ganglion cells are destroyed, and esophageal dilatation after 90% are destroyed. Paralleling this, the initial dysfunction is confined to the esophageal body, with LES dysfunction occurring late in the course of the disease The most obvious clinical distinction between idiopathic achalasia and esophageal involvement in Chagas disease is evidence of additional tubular organ involvement (cardiomyopathy, megaduodenum, megacolon, megarectum, megaureter) in Chagas disease.70 With respect to esophageal pathology, the 2 are otherwise indistinguishable. The diagnosis of Chagas disease is made in the acute phase by visualizing the parasite in a blood smear. In the chronic phase, the diagnosis is confirmed by serologic tests using complement fixation or PCR. The treatment of the achalasia syndrome in Chagas disease is similar to that for idiopathic achalasia. Treatment of the infection itself is of limited efficacy in the acute phase and of no proved efficacy with chronic disease. 

Achalasia The differential diagnosis of achalasia includes other esophageal motility disorders and diseases of distinct pathophysiology that duplicate the functional consequences of achalasia. With respect to other motility disorders, there are many similarities between DES and achalasia, especially the subtype of spastic achalasia. In fact, the only distinction between these entities is the demonstration of incomplete LES relaxation in type III achalasia and there are case reports of DES evolving into spastic achalasia.61 However, given the rarity of both conditions and the historical heterogeneity on how they are diagnosed, it seems likely that only a small minority of achalasia cases are part of a continuum with DES. With respect to other diseases that duplicate the functional consequences of idiopathic achalasia, the main considerations are Chagas disease and pseudoachalasia that is associated with infiltrative diseases, malignancy, obstruction, or surgery. 

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Pseudoachalasia Neither the radiographic nor the manometric features of achalasia are specific for idiopathic achalasia or achalasia associated with Chagas disease. Tumor-related pseudoachalasia, most commonly of the gastric cardia, accounts for up to 5% of cases with manometrically defined achalasia. Pseudoachalasia becomes more likely than idiopathic achalasia with advanced age (>50 years), abrupt and recent onset of symptoms (50% fragmented swallows and not ineffective

Minor disorders of peristalsis Impaired clearance

No

4

IRP normal and >50% ineffective swallows

Yes

No 5

IRP normal and >40% effective swallows

Yes

Normal

Fig. 44.13  Algorithm for applying the Chicago Classification of esophageal motor disorders. DCI, distal contractile interval; DL, distal latency; EGJ, esophagogastric junction; IBC, isobar contour; IRP, integrated relaxation pressure; PEP, panesophageal pressurization; ULN, upper limit of normal. (See Table 44.2 for more detail.)

Type I

Type II

Type III

mm Hg 150

air 100

liquid

50 30 0

IRP= 22.3 mm Hg 5 sec

IRP= 24.2 mm Hg 5 sec

IRP= 29.8 mm Hg 5 sec

Fig. 44.14  Achalasia subtypes. The 3 subtypes are distinguished by distinct manometric patterns of esophageal body contractility. In the patient with classic achalasia (Type I), there is no significant pressurization within the body of the esophagus and EGJ relaxation is impaired; IRP 22.3 mm Hg in this example. A swallow from a Type II patient, the “achalasia with compression” subtype, shows rapid pan-esophageal pressurization of the fluid column trapped between the sphincters as the esophagus shortens. The pressure topography plot in the Type III patient is typical of spastic achalasia. Although this swallow is also associated with rapidly propagated pressurization, the pressurization is attributable to an abnormal lumen-obliterating contraction. (Modified from Pandolfino JE, Kwiatek MA, Nealis T, et al. Achalasia: A new clinically relevant classification by high resolution manometry. Gastroenterology 2008; 135:1526-33. With permission from the Esophageal Center at Northwestern.)

CHAPTER 44  Esophageal Neuromuscular Function and Motility Disorders

A: EGJ Outflow Obstruction: achalasia phenotype Fig. 44.15  EGJ outflow obstruction. The criteria for EGJ outflow obstruction are an elevated IRP associated with some preserved weak or normal peristalsis, thereby not meeting the diagnostic criteria for types I, II, or III achalasia. Ultimately, this pattern may prove to be a phenotype of achalasia, as in Panel A (top). This patient, who also had a large epiphrenic diverticulum (Panel A, bottom), was treated with a laparoscopic myotomy and diverticulectomy with good result. Alternatively, EGJ outflow obstruction pattern can be associated with mechanical obstruction (Panel B). This patient had a patulous EGJ and a 9-mm endoscope passed with no resistance noted. However, the IRP was increased, and there was compartmentalized pressurization between the preserved peristaltic contraction and the EGJ (Panel B, top). The esophagogram (Panel B, bottom) revealed a subtle stenosis just proximal to the EGJ (arrow), where passage of a 12.5-mm barium tablet was delayed. The patient responded to 18-mm balloon dilation and therapy with a PPI. (With permission from the Esophageal Center at Northwestern.)

mm Hg 150

655

B: EGJ Outflow Obstruction: obstructing stricture

Normal peristalsis

100 Locus of diverticulum above EGJ

Compartmentalized pressurization

50 30

0

IRP= 22.3 mm Hg

confirmed the initial observation of that seminal study, that type II achalasia is the most responsive to treatment and type III the least responsive. Patients with impaired EGJ relaxation, defined by an abnormal IRP with persistent peristaltic activity failing to meet diagnostic criteria for achalasia, are categorized as having EGJ outflow obstruction in the Chicago Classification.64 From the outset, these were recognized to be a heterogeneous group of patients, only some of whom benefitted from achalasia treatments.76 Two representative examples of EGJ outflow obstruction are illustrated in Fig. 44.15. Hence, in some cases, such as in Fig. 44.15A, this may be a variant or early presentation of achalasia. However, recent series have reported that many patients with EGJ outflow obstruction were minimally symptomatic or even asymptomatic, that in 20% to 40% of cases the “disorder” resolved spontaneously, and that only 12% to 40% end up being treated as achalasia.77,78 Following the analysis of EGJ relaxation, quantitative features of the distal contraction are analyzed to identify disorders of peristalsis. This analysis is largely based on the DCI and DL, metrics based on key topographic landmarks: the onset of UES relaxation, the first pressure trough (transition zone), and the CDP (see Fig. 44.3). The CDP approximates the proximal margin of the LES and is identified as the inflection point along the 30 mm Hg isobaric contour where deceleration occurs, signifying the transition from peristalsis to the ampullary emptying.16 The interval between UES relaxation and the CDP defines the DL of the contraction, as illustrated in Fig. 44.3. DL values of less

IRP= 27.2 mm Hg

Barium tablet localized 12 mm restriction Large diverticulum 4 cm above EGJ EGJ

than 4.5 seconds define premature contractions, likely indicative of impaired inhibitory neuronal control to define failed contractions (DCI < 100 mm Hg•sec•cm), weak contractions (DCI < 450 mm Hg•sec•cm), and hypercontractility (DCI > 8000 mm Hg•sec•cm). Following analysis of individual swallows by the criteria outlined earlier, the component results are synthesized into a global manometric diagnosis by the criteria detailed in Table 44.2. Patients with normal EGJ relaxation, normal integrity, normal DL, normal contractile front velocity, and a DCI less than 5000 mm Hg•sec•cm are normal. The abnormalities encountered are described in specific functional terms, with the intent that these then be interpreted within the clinical context. The classification detailed in Table 44.2 represents the current Chicago Classification version vetted with a consensus approach by the international HRM Working Group.64 

Intraluminal Impedance Measurement Intraluminal impedance monitoring was described more than a decade ago as a method to assess intraluminal bolus transit without using fluoroscopy. The technique uses an intraluminal catheter with multiple, closely spaced pairs of metal rings. An alternating current is applied across each pair of adjacent rings, and the resultant current flow between the rings is dependent on the impedance of the tissue and luminal content between the rings. Impedance decreases when the electrodes are bridged by liquid and increases when they are surrounded by air. Hence, data

44

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PART V  Esophagus

TABLE 44.2  Chicago Classification v3.0 of Esophageal Motility Disorders Diagnosis

Diagnostic Criteria

Achalasia Type I (classic)

100% failed peristalsis, IRP > ULN

Type II (with esophageal compression)

100% failed peristalsis and panesophageal pressurization with ≥20% of swallows; mean IRP > ULN

Type III (spastic)

No normal peristalsis, premature contractions with ≥20% of swallows, mean IRP > ULN

EGJ outflow obstruction

Mean IRP ≥ ULN; sufficient evidence of peristalsis such that criteria for achalasia are not met

Major Disorders of Peristalsis (Patterns Not Observed in Normal Individuals) DES Mean IRP < ULN, ≥20% premature contractions with DCI >450 mm Hg•sec•cm, some normal peristalsis may be present Hypercontractile (jackhammer) At least 2 swallows with DCI >8000 mm esophagus Hg•sec•cm, may involve or even localize to the LES Absent contractility

Mean IRP ≤10 mm Hg, 100% absent contractility (DCI 10 seconds) than swallow-induced LESRs, and are accompanied by inhibition of the crural diaphragm.43 tLESRs account for nearly all reflux episodes in

healthy subjects and 50% to 80% of episodes in GERD patients, depending on the presence of hiatal hernia and severity of associated esophagitis (Fig. 46.3).44 However, one study suggests that low basal LES pressure, rather than tLESRs, may be the primary mechanism of GER in patients with nonreducible hiatal hernias (see Fig. 46.3).45 tLESRs are not always associated with GER. In normal subjects, 40% to 60% of tLESRs are accompanied by reflux episodes, compared with 60% to 70% in GERD patients.44,46 Possible factors determining whether reflux occurs include abdominal straining, presence of a hiatal hernia, degree of esophageal shortening, and duration of tLESRs. The dominant stimulus for a tLESR is distention of the proximal stomach by either food or gas, which is not surprising given that a tLESR is the mechanism of belching. Stretch receptors seem to be more relevant than tension receptors in triggering tLESRs.39 More varying stimuli are dietary fat, stress, and subthreshold (for swallowing) stimulation of the pharynx.47 Various drugs may reduce tLESRs, including CCK A

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PART V  Esophagus

100 90

Reflux episodes (%)

80 70 60 50 40 30 Control Nonerosive GERD Mild esophagitis Severe esophagitis

20 10 0 tLESR

Swallow- Absent basal Straining induced LES pressure LESR

Fig. 46.3  Percentage of reflux episodes in control subjects and in patients with GERD occurring by the following mechanisms: transient lower esophageal sphincter relaxation (tLESR), swallow-induced LESR, absent basal LES pressure, and straining in the presence of low LES pressure. (From Holloway RH. The anti-reflux barrier and mechanisms of gastro-oesophageal reflux. Ballieres Clin Gastroenterol 2000; 14:681-99.)

(CCK-1) receptor antagonists, anticholinergic drugs, morphine, somatostatin, nitric oxide inhibitors, 5-hydroxytryptamine 3 antagonists, and γ-aminobutyric acid (GABAB) agonists.47 The dominant stimulus for tLESRs is distension of the proximal stomach, which activates mechanoreceptors in the intraganglionic lamellar endings of vagal afferents.48 These fibers project eventually to the brainstem and the dorsal motor nuclei of the vagus. These neurons project to the inhibitory neurons localized in the myenteric plexus of the distal esophagus. This results in an integrated motor response involving LES relaxation, longitudinal muscle contractions reducing esophagogastric junction (EGJ) obstruction and repositioning the LES above the crura, crural diaphragm inhibition, and contraction of the costal diaphragm.49 Several neurotransmitters are involved in the control of tLESRs including GABA, glutamate, and endocannabinoids.50 

Swallow-Induced Lower Esophageal Sphincter Relaxations About 5% to 10% of reflux episodes occur during swallowinduced LESRs. Most episodes are associated with defective or incomplete peristalsis.46 During a normal swallow-induced LESR, reflux is uncommon because (1) the crural diaphragm does not relax, (2) the duration of LESR is relatively short (5 to 10 seconds), and (3) reflux is prevented by the oncoming peristaltic wave (see right side of tracing in Fig. 46.2). Reflux during swallow-induced LESRs is more common with a hiatal hernia. This may be due to the lower compliance of the EGJ in hernia patients, permitting it to open at pressures equal to or lower than intragastric pressure, thereby allowing reflux of gastric juices accumulating in the hiatal hernia.43,51 

Hypotensive Lower Esophageal Sphincter Pressure— Strained-Induced or Free Reflux GER can occur in the context of a hypotensive LES by either strain-induced or free reflux.45,52 Strain-induced reflux occurs when a relatively hypotensive LES is overcome by an abrupt increase in

intra-abdominal pressure from coughing, straining, or bending over. This type of reflux is unlikely when the LES pressure is greater than 10 mm Hg and there is no hiatal hernia.42 Free reflux is characterized by a fall in intraesophageal pH without an identifiable change in intragastric pressure, usually occurring when LES pressure is less than 5 mm Hg. Reflux due to a low or absent LES pressure is uncommon, usually observed in patients with end-stage scleroderma or after myotomy for achalasia.44 Mostly it occurs in patients with severe esophagitis, in whom it may account for up to 25% of reflux episodes; it rarely occurs in patients without esophagitis.44 These last 3 reflux mechanisms are nearly always seen in association with the presence of a hiatal hernia. These observations support the concept that the functional integrity of the EGJ depends on the intrinsic LES and extrinsic sphincter function of the diaphragmatic hiatus. In essence, GER requires 2 “hits” to the EGJ.42 Patients with a normal EGJ require inhibition of the LES and crural diaphragm for reflux to occur (i.e., tLESRs). In contrast, when a hiatal hernia is present compromising the function of the crural sphincter, reflux can occur with only relaxation of the LES, during periods of LES hypotension, swallowinginduced relaxation, and straining.51,52 

Hiatal Hernia Many individuals demonstrate no evidence of GERD despite the presence of a hiatal hernia. Other individuals with no recognizable hernia have documented GERD due to other factors such as excessive or prolonged tLESRs. Nevertheless, hiatal hernia occurs in 54% to 94% of patients with reflux esophagitis, a rate strikingly higher than that in the healthy population.53 Studies have also found that in individuals with reflux symptoms, the presence of hiatal hernia confers a significantly increased risk of erosive esophageal injury.54 Recent epidemiologic data have confirmed the importance of hiatal hernia in patients with Barrett’s esophagus and esophageal adenocarcinoma.55 The hiatal hernia promotes reflux through several mechanisms (Fig. 46.4). Proximal displacement of the LES from the crural diaphragm into the chest reduces basal LES pressure and shortens the length of the high-pressure zone; this is primarily due to loss of the intra-abdominal LES segment.50 Hiatal hernia eliminates the increase of LES pressure that occurs during straining and increases tLESR frequency during gastric distention with gas.56,57 Hiatal hernias serve as a persistent vestibule for gastric acid (the so-called acid pocket). Therefore, there is an increased tendency for reflux to occur from the hernia sac during swallow-induced LESRs and tLESRs. Hiatal hernias that are large (≥3 cm) and nonreducible (hernias in which the gastric rugal folds remain above the diaphragm between swallows) are especially prone to reflux.58 Finally, increased EGJ compliance, especially in GERD patients with hiatal hernia, has been identified.51 For the same degree of intragastric pressure, the esophageal junction opens at a lower pressure and the cross-sectional area is greater and more symmetrical as intragastric pressure increases. The etiology of a hiatal hernia remains unclear. Familial clustering of GERD suggests the possibilities of an inherited smooth muscle disorder.27 Animal studies propose that reflux itself causes esophageal shortening, promoting the development of a hiatal hernia.59 Other studies find an association with obesity60 and heavy lifting,61 raising the possibilities that over time, chronic intra-abdominal stressors may weaken the esophageal hiatus, causing the development of a hiatal hernia. This theory is attractive because it helps to reconcile the increased prevalence of hiatal hernias as the population grows older.53

The Acid Pocket Gastric pH is usually around 2 in the fasting state. During meals, and for approximately 90 minutes thereafter, the pH remains

CHAPTER 46  Gastroesophageal Reflux Disease

Weakened and shortened LES

Loss of diaphragmatic support for the LES Loss of the intraabdominal LES segment Retention of gastric fluid in hernial sac

Stretching and rupture of the phrenoesophageal ligament Widened diaphragmatic hiatus

Fig. 46.4  Schematic diagram showing the effect of a hiatal hernia on the antireflux barrier.  LES, Lower esophageal sphincter.

elevated owing to the buffering effects of the food. Herein lies a paradox because most episodes of acid reflux occur immediately after a meal. This paradox is explained by the identification of a zone in the gastric cardia that remains unbuffered, now referred to as the acid pocket.62,63 This pocket is postulated to be the source of acidic refluxate and has a pH considerably lower than the distal esophagus and remainder of the stomach after a meal. A subsequent study confirmed that this zone is poorly buffered by a meal in both normal subjects and those with symptomatic GERD.64 In GERD patients, the presence of an acid pocket is more common than in controls and is larger as a result of extension more distally from the LES.65 In GERD patients with hiatal hernia, the acid pocket is further enlarged because of the proximal migration of the LES. In addition, when the acid pocket is located about the diaphragm, especially in a hiatal hernia, more than 70% of the tLESRs were accompanied by acid reflux. In contrast, less than 20% of tLESRs were accompanied by acid reflux when the acid pocket was below the diaphragm.58 

Esophageal Acid Clearance The second tier of protection against reflux damage is esophageal acid clearance. This phenomenon involves 2 related but separate processes: volume or bolus clearance, which is the actual removal of the reflux material from the esophagus, and acid clearance, which is the restoration of normal esophageal pH following acid exposure through titration with base from saliva and esophageal gland secretions. Although the competency of the antireflux barrier determines the frequency and volume of GER, esophageal acid clearance determines the duration of acid exposure to the mucosa and probably the severity of mucosal damage.

Volume Clearance Esophageal peristalsis clears acid volume in the upright and supine positions but is inoperative during deep rapid eye movement sleep. Helm and colleagues66 showed that 1 or 2 primary

675

peristaltic contractions completely clear a 15-mL fluid bolus from the esophagus. Primary peristalsis is elicited by swallowing. Secondary peristalsis, initiated by esophageal distention from acid reflux, is much less effective in clearing the refluxate, thus offering only an ancillary protective role. Peristaltic dysfunction (i.e., failed peristaltic contractions, hypotensive or weak [5 mm confined to folds but not continuous between the tops of mucosal folds

Grade C

Mucosal breaks continuous between tops of 2 or more mucosal folds but not circumferential

Grade D

Circumferential mucosal break

esophagitis, biopsies are usually not taken except to exclude neoplasm, infection, or bullous skin disease. Therefore, the current primary indication for esophageal biopsies are to define Barrett’s epithelium and exclude EoE.160 When Barrett’s is suspected, biopsies are mandatory and best done when esophagitis is healed (see Chapter 47). 

Esophageal Reflux Testing Esophageal reflux monitoring has undergone substantial changes in the past 10 years.145 Wireless pH capsules and the ability to measure all forms of reflux, both acid and nonacid are important

Fig. 46.8  Histopathology of GERD.  Inflammatory cells (eosinophils and neutrophils) are interspersed between squamous epithelial cells. (Courtesy Edward Lee, MD, Washington, DC.)

advances in the field of reflux testing. Ambulatory intraesophageal pH monitoring is still the standard for establishing pathologic acid reflux.145,161,162 For catheter-based pH testing, the

682

PART V  Esophagus

pH 8.0 Esophagus 6.0 4.0 2.0 0.0 Day 1

8 AM

Day 2

Regurgitation

8 AM

Z1

Impedance (ohms)

Z2

Z3 Z4 Z5 Z6

pH 4 pH drops below 4.0

A

Time

pH remains above 4.0

B

probe is passed nasally, positioned 5 cm above the manometrically determined LES, and connected to a battery-powered data logger capable of collecting pH values every 4 to 6 seconds. An event marker is activated by the patient when symptoms, meals, and body position changes occur. Patients are encouraged to eat normally and engage in regular daily activities, with monitoring carried out for 18 to 24 hours. Reflux episodes are defined by a pH drop of less than 4. Conventionally measured parameters include percent of total time when pH is less than 4, percentage of time upright and supine when pH is less than 4, total number of reflux episodes, duration of longest reflux episode, and number of episodes greater than 5 minutes. The percentage of total time pH is less than 4 is the most reproducible measurement for GERD, with reported upper limits of normal ranging from 4% to 5.5%.161 Ambulatory pH testing discerns positional variations in GER, meal- and sleep-related episodes, and helps relate symptoms to reflux events. The first of the 3 new technology advancements in reflux testing was the catheter-free system (Fig. 46.9, upper panel).163 This system uses a wireless pH capsule that is affixed to the esophageal mucosa with a delivery system that drives a small needle into the epithelium. The capsule then transmits pH data to a portable receiver using radiofrequency signals. Catheter-free testing is now the preferred method of pH testing because monitoring can be extended beyond 24 hours (usually 48 hours), and limitations on normal daily activities and meals are negligible.164 Because the

Time

8 AM Fig. 46.9  Tracings from 48-hour esophageal pH and multichannel impedance-pH studies. Top panel is a 48-hour pH capsule study in a patient with GERD. Meals/drinks are shown by the yellow lines, supine periods are shown in blue. The orange bars represent symptoms that were associated with acid reflux. The bottom panels are examples of acid and nonacid reflux detected by multichannel impedance-pH monitoring. A, Acid reflux, with a typical pattern of sequential impedance drops in a retrograde direction, reaching the third impedance-measuring segment (Z3) and associated with an esophageal pH fall to less than 4.0. B, Nonacid reflux in a patient on a PPI who reports an episode of regurgitation during this reflux episode, with a typical impedance pattern of retrograde flow reaching Z1 and despite esophageal pH remaining above 4.

capsule only accurately measures acid reflux (pH < 4), all studies must be performed off PPIs for at least 7 days.165 The second technology improvement combines impedance with pH testing, allowing the measurement of acid and nonacid reflux (see Fig. 46.9, lower panel). The latter is particularly important for patients on PPIs who continue to reflux, but now most episodes have pH higher than 4.160 Nonacid reflux is measured by the detection of a retrograde bolus of ion-rich fluid in the esophagus. Refluxates that are a mixture of liquid and air are also readily detected. In a large group of normal subjects off PPIs, roughly 40% of reflux episodes were either weakly acidic (pH 4 to 6.5) or alkaline (pH > 6.5).166 In a multicenter study using combined impedance-pH testing, 37% of patients experienced continued reflux symptoms despite twice-daily PPI therapy that was due to nonacid reflux.167 The most recent technologies for detecting GERD measure mucosal integrity alteration during endoscopy by detecting mucosal impedance changes or based on intraluminal impedance testing (nocturnal baseline impedance and post swallow-induced peristaltic wave index).168-171 Mucosal impedance measurement have identified patients with GERD and EoE with high degree of accuracy. It is too early to assess the clinical impact of this new technology, but the efficiency of diagnosing GERD without the need for prolonged ambulatory testing is promising. The role of nocturnal baseline impedance and post swallow-induced peristaltic wave is anticipated to be limited given need for catheter-based

CHAPTER 46  Gastroesophageal Reflux Disease

testing and complicated means of measuring both parameters. Finally, salivary pepsin testing and a catheter based transoral pH monitoring are purported to help in the diagnosis of extraesophageal reflux; however, studies on their clinical benefit have shown mixed results.145 A critical limitation of esophageal pH monitoring is that there exists no absolute threshold value that reliably identifies GERD patients. Studies comparing patients with endoscopic esophagitis who underwent pH tests report sensitivities from 77% to 100%, with specificities from 85% to 100%.145 However, esophagitis patients rarely need pH testing; rather, patients with normal endoscopy and suspected GERD might benefit most from this test. Unfortunately, data on these patients are less conclusive, with considerable overlap between controls and nonerosive refluxers.161 Other drawbacks of pH testing include possible equipment failure, pH probe missing reflux events because the probe is buried in a mucosal fold, and false-negative studies due to dietary or activity limitations from poor tolerability of the nasal probe. Ambulatory reflux pH monitoring is the only test that records and correlates symptoms with reflux episodes over extended periods of time. However, because only 10% to 20% of reflux episodes are associated with symptoms, different statistical analyses have evolved, attempting to define a significant association between symptoms and reflux episodes, including the symptom index, symptom sensitivity index, and symptom association probability.171 Unfortunately, no studies have defined the accuracy of these symptom scores in predicting response to therapy. Furthermore, validation studies were done only for heartburn, regurgitation, and chest pain with acid reflux; there were no studies with atypical reflux symptoms or nonacid reflux. More recent studies have questioned the validity of symptom association probability and have warned against its use especially in those with normal reflux parameters.172,173 Therefore, pH testing can define an association between complaints and GER, but only treatment trials address the critical clinical issue of causality. Clinical indications for ambulatory reflux monitoring are established.145 Before fundoplication, pH testing should be done in patients with normal endoscopy to ensure the presence of pathologic acid reflux. After antireflux surgery, persistent or recurrent symptoms warrant repeat pH testing. In these situations, pH monitoring is performed with the patient off antireflux medications. Esophageal reflux testing is particularly helpful in evaluating patients with GERD-like symptoms who are resistant to treatment and who have normal or equivocal endoscopic findings. However, here there is controversy whether this should be done on or off PPIs.162 For this indication, impedance-pH testing can be done on PPI therapy to define 2 populations: those with and those without continued abnormal acid or nonacid exposure times. The group with persistent GER needs intensified medical therapy, whereas patients with symptoms and good reflux control have another etiology for their complaints. The off-PPI approach is gaining popularity because 50% to 60% of patients with poorly responding symptoms and normal endoscopy do not have GERD. A negative pH test off therapy is useful because it directs the diagnostic workup toward other causes and enables cessation of unnecessary PPI therapy. However, a recent study174 found that more than 42% of patients with negative tests for acid reflux still continued PPI therapy. Finally, ambulatory pH testing may help in defining patients with extraesophageal manifestations of GERD. However, its most important utility is in ruling out reflux as the cause for patients’ persistent reflux. Initially most of these studies were done off antireflux medications to confirm the coexistence of GERD; however, this does not guarantee symptom causality. Therefore, an approach is to first treat aggressively with PPIs, reserving pH testing for those patients not responding after 4 to 12 weeks of therapy.160 

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Barium Esophagogram The barium esophagogram is an inexpensive, readily available, and noninvasive esophageal test.175 It is most useful in demonstrating anatomic narrowing of the esophagus and assessing the presence and reducibility of a hiatal hernia. Schatzki’s rings, webs, or minimally narrowed peptic strictures may only be seen with an esophagogram, being missed by endoscopy, which may not adequately distend the esophagus. Giving a 13-mm radiopaque pill or marshmallow along with the barium liquid can help to identify these subtle narrowings. The barium esophagogram allows good assessment of peristalsis and is helpful preoperatively in identifying a weak esophageal pump. The ability of barium esophagogram to detect esophagitis varies, with sensitivities of 79% to 100% for moderate to severe esophagitis, whereas mild esophagitis is usually missed. Barium testing also falls short when addressing the presence of Barrett’s esophagus. The spontaneous reflux of barium into the proximal esophagus is very specific for reflux, but it is not sensitive. Provocative maneuvers (e.g., leg lifting, coughing, Valsalva, water siphon) can elicit stress reflux and improve the sensitivity of the barium esophagogram, but some argue that these maneuvers also decrease its specificity.176 

Esophageal Manometry As with reflux testing, the advent of multichannel high-resolution manometry has revolutionized this esophageal function test.177 With 32 to 36 pressure transducers spanning the entire esophagus, manometry can now accurately assess LES pressure and relaxation, as well as peristaltic activity, including contraction amplitude, duration, and velocity. However, esophageal manometry is generally not indicated in the evaluation of the uncomplicated GERD patient, because most have a normal resting LES pressure. Esophageal manometry to document adequate esophageal peristalsis and exclude variants of achalasia and scleroderma is traditionally recommended before antireflux surgery.160 If the study identifies ineffective peristalsis (low amplitude or frequent failed peristalsis) or aperistalsis, then a complete fundoplication may be contraindicated. However, this assumption is challenged because reflux control was better, and dysphagia no more common, in patients with weak peristalsis after a complete, as opposed to a partial, fundoplication.178 An improvement of traditional manometry, combining it with impedance testing, is helping to clarify this controversy. Using this technique, a study found that less than 50% of patients with ineffective peristalsis had a significant delay in esophageal bolus transit measured by impedance.179 Therefore, potentially only these patients with a significant physiologic defect in motility will require a modified fundoplication. 

CLINICAL COURSE The clinical course of GERD depends to a great extent on whether the patient has erosive or nonerosive disease. There is controversy as to whether GERD exists as a spectrum of disease severity or as a categorical disease in 3 distinct groups: erosive, nonerosive, and Barrett’s esophagus. Patients tend not to cross over from one group to another; in follow-ups ranging from 6 months to longer than 22 years, less than 25% of patients with nonerosive disease evolved over time to having erosive esophagitis, nearly all to LA grade A/B disease, or to having complications of GERD.180,181

Nonerosive Disease Early studies from tertiary referral centers suggested that the majority of GERD patients had esophagitis.182 However, recent data suggest that up to 70% of GERD patients have a normal

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Fig. 46.10  Classic peptic esophageal stricture demonstrated by barium esophagogram (A) and endoscopy (B). The film shows a large hiatal hernia (HH) common to all GERD strictures. The black arrow points to a short, thick fibrous stricture associated with multiple pseudodiverticula (white arrowheads). Although not seen on barium examination, the endoscopic view also demonstrates circumferential esophagitis (Los Angeles grade D).

HH

B

A endoscopic examination.183,184 Endoscopy-negative GERD patients are more likely to be female, younger, thin, and without hiatal hernia, and they have a higher prevalence of functional GI disorders.185 Despite their mild mucosal damage, these patients demonstrate a chronic pattern of symptoms with periods of exacerbation and remission.186 Nonerosive GERD is suspected in the patient with typical reflux symptoms and a normal endoscopy and confirmed by the patient’s response to antisecretory therapy. Esophageal pH testing identifies 3 distinct subsets of nonerosive GERD patients. First are the patients with excessive acid reflux who usually respond to PPI therapy. Second are the patients with normal acid reflux parameters but a good correlation between their symptoms and acid reflux episodes. This group represents 30% to 50% of nonerosive GERD patients and, based on recent Rome IV criteria, is classified as “reflux hypersensitivity.”187 These patients probably have heightened esophageal sensitivity to acid and are less likely to respond to antireflux therapy.188 The third group is characterized by normal acid exposure times and poor symptom correlation. This group is classified as “functional heartburn.”187 

Erosive Disease Patients with erosive esophagitis tend to be male, older, and overweight and are more likely to have hiatal hernias.185 The clinical course of these patients with erosive esophagitis is more predictable and associated with complications of GERD. Longitudinal studies have shown that up to 85% of patients with erosive GERD and given no maintenance reflux therapy will relapse within 6 months of stopping PPI therapy; the relapse rate is highest in patients with more severe grades of esophagitis (see Table 46.2).189,190 Several studies confirm that erosive esophagitis patients are prone to reflux complications, including ulcers, strictures, and Barrett’s esophagus. In a Finnish study, 20 patients with erosive GERD treated with lifestyle changes, antacids, and prokinetic drugs were followed for a median of 19 years. Fourteen patients continued to have erosions, and 6 new cases of Barrett’s esophagus were detected.180 In another more recent European study,181 patients with LA grade C/D esophagitis developed Barrett’s esophagus over 2 years at a rate of 5.8%, compared with only 1.4% for LA grade A/B and 0.5% for nonerosive GERD. 

COMPLICATIONS Hemorrhage, Ulcers, and Perforation GERD-related noncancer deaths are rare (0.46 per 100,000 persons). The most common fatal causes are hemorrhagic esophagitis, aspiration pneumonia, ulcer perforation, and rupture with severe esophagitis.191 Major hemorrhage and esophageal perforation are usually associated with deep esophageal ulcers or severe esophagitis.192 Esophageal perforations are very rare in the PPI era but can result in mediastinitis and death. Clinically important hemorrhage has been reported in 7% to 18% of GERD patients,193 and may result in iron deficiency anemia. 

Peptic Esophageal Strictures Strictures occur in 7% to 23% of patients with untreated reflux esophagitis. They are commonly seen in older men194 and linked to chronic NSAID use.195 Stricture formation is complex, starting as reversible inflammation with edema, cellular infiltration, and vascular congestion, progressing to collagen deposition, and ending in irreversible fibrosis. As dysphagia progresses, heartburn often decreases, reflecting the stricture acting as a barrier to further reflux. Dysphagia is usually limited to solids. Unlike malignant strictures, patients with peptic strictures have a good appetite, alter their diet, and lose little weight. Peptic strictures are smooth-walled, tapered, circumferential narrowings in the lower esophagus, usually less than 1 cm long but occasionally extend to 8 cm (Fig. 46.10). In these unusual cases, the clinician should suspect a predisposing condition, such as ZES, pill esophagitis, or prolonged NG intubation.194 A mid- to upper esophageal stricture should raise concern for Barrett’s esophagus or malignancy. Although once controversial, today a Schatzki’s ring is considered a forme fruste of an early peptic stricture.196 All stricture patients should undergo endoscopy to confirm the benign nature of the lesion and take biopsies to exclude EoE, cancer, and Barrett’s esophagus. 

Barrett’s Esophagus See Chapter 47. 

CHAPTER 46  Gastroesophageal Reflux Disease

TREATMENT OF UNCOMPLICATED DISEASE The rationale for GERD therapy depends on a careful definition of specific aims.197 In patients without esophagitis, the therapeutic goals are to relieve reflux symptoms and prevent frequent symptomatic relapses. In patients with esophagitis, the goals are to relieve symptoms and heal esophagitis while preventing further relapses and complications.

Nonprescription Therapies Although GERD is common, many sufferers do not seek medical care, instead choosing to change their lifestyles and self-medicate with over-the-counter (OTC) antacid preparations. These observations have led to the “iceberg” model of the GERD population. The vast majority of heartburn suffers are invisible because they self-medicate and do not seek professional help; only those at the tip of the iceberg, typically patients with severe symptoms or reflux complications, are seen by physicians.21

Lifestyle Modifications Selective lifestyle changes, carefully explained to the patient, should be part of the initial management plan and are especially helpful in those with mild, intermittent complaints. These include elevating the head of the bed, losing weight if overweight, restricting alcohol and smoking, making dietary changes, refraining from lying down after meals, and avoiding bedtime snacks. Physiologic studies show that these maneuvers enhance esophageal acid clearance, decrease acid reflux–related events, or ease heartburn symptoms.198 Head-of-the-bed elevation can be done by using 6- to 8-inch blocks or a foam wedge under the mattress to elevate the upper torso. Eating several hours before retiring and avoiding bedtime snacks keeps the stomach empty at night, thereby decreasing nocturnal reflux episodes. Losing weight aims to reduce the incidence of reflux by the “abdominal stress” mechanism. Targeted weight loss may be helpful, whereas discrete periods of weight gain can be associated with exacerbation of reflux symptoms.199 Cessation of smoking and alcohol reduction is valuable because both agents lower LES pressure, reduce acid clearance, and impair intrinsic squamous epithelial protective functions.21,73 Reducing meal size and avoiding fats, carminatives, and chocolate reduces reflux frequency by decreasing episodes of tLESRs, as well as lowering LES pressure.21 In addition, some patients complain of heartburn after citrus drinks, spicy foods, tomato-based products, coffee, tea, or cola drinks. Stimulation of gastric acid secretion or esophageal sensitivity to low pH (or perhaps hyperosmolar solutions) may account for these symptoms.200 However, indiscriminate food prohibition should be avoided but rather tailored to individual sensitivity to better promote compliance. Finally, patients should avoid, if possible, drugs that lower LES pressure (see Table 46.1) or promote localized esophagitis, such as certain bisphosphonates (see Chapter 45). How good are the clinical studies assessing the efficacy of lifestyle changes? In an evidence-based review,21 studies of smoking, alcohol, chocolate, fatty foods, and citrus products had sound physiologic data that their intake can adversely affect symptoms or promote reflux on esophageal pH tests. However, there was little convincing evidence that cessation of these products predictably improved reflux symptoms. Only elevation of the head of the bed, left lateral decubitus positioning, and weight loss were associated with GERD improvement in case-controlled studies.21 

Over-the-Counter Medications These drugs are used in treating mild, infrequent heartburn symptoms triggered by lifestyle indiscretions. Antacids increase LES pressure but work primarily by buffering gastric acid, albeit

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for short periods. Heartburn symptoms are rapidly relieved, but patients may need to take antacids frequently, usually 1 to 3 hours after meals. Gaviscon, containing alginic acid and antacids, mixes with saliva to form a highly viscous solution that floats on the gastric pool, acting as a mechanical barrier. Recent studies found that the raft colocalized with the postprandial acid pocket and displaced it below the diaphragm, resulting in significant suppression of postprandial acid reflux.201 A meta-analysis of OTC medications found that compared with placebo, antacids showed minimal symptomatic improvement (absolute benefit of 8%, number to treat [NNT] of 13), whereas Gaviscon was better (absolute benefit of 26%, NNT of 4).202 However, these therapies do not heal esophagitis, and long-term trials suggest symptom relief in only 20% of patients.203,204 OTC H2RAs are available at doses usually one half the standard prescription dose. Although onset of relief is not as rapid as with antacids, the OTC H2RAs relieve symptoms for 6 to 10 hours. Based on a meta-analysis of 3 studies, H2RAs given before a provocative meal were superior to placebo (absolute benefit of 11% to 16%, NNT of 9 to 6) in symptom relief/improvement.202 Therefore, they are particularly useful when taken before potentially refluxogenic activities. Like antacids, OTC H2RAs are ineffective in healing esophagitis.205 The long-term safety and efficacy of PPIs led the FDA to approve omeprazole at full dose (20 mg) for OTC use in 2003. Drug labeling suggested daily use for only 2 weeks and recommended physician follow-up for persistent symptoms. Despite initial “real world” concerns of abusing this drug, early actualuse data support that consumers accurately self-select if OTC omeprazole is appropriate for use, comply with a 2-week regimen, and seek physician care for longer-term management of frequent heartburn.206 

Prescription Medications Patients with frequent heartburn, esophagitis, or complications usually see a physician and receive prescription medications. Prokinetic drugs attempt to correct the GERD-related motility disorders associated with GERD. However, the most clinically effective drugs for short- and long-term reflux treatment are acid suppressive drugs.

Prokinetic Drugs Until recently, 3 prokinetic drugs were available in the US for treating GERD: bethanechol, a cholinergic agonist; metoclopramide, a dopamine antagonist; and cisapride, a serotonin (5-hydroxytryptamine 4) receptor agonist that increases acetylcholine release in the myenteric plexus. These drugs improve reflux symptoms by increasing LES pressure, acid clearance, or gastric emptying. However, none alters tLESRs, and their effectiveness decreases with disease severity.207 Current prokinetics provide modest benefit in controlling heartburn, particularly in patients with delayed gastric emptying, but have unreliable efficacy in healing esophagitis unless combined with acid-inhibiting drugs.207 The current use of prokinetic drugs are greatly limited by their side-effect profile. Bethanechol commonly causes flushing, blurred vision, headaches, abdominal cramps, and urinary frequency. Metoclopramide, which crosses the blood-brain barrier, has a 20% to 50% incidence of fatigue, lethargy, anxiety, and restlessness and rarely causes tremor, parkinsonism, dystonia, or tardive dyskinesia, especially in older patients. Side effects may be decreased by reducing the dosing regimen to twice a day, taking a larger single dose before dinner or at bedtime, or using a sustained-release tablet. Domperidone, another dopamine antagonist not crossing the blood-brain barrier, has fewer side effects, primarily hyperprolactinemia and nipple tenderness/discharge.

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100

(3)

(17) (13)

60

(12)

PPI (10) (10)

40 (3)

H2RA

80 Percentage of patients healed

Patients free of heartburn (%)

80

(2) (26)

(27) (4)

(23)

40 (2)

0

(25) (25) (9)

H2RA (5)

20

20

(22)

PPI

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(5)

(8) Placebo

0 0

1–2

A

3–4

0

6–8

Weeks

B

2

4

6

8

12

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Fig. 46.11 A, Symptom relief time curve over 8 weeks for a PPI or H2RA corrected for patients free of heartburn at baseline. More patients treated with a PPI for 2 weeks were asymptomatic as compared with those treated with an H2RA, even after a much longer duration of treatment with the H2RA. B, Esophagitis healing time curve for PPI, H2RA, and placebo over 12 weeks. Treatment with a PPI for 4 weeks healed esophagitis in more patients than in the other 2 groups over 12 weeks, implying a substantial therapeutic gain. The numbers of studies included for each time point and treatment are shown in parentheses. (Data based on meta-analysis from Chiba N, Gara CJ, Wilkinson JM, Hunt RH. Speed of healing and symptom relief in grade II to IV gastroesophageal reflux disease: A meta-analysis. Gastroenterology 1997; 112:1798-810.)  

It is not approved for GERD use in the US but is readily available from Canada or compounding pharmacies. Cisapride was the best prokinetic drug for treating GERD but was withdrawn from the U.S. market in 2000 because of reports of serious cardiac dysrhythmias (ventricular tachycardia, ventricular fibrillation, torsades de pointes, and QT prolongation), with associated cardiac arrest and deaths related to possible drug interactions.208 European investigators are rejuvenating interest in prokinetic drugs for GERD with studies on macrolides such as azithromycin. This class of drugs increases gastric emptying, increases LES and proximal stomach tone, and, among patients with a small hiatus hernia, displaces the acid pocket below the diaphragm.209 Small clinical studies found azithromycin decreased acid reflux episodes and total acid exposure in GERD patients with hiatal hernia209 and lung transplant patients.210 

Transient Lower Esophageal Sphincter Relaxation Inhibitors Regulating the frequency of tLESRs is an attractive target for GERD treatment because of its pivotal role in all types of reflux episodes. Currently, the only medication available that decreases tLESRs is baclofen, a GABAB agonist used for many years to treat spasticity. Baclofen (5 to 20 mg 3 times daily) significantly reduces tLESRs, decreases both acid and duodenal reflux, and improves symptoms in GERD patients treated for 4 weeks to several months.211,212 The critical issue with baclofen is tolerability. Side effects including drowsiness, dizziness, nausea, and vomiting require discontinuation in up to 20% of patients.211 Other GABAB agonists with improved tolerability have been developed (lesogaberan, arbaclofen placarbil) but were abandoned mainly because of limited clinical efficacy. For example, lesogaberan as add-on therapy to PPIs in patients with refractory GERD symptoms resulted in a low, although significant, 16% remission

rate compared with 8% remission for PPIs alone.213 Among 150 patients with frequent heartburn and/or regurgitation, arbaclofen placarbil (20, 40, 60 mg twice daily) was no better than placebo over 4 weeks in reducing heartburn events.214 Finally, a negative allosteric modulator of mGluR5 receptor (ADX 10059) as monotherapy was shown to improve reflux symptoms and decrease reflux events but failed to demonstrate significant clinical efficacy in refractory GERD patients; further development of this component has been halted.215 

H2RAs These drugs (cimetidine, ranitidine, famotidine, and nizatidine) are more effective in controlling nocturnal than meal-stimulated acid secretion.216 The 4 H2RAs are equally effective when used in proper doses, usually twice a day before meals. GERD trials find that heartburn can be significantly decreased by H2RAs, when compared with placebo, although symptoms are rarely abolished. A comprehensive meta-analysis found that the overall esophagitis healing rates with H2RAs rarely exceeded 60% after up to 12 weeks of treatment, even when higher doses were used (Fig. 46.11B).217 Healing rates differ in individual trials, depending primarily on the severity of esophagitis being treated: grades I and II esophagitis heal in 60% to 90% of patients, whereas grades III and IV heal in only 30% to 50% despite high-dose regimens.217 Although PPIs are more effective than H2RAs, nocturnal gastric acid breakthrough while on PPI therapy may cause reflux symptoms in some patients. H2RAs given at bedtime successfully eliminated this problem in a study, suggesting a new indication for H2RAs in the PPI era.218 However, this study used only a single evening dose and did not account for the tolerance that frequently develops to H2RAs over weeks to months.219 This tolerance impairs the effectiveness of chronic nocturnal dosing of H2RAs to eliminate nocturnal acid breakthrough,220

CHAPTER 46  Gastroesophageal Reflux Disease

but suggests a useful role in as-needed medications in situations in which lifestyle indiscretions may promote nocturnal complaints. The H2RAs are very safe, with a side effect rate of about 4%, most of which are minor and reversible.216 Serum concentrations of phenytoin, procainamide, theophylline, and warfarin are higher after the administration of cimetidine and, to a lesser degree, ranitidine, whereas these interactions are not reported with the other 2 H2RAs. H2RAs do not inhibit the antiplatelet effect of clopidogrel. 

PPIs PPIs inhibit meal-stimulated and nocturnal acid secretion to a significantly greater degree than H2RAs221 but rarely render patients achlorhydric. After oral ingestion, acid inhibition is delayed because PPIs need to accumulate in the parietal cell secretory canaliculus to bind irreversibly to actively secreting proton pumps.222 Therefore, the slower a PPI is cleared from plasma, the more it is available for delivery to the proton pumps. PPIs should be taken before the first meal of the day, when most proton pumps become active. Because not all pumps are active at any given time, a single PPI dose will not inhibit all pumps. A second dose, if necessary, can be taken before the evening meal; however, this is an off-label indication. PPIs do not “cure” reflux disease, rather they treat GERD in an indirect way by decreasing the number of acid reflux episodes. In exchange, the weakly acidic (pH > 4) episodes are increased, while the total number of reflux episodes and proximal extent are not affected by PPI therapy.164 PPIs (omeprazole, lansoprazole, rabeprazole, pantoprazole, and esomeprazole) have superior efficacy compared with H2RAs on the basis of their ability to maintain an intragastric pH greater than 4 from 10 to 14 hours daily compared with approximately 6 to 8 hours daily with the H2RAs.222,223 PPIs are superior to H2RAs in completely relieving heartburn symptoms in patients with severe GERD, usually within 1 to 2 weeks (see Fig. 43.11A).217 PPI therapy has been shown in a Cochrane meta-analysis to be superior to placebo and H2RAs in nonerosive GERD and for undiagnosed reflux symptoms in primary care, although the effect is 20% to 30% lower than in patients with esophagitis.224,225 Unlike heartburn, the GERD symptom of regurgitation does not have a robust response to PPIs. In a recent review of 7 placebo-controlled trials, the therapeutic gain for regurgitation averaged only 17% relative to placebo and was at least 20% less than that observed for heartburn.226 Controlled studies and a large meta-analysis report complete healing of even severe ulcerative esophagitis after 8 weeks in more than 80% of patients taking PPIs, compared with 51% on H2RAs and 28% receiving placebo (see Fig. 43.11B).217,227–229 In another recent Cochrane review,230 PPIs were superior to H2RAs in healing esophagitis at 4 to 8 weeks (risk ratio, 0.47), with an NNT of 3. In patients not healing initially, prolonged therapy with the same dose or an increased PPI dose usually resulted in 100% healing.231 Until recently, therapeutic efficacy among PPIs was similar. However, large studies have found esomeprazole 40 mg superior to omeprazole 20 mg and to lansoprazole 30 mg in healing esophagitis.232,233 A meta-analysis of 10 randomized clinical trials234 comparing esomeprazole to all other PPIs found the therapeutic advantage is minimal with LA grade A/B esophagitis (NNT of 50 and 33, respectively) and greater with severe LA grade C/D esophagitis (NNT of 14 and 8, respectively). This superiority is related to higher systemic bioavailability and less interpatient variability with esomeprazole. Despite their frequent use twice daily in treating GERD, only a recent Japanese study235 documents the superiority of off-label dosing of twice-daily PPIs for healing esophagitis over 8 weeks compared with oncedaily dosing. Healing rates were similar for rabeprazole 20 mg twice daily (77%) and 10 mg twice daily (78%) and significantly

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superior to rabeprazole 20 mg each morning (59%). Several PPIs are available in the US for IV use.236 Recent approaches to enhance acid suppression with PPIs include immediate-release omeprazole and dexlansoprazole. The former contains non–enteric coated omeprazole and an antacid that protects the omeprazole from acid degradation in the stomach and allows for rapid absorption. Immediate-relief omeprazole can be dosed on an empty stomach at bedtime and provides more rapid control of nighttime gastric pH and nocturnal acid breakthrough than esomeprazole or lansoprazole.237 Dexlansoprazole MR is the R-enantiomer of lansoprazole, with 2 distinct drug release periods (90 minutes and 4 to 5 hours after ingestion) that prolong the plasma concentration-time profile, thus extending the duration of acid suppression. Precise meal time may not be required for optimal efficacy.238,239 In a recent placebo-controlled study among 178 patients receiving twice-daily PPIs, stepping down to once-daily dexlansoprazole 30 mg, maintained excellent symptom relief over 6 weeks in 88% of patients.240 PPIs are well tolerated, with headaches and diarrhea being the most common side effects. Fasting serum gastrin levels increase with all the PPIs, but the elevations generally do not exceed the normal range and return to baseline values within 1 to 4 weeks of drug discontinuation. Omeprazole decreases the clearance of diazepam, warfarin, and clopidogrel owing to competition for the cytochrome P450 isoenzyme P2C19.241 

Maintenance Therapies GERD may be a chronic relapsing disease, especially in patients with low LES pressure, severe grades of esophagitis, and difficultto-manage symptoms.204 After esophagitis is healed, recurrence within 6 months of stopping medication occurs in more than 80% of patients with severe esophagitis and in 15% to 30% of those with milder esophagitis.189,242 Cochrane reviews have identified the superiority of PPIs over H2RAs in maintaining the remission of esophagitis over 6 to 12 months.243 Among 10 randomized trials, the relapse rate for esophagitis was 22% on PPIs versus 58% with H2RAs (NNT of 2.5). The FDA has approved all the PPIs, sometimes at one half the acute dose, for maintenance therapy, but only ranitidine 150 mg twice a day among the H2RAs has maintenance indications for mild esophagitis. Many clinicians now place their patients with severe disease (daily symptoms, severe esophagitis, or complications) on chronic PPI therapy indefinitely. The efficacy of this approach is supported by open, compassionate-use data, primarily from the Netherlands and Australia.244 In a study of 230 patients with severe esophagitis healed with 40 mg omeprazole, all subjects remained in remission for up to 11 years on maintenance omeprazole. More than 60% were maintained on omeprazole 20 mg a day, whereas higher doses of 60 mg or more were necessary in only 12% of patients, confirming a lack of tolerance to PPIs. Relapses were rare (1 per 9.4 years of follow-up), strictures did not occur, and Barrett’s esophagus did not progress. Although PPIs offer the best symptom relief and esophagitis healing, many patients do well long term on lower-dose treatments after having their complaints initially alleviated with PPIs. Using this “step-down approach,” a Veterans Affairs study reported that 58% of 71 patients on chronic PPIs could be switched to H2RAs and/or prokinetics or taken off medication completely.245 Younger age and severe heartburn symptoms predicted a PPI requirement. Overall, this approach saved money for the health care system. A similar study by the same investigators found that 80% of patients using multiple-dose PPIs could be stepped down to single-dose PPI, remaining symptom free for 6 months with considerable cost savings.246 Hence, the adage “once on a PPI, always on a PPI” is not true. Patients who continue to have symptoms despite PPI therapy likely have other etiologies for their symptoms than GERD.247 

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PART V  Esophagus

Safety of PPI Therapy As a class, PPIs are very safe drugs. Owing to their efficacy and safety, the worldwide sales of PPIs approached 14 billion dollars in 2009.1 The initial concerns about the development of gastric carcinoid tumors and colon cancer has not been confirmed.248,249 More recently, the literature has been overwhelmed with reports raising concerns about potential adverse events from long-term acid suppression.250 In the US, such reports have led the FDA to issue a number of broad-based product warnings (“black box warnings”) including all the available PPIs, either prescription or OTC. However, these studies are all from retrospective carecontrol studies and demonstrate association, not causality.250 No prospective, observational, or randomized trial can substantiate the concerns discussed as follows. Fundic gland polyps are the most common gastric polyp found at endoscopy. Their association with chronic PPI use has been a topic of debate since these drugs were first described. A recent study evaluated 599 patients, of whom 322 used PPIs and 107 had fundic gland polyps.251 Long-term PPI use was associated with up to a 4-fold increase in the risk of fundic gland polyps. Low-grade dysplasia was found in one fundic gland polyp. These polyps arise because of parietal cell hyperplasia and parietal cell protrusions resulting from acid suppression. Recent studies confirm that chronic acid suppression may be associated with an increased risk of community-acquired pneumonias and enteric infections. In a large Scandinavian population-based study,252 the adjusted relative risk for pneumonia among current PPI users, compared with those who stopped using PPIs, was 1.89. Current users of H2RAs had a 1.63-fold increased risk of pneumonia compared with those who stopped. A significant positive dose-response relationship was observed in the PPI users. Likewise, systematic reviews and meta-analyses found an increased risk of enteric infections (Salmonella, Campylobacter, and Clostridioides difficile) and of spontaneous bacterial peritonitis253,254 with acid suppression. The relationship with community- and hospital-acquired C. difficile interaction is particularly alarming, with PPI use beginning to approach antibiotics as a risk factor for this infection. Chronic use of PPIs is purported to affect the absorption of calcium, vitamin B12, magnesium, and iron. A nested case-controlled study from the United Kingdom among 13,556 patients found that the risk of hip fractures increased with chronic PPI use over 1 year (adjusted odds ratio, 1.44), especially patients receiving high-dose PPIs (adjusted odds ratio, 2.65). A smaller but still significant risk was observed in chronic H2RA users.255 A large Canadian study256 reached similar conclusions but found the risk for hip fractures became apparent only after 5 years of treatment (adjusted odds ratio, 1.62) and after 7 years for all osteoporotic fractures (adjusted odds ratio, 1.92). However, more recent cross-sectional, longitudinal, and prospective studies (even done by the same Canadian center257) do not support these earlier observations, suggesting issues of undetected biases and future need for randomized studies to address this issue.250,258 It has been suggested that if PPIs cause osteoporosis, they may interfere with insoluble calcium absorption or possibly inhibit the osteoclastic proton transport system, potentially reducing bone resorption. PPIs could retard the absorption of vitamin B12 by decreasing gastric acidity, reducing the release of cobalamin from dietary protein, or by promoting SIBO, thereby increasing luminal cobalamin consumption. However, cohort and case-control studies have not shown a convincing link between PPI use and vitamin B12 deficiency.250 Most recently a series of case reports (C12) exposed to the mucosa of the duodenum result in release of CCK. CCK relaxes fundic tone, decreases antral contraction, and increases pyloric tone, all of which result in delay in gastric emptying. In contrast, short- and medium-chain fatty acids ( protein > carbohydrate

Delay

Tryptophan

Delay

Undigestible fibers

Delay

Fatty acids in ileum

0.0

2.5

Hyperglycemia

Delay

Hypoglycemia

Acceleration

Illusory self-motion (vection)

Delay

Sensations of fullness continue during the lag phase when the food is being triturated. Once the linear phase of gastric emptying begins, there is a progressive perception of decreasing stomach fullness and increasing stomach emptiness over time. Four or 5 hours after a solid meal, the stomach is indeed empty and the healthy individual feels hungry once again. The physiologic mechanisms of hunger and satiety (and stomach emptiness and fullness) are under intense investigation. In the fasting state plasma motilin levels increase during the phase 3 of the MMC, but correlations between the sensation of hunger and increases of motilin or onset of phase 3 have not been described. As discussed in Chapters 4 and 7, ghrelin is a 28–amino acid peptide secreted from endocrine cells of the oxyntic glands in the gastric fundus.86 Ghrelin levels also increase in the plasma during fasting (hunger) and stimulate food intake, probably acting via vagal afferent nerves.87 Orexins or appetite-stimulating peptides are synthesized by neurons in the lateral hypothalamus, promote food intake, and stimulate gastric contractility (in the rat) by actions on the dorsal motor nucleus of the vagus with projections to the gastric fundus and corpus.88 After ingestion of food, ghrelin levels decrease89 and are profoundly suppressed after gastric bypass surgery.90 Ghrelin also has promotility effects on the stomach and is being evaluated for the treatment of gastroparesis.91,92 Other hormones are candidates for important roles in the sensation of fullness or satiety, and these hormones are released after the ingestion of meals. CCK is released from the duodenal mucosa exposed to fatty acids. CCK receptors participate in fullness and nausea sensations elicited by intraduodenal lipid and gastric distention.93,94 Leptin is synthesized in the stomach and released after food ingestion; circulating leptin reduces food intake via CNS regulation of the arcuate nucleus.95 Glucagon-like polypeptide-1 enhances fullness after a standard meal, reduces

10.0

7.5

10.0

Distal 0.0

B Delay

7.5

Middle

Delay (“ileal brake”)

Other

5.0 Time (min)

Proximal

Delay (“duodenal tasting,” “duodenal brake”)

Colonic Constipation, IBS

Distal

A

Meal Related Volume

Small Intestinal Fatty acids in duodenum

50

Proximal

2.5

5.0 Time (min)

Fig. 50.16  Electrical recordings from electrodes secured to the mucosa of the proximal, middle, and distal antrum in a healthy subject. A, 3-cycle-per minute (cpm) electrical slow waves in the proximal, middle, and distal electrode leads. The slow waves are propagated in an aborad direction as indicated by the dotted lines. B, Disruption of propagation and the onset of a 5- to 6-cpm tachygastria in the distal lead during hyperglycemia (glucose clamping), with a blood glucose level of 240 mg/dL. (Modified from Coleski R, Hasler WL. Coupling and propagation of normal dysrhythmic gastric slow waves during acute hyperglycemia in healthy humans. Neurogastroenterol Motil 2009; 21:492-99.)

antral motility, and increases gastric volume.59,96 Apolipoprotein A-IV is released from the small intestine during absorption of TGs and decreases food intake and gastric motility, in part, via CCK and vagal afferent pathways.97 Polypeptide-YY is released from the ileocolonic area after meals and is an important mediator of the “ileal brake” effect98 and appetite suppression.99,100 The brain and these gut hormones are clearly linked in the regulation of food intake and the regulation of gastric neuromuscular activity that produces stomach emptying.59,100 The cephalic phase of gastric physiology is well known but has not been reexplored for many years. The sight, smell, and taste of food stimulate central vagal efferent activity that increases gastric acid secretion, gastric contractility, and increases 3-cpm GMA.100-102 Sham feeding, during which the subject chews and spits out the test meal rather than swallowing it, elicits the cephalic-vagal reflex. Sham feeding a warm hot dog on a bun elicits enhanced 3-cpm activity on the EGG, whereas sham feeding a cold tofu dog, a food that the subjects considered disgusting, resulted in blunted or no increase in the 3-cpm myoelectrical activity (Fig. 50.18).103 Thus, sensory and emotional attributes of food during the cephalic phase of ingestive behavior also affect the neuromuscular activity of the stomach. 

DEVELOPMENTAL ASPECTS OF GASTRIC NEUROMUSCULAR FUNCTION Gastric peristalsis appears between 14 and 23 weeks of gestation. Grouped or clustered peristaltic waves are evident by 24

748

PART VI  Stomach and Duodenum CNS perceptions Discomfort, nausea, pain

Visceral perceptions Discomfort, nausea, pain

Dorsal column

Dorsal root ganglion A-delta fiber

Spinothalamic tract

C fiber

To CNS

IML

Motor n.

Somatic nerves

Vagus nerve

Splanchnic nerves SPINAL CORD

Somatic perceptions Discomfort, pain

SKIN

Celiac ganglia C fiber A-delta fiber Afferent n.

Vertebral ganglia T5-T9 Visceral and motor reflexes

A-delta fiber C fiber Pacemaker region

Efferent n.

Afferent n. Efferent n. Gastric dysrhythmias Bradygastria Tachygastria

STOMACH

60 sec

Fig. 50.17  Afferent and efferent neural connections between the stomach and CNS. The vagus nerve contains afferent nerves with A-delta and C pain fibers with cell bodies in the nodose ganglia and connections to the nucleus tractus solitarius (not shown). Low-threshold mechanoreceptors and chemoreceptors stimulate visceral sensations such as gastric emptiness or fullness and symptoms such as nausea and discomfort. These stimuli are mediated through vagal pathways and become conscious perceptions of visceral sensations if sensory inputs reach the cortex. The splanchnic nerves also contain afferent nerves with A-delta and C fibers that synapse in the celiac ganglia with some cell bodies in the vertebral ganglia (T5-T9). Interneurons in the white rami in the dorsal horn of the spinal cord cross to the dorsal columns and spinothalamic tracts and ascend to sensory areas of the medulla oblongata. These splanchnic afferent fibers are thought to mediate high-threshold stimuli for visceral pain. In contrast to visceral sensations, somatic nerves such as those from the skin carry sensory information via A-delta and C fibers through the dorsal root ganglia and into the dorsal horn and then through dorsal columns and spinothalamic tracts to cortical areas of somatic representation. Changes in gastric electrical rhythm, excess amplitude contractions, or stretch on the gastric wall are peripheral mechanisms that elicit changes in afferent neural activity (via vagal and/or splanchnic nerves) that may reach consciousness to be perceived as visceral perceptions (symptoms) emanating from the stomach. IML, intermediolateral nucleus; n., nerve.

weeks.104 The neuroregulatory mechanisms responsible for the coordination of antropyloroduodenal motility in gastric emptying are well developed by 30 weeks of gestation.105 EGG recordings show normal 3-cpm activity in preterm infants delivered at 35 weeks that are similar to EGG signals recorded in full-term infants.106,107 On the other hand, EGG recordings from premature infants (220 mg/dL) is associated with tachygastrias and delayed gastric emptying in healthy subjects and in patients with diabetes.63,179,180 Hyperglycemia is also associated with loss of ICCs,151 antral hypomotility,181 isolated pyloric contractions,182 gastric dysrhythmias,63,179 and impaired prokinetic action of prokinetic drugs like erythromycin.183 Relatively minor increases in the blood sugar level, even elevations within the physiologic range, delay gastric emptying in normal volunteers and diabetic patients.180 Acute hyperglycemia produced by glucose clamp methodology elicits fullness, decreased antral contractility, gastric dysrhythmias, blunts the contractile pyloric response to intraduodenal lipid infusion, and modifies upper GI sensations.63,179,180 Gastric neuromuscular abnormalities documented in patients with type 1 diabetes include abnormal intragastric distribution of food,184 reduced receptive relaxation and accommodation,185 reduced incidence of the antral component of the MMC, antral dilation, postprandial antral hypomotility,181 and electrical dysrhythmias.133,173,186 In patients with DGP, the ICCs are depleted and enteric nerve endings are abnormal,20,21 pathologic findings that help explain the mechanism of gastric dysrhythmias and poor gastric contractile responses to test meals. Loss of the antral

>5

Interstitial Celle of Cajal/HPF

4

3

2

1

0 Normal 3 cpm GMA + Normal gastric emptying

Gastric dysrhythmias + Normal gastric emptying

Gastric dysrhythmias + Gastroparesis

Normal 3 cpm GMA + Gastroparesis (obstruction)

Fig. 50.21 Schematic of relationships among ICCs, GMA, gastric emptying is shown. Normal numbers of ICCs (>5/high-power field [HPF]) are associated with normal 3-cpm GMA and normal gastric emptying. Modest depletion of ICCs (3-4 ICCs/HPF) is associated with gastric dysrhythmias and normal gastric emptying, whereas severe ICC depletion (1-2 ICCs/HPF) is associated with gastric dysrhythmias and gastroparesis. In contrast, in the obstructive gastroparesis subtype, normal 3-cpm GMA is present, and reflects normal numbers of ICCs and pyloric dysfunction.  

­

753

50

754

PART VI  Stomach and Duodenum

TABLE 50.3  Causes of Gastroparesis Diagnosis

Incidence (%)

IGP* (20% have obstructive gastroparesis)

40

Diabetic gastroparesis (type 1 and 2 diabetes mellitus) (20% have obstructive gastroparesis)

35

Postsurgical gastroparesis (antrectomy, vagotomy, fundectomy, fundoplication)

20

Ischemic gastroparesis

Arg, Q5R) mutation of the intrinsic factor in pernicious anemia and other causes of low vitamin B12. Ann Hematol 2008;87:599–600. 324. Andres E, Henoun Loukili N, Noel E, et al. Effects of oral crystalline cyanocobalamin 1000 μg/d in the treatment of pernicious anemia: an open-label, prospective study in ten patients. Curr Ther Res Clin Exp 2005;66:13–22. 325. Sasaki Y, Aihara E, Ohashi Y, et al. Stimulation by sparkling water of gastroduodenal HCO3– secretion in rats. Med Sci Monit 2009;15:BR349–56. 326. Dalenback J, Fandriks L, Olbe L, Sjövall H. The pH/PCO2 method for continuous determination of human gastric acid and

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bicarbonate secretion. A validation study. Scand J Gastroenterol 1995;30:861–71. 327. Garner A, Flemström G. Gastric HCO3– secretion in the Guinea pig. Am J Physiol 1978;234:E535–41. 328. Flemström G, Isenberg JI. Gastroduodenal mucosal alkaline secretion and mucosal protection. News Physiol Sci 2001;16:23–8. 329. Cox KH, Ir-Kirk TL, Cox JV. Variant AE2 anion exchanger transcripts accumulate in multiple cell types in the chicken gastric epithelium. J Biol Chem 1996;271:8895–902. 330. Stuarttilley A, Sardet C, Pouyssegur J, et al. Immunolocalization of anion exchanger AE2 and cation exchanger NHE-1 in distinct adjacent cells of gastric mucosa. Am J Physiol 1994;266:C559–68. 331. Wang Z, Petrovic S, Mann E, Soleimani M. Identification of an apical Cl−/HCO3− exchanger in the small intestine. Am J Physiol Gastrointest Liver Physiol 2002;282:G573–9. 332. Kraniak J, Koyanagi H, Fromm D. Do isolated gastric mucosal surface cells from rabbits secrete HCO3−. J Surg Res 1995;58:211–7. 333. De Beus AM, Fabry TL, Lacker HM. A gastric acid secretion model. Biophys J 1993;65:362–78. 334. Singh K, Nain CK, Singh V. Effect of omeprazole on gastric bicarbonate secretion in patients with duodenal ulcer. Indian J Gastroenterol 1998;17:136–7. 335. Feldman M. Gastric bicarbonate secretion in humans: effect of pentagastrin, bethanechol, and 11,16,16-trimethyl prostaglandin E2. J Clin Invest 1983;72:295–303. 336. Johansson C, Kolberg B. Stimulation by intragastrically administered E2 prostaglandins of human gastric mucus output. Eur J Clin Invest 1979;9:229–32. 337. Mertz-Nielsen A, Hillingso J, Bukhave K, Rask-Madsen J. Indomethacin decreases gastroduodenal mucosal bicarbonate secretion in humans. Scand J Gastroenterol 1995;30:1160–5. 338. Takeuchi K, Yagi K, Kato S, Ukawa H. Roles of prostaglandin Ereceptor subtypes in gastric and duodenal bicarbonate secretion in rats. Gastroenterology 1997;113:1553–9. 339. Takeuchi K, Ukawa H, Furukawa O, et al. Prostaglandin E receptor subtypes involved in stimulation of gastroduodenal bicarbonate secretion in rats and mice. J Physiol Pharmacol 1999;50:155–67. 340. Takeuchi K, Koyama M, Hayashi S, et al. Prostaglandin EP receptor subtypes involved in regulating HCO3− secretion from gastroduodenal mucosa. Curr Pharm Des 2010;16:1241–51. 341. Demitrack ES, Soleimani M, Montrose MH. Damage to the gastric epithelium activates cellular bicarbonate secretion via SLC26A9 Cl−/HCO3−. Am J Physiol Gastrointest Liver Physiol 2010;299:G255–64. 342. Cryer B, Lee E, Feldman M. Factors influencing gastroduodenal mucosal prostaglandin concentrations: roles of smoking and aging. Ann Intern Med 1992;116:636–40. 343. Feldman M, Cryer B. Effects of age on gastric alkaline and nonparietal fluid secretion in humans. Gerontology 1998;44:222–7. 344. Newton JL. Changes in upper gastrointestinal physiology with age. Mech Ageing Dev 2004;125:867–70. 345. Zolotarev VA, Andreeva YV, Vershinina E, Khropycheva RP. Interaction of constitutive nitric oxide synthases with Cyclooxygenases in regulation of bicarbonate secretion in the gastric mucosa. Bull Exp Biol Med 2017;163(1):6–9. https://doi.org/10.1007/s10517-0173724-z. Epub 2017 Jun 3. PMID: 28577107. 346. Takeuchi K, Ise F, Takahashi K, Aihara E, Hayashi S. H2S-induced HCO3− secretion in the rat stomach–involvement of nitric oxide, prostaglandins, and capsaicin-sensitive sensory neurons. Nitric Oxide 2015 30;46:157–64. https://doi.org/10.1016/j.niox.2014.11.001. Epub 2014 Nov 7. PMID: 25460323. 347. Allen A, Flemström G, Garner A, Kivilaakso E. Gastroduodenal mucosal protection. Physiol Rev 1993;73:823–57. 348. Corfield AP, Carroll D, Myerscough N, Probert CS. Mucins in the gastrointestinal tract in health and disease. Front Biosci 2001;6:D1321–57. 349. Nam SY, Kim N, Lee CS, et al. Gastric mucosal protection via enhancement of MUC5AC and MUC6 by geranylgeranylacetone. Dig Dis Sci 2005;50:2110–20. 350. Ichikawa T, Ota H, Sugiyama A, et al. Effects of a novel histamine H2-receptor antagonist, lafutidine, on the mucus barrier of human gastric mucosa. J Gastroenterol Hepatol 2007;22:1800–5. 351. Iijima K, Ichikawa T, Okada S, et al. Rebamipide, a cytoprotective drug, increases gastric mucus secretion in human: evaluations with endoscopic gastrin test. Dig Dis Sci 2009;54:1500–7.

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Gastritis and Gastropathy Mark Feldman, Pamela J. Jensen, Colin W. Howden

CHAPTER OUTLINE DEFINITIONS ��������������������������������������������������������������������� 781 ACUTE GASTRITIS������������������������������������������������������������� 781 CHRONIC GASTRITIS��������������������������������������������������������� 782 Hp Gastritis��������������������������������������������������������������������� 782 Chronic Atrophic Gastritis (Gastric Atrophy)��������������������� 788 Carditis��������������������������������������������������������������������������� 791 OTHER INFECTIOUS GASTRITIDES������������������������������������� 791 Viral ������������������������������������������������������������������������������� 791 Bacterial������������������������������������������������������������������������� 792 Fungal����������������������������������������������������������������������������� 793 Parasitic������������������������������������������������������������������������� 794 GRANULOMATOUS GASTRITIDES ������������������������������������� 794 Sarcoid��������������������������������������������������������������������������� 795 Xanthogranulomatous Gastritis��������������������������������������� 795 DISTINCTIVE GASTRITIDES����������������������������������������������� 795 Collagenous ������������������������������������������������������������������� 795 Lymphocytic������������������������������������������������������������������� 795 Eosinophilic��������������������������������������������������������������������� 796 GASTRITIS IN INFLAMMATORY BOWEL DISEASE������������� 797

DEFINITIONS Patients, clinicians, endoscopists, and pathologists often define gastritis differently. Some define it as a symptom complex, others as an abnormal endoscopic appearance of the stomach, and still others use the term to connote microscopic inflammation of the stomach, usually its mucosa. This last definition of gastritis is preferred and is used in this chapter. Other noninflammatory conditions of the stomach are referred to as gastropathies. There is a weak relationship between histologic gastritis and symptoms. In fact, many patients with gastritis are asymptomatic. The relationship between microscopic and gastroscopic abnormalities is also imprecise. In a study of 400 patients, histologic gastritis was present despite a normal gastroscopic examination in 14%; another 20% had an abnormal gastroscopic examination without gastritis.1 The latter patients (abnormal gastroscopy without gastritis) often have reactive gastropathy (discussed later). Gastric biopsies must be obtained to be able to diagnose gastritis. Potential indications for gastroscopic biopsies may include patients undergoing EGD for dyspepsia,2 patients with gastric erosion(s) or ulcer(s), thick gastric fold(s), gastric polyp(s) or mass(es), and for diagnosis of Hp infection (discussed later). Two biopsies should be taken from the antrum (lesser and greater curvatures), one from the incisura angularis, and 2 more from the gastric body (lesser and greater curvatures). The biopsy samples

Crohn Disease����������������������������������������������������������������� 797 UC����������������������������������������������������������������������������������� 797 GASTRITIS CYSTICA PROFUNDA��������������������������������������� 797 ALLERGIC GASTRITIS ������������������������������������������������������� 798 REACTIVE GASTROPATHIES����������������������������������������������� 798 Medications, Toxins, and Illicit Drugs������������������������������� 799 Bile Reflux����������������������������������������������������������������������� 799 Stress����������������������������������������������������������������������������� 799 Radiation������������������������������������������������������������������������� 800 Graft-Versus-Host Disease ��������������������������������������������� 800 Ischemia������������������������������������������������������������������������� 800 Prolapse������������������������������������������������������������������������� 800 HYPERPLASTIC GASTROPATHIES, INCLUDING MÉNÉTRIER’S DISEASE����������������������������������������������������� 800 PORTAL HYPERTENSIVE GASTROPATHY��������������������������� 801 DIFFERENTIAL DIAGNOSIS ����������������������������������������������� 802 TREATMENT����������������������������������������������������������������������� 802 Hp Infection��������������������������������������������������������������������� 802 Other Types of Gastritis and Gastropathy������������������������� 805

from different areas should be placed in separate containers and the locations of biopsy sites should be identified for the pathologist on an accessioning form. Every biopsy represents an excellent opportunity for the clinician and pathologist to communicate to correlate clinical data, endoscopic findings, and histopathology. Errors may occur when the pathologist attempts to interpret biopsies without clinical input. The Sydney classification system attempted to unify terminology for endoscopic and histologic gastritis and gastropathy.3 However, the complexity of the Sydney system and frequent failure to obtain adequate numbers of biopsies precluded widespread clinical use outside of clinical research studies. This chapter provides an etiology-based classification of gastritis and gastropathies. 

ACUTE GASTRITIS Acute gastritis, characterized by dense infiltration of the stomach with neutrophilic leukocytes, is rare. This rarity is in distinction to the much more common “active” gastritis, where neutrophils can be present along with chronic inflammatory cells (lymphocytes, plasma cells), as in Hp gastritis (see later). Most forms of acute neutrophilic gastritis are due to infections with invasive organisms.

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Phlegmonous (suppurative) gastritis is an infection of the gastric submucosa and muscularis propria, often sparing the mucosa.4-19 Many types of invasive microorganisms have been identified, including gram-negative bacilli, anaerobes, gram-positive cocci including group A streptococci, and fungi (e.g., mucormycosis; see later). The gastric phlegmon may simulate a mass. The esophagus may also be involved or even be the apparent source of the infection. Infection may spread to the adjacent liver and spleen with abscess formation. Acute phlegmonous/necrotizing gastritis has been associated with a variety of conditions including recent large intake of alcohol, respiratory tract infection, and AIDS and other immunocompromised states, including liver transplantation. An especially severe form of phlegmonous gastritis is emphysematous gastritis, due to gastric infections with gas-producing organisms, such as Clostridium perfringens, E. coli, and S. aureus. Gas in the wall of the stomach and in the portal venous system is often present (Fig. 52.1). Imaging studies (plain films, CT) show gas bubbles conforming to the contour of the stomach, often in the form of cystic gas pockets. Although full recovery from phlegmonous or emphysematous gastritis may occur, the condition may progress to gastric (and esophageal) gas gangrene and be fatal. Risk factors for emphysematous gastritis include recent gastroduodenal surgery, ingestion of corrosive materials, gastroenteritis, or GI infarction. Patients with phlegmonous or emphysematous gastritis typically appear septic and present with acute upper abdominal pain, peritonitis, purulent ascitic fluid, fever, and hypotension.

Fig. 52.1  CT of emphysematous gastritis. Abdominal CT image in a 67-year-old male diabetic with coronary artery disease and prior stroke who was admitted from his nursing home with sudden onset of nausea, vomiting, and abdominal pain. Physical examination showed diffuse tenderness throughout the abdomen. CT shows curvilinear air in the posterior wall of the fluid-filled stomach, as well as portal venous gas. He was treated successfully with broad-spectrum antibiotics, with resolution of the emphysema documented on a repeat scan 2 weeks later. (Courtesy T. Ynosencio, MD, Baylor University Medical Center, Dallas, TX.)

Diffuse antral gastritis

Environmental metaplastic atrophic gastritis

Preoperative diagnosis is possible with plain films, US, or CT. Gastroscopy with or without biopsy and culture of gastric contents may establish the diagnosis. Grossly, the stomach wall appears thick and edematous with multiple perforations, and the mucosa may demonstrate a granular, green-black exudate. Microscopically, the edematous submucosa reveals an intense polymorphonuclear infiltrate and numerous gram-positive and/or gram-negative bacteria, as well as vascular thrombosis. The mucosa may demonstrate extensive areas of necrosis. The mortality rate of phlegmonous gastritis is close to 70%, probably because it is so rare and difficult to diagnose and because treatment is initiated too late. The definitive treatment is either gastric resection or drainage (source control), combined initially with systemic broad-spectrum antibiotics directed against the most common organisms (Escherichia coli and other gram-negative bacilli, anaerobic and group A streptococci, and Staphylococcus aureus). Vancomycin and piperacillin/tazobactam is one empiric regimen that can be used. Acute phlegmonous gastritis can paradoxically be associated with both granulocytic leukemia and with neutropenia. Although not as common as neutropenic cecitis (typhlitis) or enterocolitis, neutropenic gastritis can be an isolated finding. Other forms of acute gastritis are discussed later (see Infectious Gastritis). 

CHRONIC GASTRITIS Chronic gastritis is much more common than acute gastritis, although it may be clinically silent. Its prevalence is declining in developed countries.20 The major importance of these chronic gastritides (including Hp-gastritis) relates to the fact that they are risk factors for other diseases such as PUD and gastric neoplasms, including adenocarcinoma and lymphoma (MALToma), discussed in detail in other chapters. Non-Hp chronic gastritis also occurs not infrequently; its cause is not known in most cases. Non-Hp gastritis was less common in African Americans than in other races and was associated with PPI use in a predominantly male US veteran population.21 Three types of chronic gastritis are recognized: diffuse antral gastritis which is usually due to Hp infection, environmental metaplastic atrophic gastritis (EMAG), and autoimmune metaplastic atrophic gastritis (AMAG; Fig. 52.2 and 52.3).

Hp Gastritis Hp is a gram-negative helical- or spiral-shaped flagellated bacterium. Infection with Hp typically causes a diffuse antral gastritis (see Fig. 52.3A). Hp gastritis initially affects the superficial layers of the mucosa. In some instances, particularly in childhood, the infection is short lived, but the infection usually results in chronic active gastritis, which is essentially a lifelong condition without treatment. Chemokines induced by Hp infection lead to

Autoimmune metaplastic atrophic gastritis

Fig. 52.2  Topographic patterns of chronic gastritis. The darker areas in the schematic of environmental metaplastic atrophic gastritis and autoimmune metaplastic atrophic gastritis represent areas of focal atrophy and intestinal metaplasia.

CHAPTER 52  Gastritis and Gastropathy

a persistent acute inflammatory infiltrate with neutrophils and other cells (active inflammation) coexisting with cells characteristic of chronic inflammation (lymphocytes, plasma cells, and macrophages). Despite this robust host immune response, the bacteria persist in most people who are infected.22 Host factors that result in clearance of Hp in some cases of acute infection remain largely unknown.23,24 A form of Hp gastritis characterized by mucosal infiltration by plasma cells that contain Russell bodies (Russell body gastritis) has been described.25,26 A form of Hp gastritis that can be recognized endoscopically is nodular gastritis, which can resolve following eradication of the organism from the stomach.27-29 Nodular gastritis/gastropathy is recognized by its chicken-skin appearance and can be seen in other conditions, including Crohn disease, syphilitic gastritis, lymphocytic (varioliform) gastritis, collagenous gastritis (all discussed later), and in AA-amyloidosis.30 

particularly in developing countries where the majority of children become infected before the age of 10.32,33 During early childhood, spontaneous clearance of the bacteria is common, but often with subsequent reinfection. In older children and adults, infection usually persists, so that the prevalence of Hp infection can exceed 80% by ages 20 to 30 in the developing areas of the world. In developed countries, such as the USA, young children can also acquire Hp, but with spontaneous clearance there is a lower chance of reinfection, and consequently, persistent infection is less frequent.33,34 In fact, serologic evidence of Hp infection is uncommon in children before age 10, but rises to 10% in adults between 18 and 30 years of age, and further increases to 50% in those age 60 or older.33 This increased prevalence of infection with age was initially thought to represent continuing acquisition throughout adult life. However, new adult infection and reinfection are quite uncommon, especially in developed countries, where reinfection is estimated to occur in less than 0.5% of cases per year. Epidemiologic evidence supports childhood-acquired infection even in developed nations, and thus the frequency of Hp infection for any age group in a locality reflects that particular birth cohort’s rate of bacterial acquisition early in life.33 In the USA, infection within any age group is less common in whites than in African Americans and Hispanics.35 Hispanic immigrants and their first-generation children are more likely to harbor Hp than their second-generation offspring.36 These differences probably relate to factors early in life that are linked to acquiring infection.

Epidemiology, Risk Factors, and Transmission Hp infection is the most common chronic bacterial infection in humans. Estimates suggest that over 50% of the world’s population is infected with the bacterium, including 70% to 80% of populations in developing nations. Genetic sequence analysis suggests that humans have been infected for more than 60,000 years corresponding to the time when they first migrated from Africa.31 A key risk factor for infection is socioeconomic status during childhood. Infection is commonly acquired at an early age,

A

B

C Fig. 52.3 Histopathology of chronic gastritides. (For normal histology, see Chapter 49.) A, Diffuse antral gastritis. Chronic inflammation within the lamina propria and neutrophils infiltrating the gastric pit epithelium. This lesion is characteristic of Hp infection (H&E, ×400). B, Environmental metaplastic atrophic gastritis. Note several glands lined by goblet cells (arrow) (H&E, ×200). C, Autoimmune metaplastic atrophic gastritis, with goblet cell metaplasia and nests of enterochromaffin-like cells (arrows) (H&E, ×400).  

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Housing density, crowded conditions in the home, number of siblings, sharing a bed, and lack of hot or running water have been linked to higher rates of infection.33,37 In Japan, the declining prevalence of Hp infection appears to parallel the nation’s postwar economic progress with improvement in hygiene and sanitation. Among Japanese born before 1950, more than 70% are infected compared with 45% born between 1950 and 1960 and 25% born between 1960 and 1970.38 Currently, childhood infection in Japan is uncommon. A similar declining prevalence is being observed in the USA, suggesting that infection-related illnesses such as PUD will decrease as the current birth cohorts in developed countries reach older age.39 Twin studies support a genetic susceptibility to Hp infection, because monozygotic twins who were raised in different households have a greater concordance of infection than dizygotic twins raised separately.40 However, twins growing up together have a higher concordance of Hp infection than twins growing up separately, suggesting environmental factors are also important for acquisition during childhood. Humans appear to be the major reservoir of Hp. The precise mode of Hp transmission from person to person remains uncertain, and multiple mechanisms may be operative. Transmission of bacteria from gastro-oral, fecal-oral, or possibly oral-oral exposure seems the most probable explanation for person-toperson spread.32,41 Within-family clustering of infection (often with genetically identical strains of Hp) also supports person-toperson transmission.33 Infected individuals are also more likely to have infected spouses or children than uninfected individuals. Support for sibling-to-sibling transmission comes from studies reporting that the likelihood of infection is correlated with the number of children in the household and that younger children were more apt to be infected if older siblings were also infected.33 In a study conducted in 6 countries in Latin America, household crowding and living with 4 or more children were risk factors for infection.17 Mother-to-child transmission is also quite likely.34,42 Gastro-oral and fecal-oral transmission of bacteria appear to be the dominant mechanisms by which Hp gain access to the human host. The bacterium can be cultured from vomitus, aerosolized vomitus, and diarrheal stools, suggesting the potential for transmission.43 Organism loads are 100-fold higher in vomitus when compared with stool and saliva; organisms are also present in aerosolized vomitus out to 1.2 m during the act of vomiting. Exposure to an infected family member during an acute GI illness, especially with vomiting, appears to be a risk factor for infection.44 Natural transmission could occur through contact with infected vomitus during an acute illness44 or with regurgitated material from an infected child. Such contact could explain the higher concordance of maternal/child Hp infection and the presumed child-to-child transmission that occurs in an infant daycare setting.45 Especially in developing countries, Hp-contaminated water might serve as an environmental source of Hp, because the organism can remain viable in water for several days.46 Hp DNA can be found in samples of municipal water from endemic areas of infection, but whether the Hp detected by PCR are viable organisms remains to be proved.31 In countries where the prevalence of Hp infection is high, children who swim in rivers and streams, drink untreated stream water, or eat uncooked vegetables are more likely to harbor Hp, providing further indirect evidence of an environmental (water-borne) source of organisms. How frequently bacteria are transmitted through oral-oral contact is not known. Although organisms can be identified in dental plaque, periodontal pockets, and saliva, the prevalence is low, as is the organism count47,48; thus, it is questionable if the mouth can serve as a source or reservoir for Hp. Also, dentists and oral hygienists who have occupational exposure to dental plaque, periodontal pockets, and oral secretions do not have an increased prevalence of Hp infection.27 In developed countries,

oral-oral transmission of infection to spouses also appears to be uncommon. Infected gastric juice may serve as a source of bacterial transmission.49,50 Iatrogenic infection has also occurred during the use of a variety of inadequately disinfected gastric devices, endoscopes, and endoscopic accessories.32 Gastroenterologists and nurses appear to be at increased risk for acquiring Hp.51 Mandated universal precautions, hand washing, standardized equipment disinfection, and use of video-endoscopes that reposition the instrument channel away from the mouth may reduce such occupational and iatrogenic transmission. Although humans are the main reservoir for Hp, domestic cats, captive primates, and sheep can also harbor these organisms. It is possible that these animals actually acquired their Hp from human sources. Isolation of viable bacteria from the saliva and gastric juice of cats suggests the possibility of transmission to humans.32 An Hp haplotype persists in the feline species in Africa, suggesting that infection may have transitioned to humans at some point in the distant past.51 

Pathogenesis A unique aspect of Hp is that this pathogen confers disease despite residing in the stomach. Gastric Hp infection per se, however, is insufficient to fully explain the wide spectrum of associated gastroduodenal diseases. Pathogenicity and clinical outcome depend on both bacterial and host factors. Thus, virulence of Hp relates to both bacterial properties allowing colonization and adaptation to the gastric environment and to pathophysiologic alterations in the host. Studies describing the genome of distinct strains of Hp have advanced our understanding of the ecology of the organism and the potential bacterial gene expression patterns that can affect disease pathogenesis.52-54 The pathogenesis of Hp gastritis is complex and not fully understood and a detailed description is beyond the scope of this chapter. Only key pathogenetic factors will be discussed, with the interested reader referred to other sources.55-77 Hp contain 6 to 8 flagella at one end of their bodies and flagella-mediated motility is one of the few characteristics shown to be required for successful Hp colonization of the host.55 The organism’s flagella allow rapid migration of Hp to a more favorable gastric location below the gastric mucus layer. Exposure of Hp to low gastric pH levels increases expression of bacterial genes encoding urease.55 Urease helps Hp adapt to the acidic gastric milieu, allowing a more neutral pH to occur near the bacteria as its urease splits urea into CO2 and ammonia (NH3), with the NH3 reacting with H+ to produce ammonium ion (NH4+).56 Hp show strict tropism for gastric-type mucosa, including in nongastric regions of the GI tract where there is gastric metaplasia. Conversely, Hp do not colonize epithelium in a stomach that has undergone intestinal metaplastic change (see later), possibly because antimicrobial factors produced by host metaplastic epithelium select against colonization. This possibility is supported by the finding that Hp rarely colonize the deeper portions of the gastric glandular mucosa, where antimicrobial O-glycans are found.57 Metaplasia may also be associated with hypochlorhydria/ achlorhydria, encouraging overgrowth of the stomach with other (non-Hp) species of bacteria. Toll-like receptors (TLRs) are a family of pattern recognition receptors with specificity for various bacterial molecules.63,43 TLRs are components of the host’s innate immune system.44 Lipopolysaccharide PS from Hp stimulates gastric epithelial cell and monocyte responses via TLR4 and TLR2.2.64-66,244 A key interaction between Hp and gastric epithelium is mediated by a segment of bacterial DNA referred to as the cag pathogenicity island (cag PAI). Genes within the cag PAI encode for a type IV secretion apparatus, cagE, that allows other bacterial

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macromolecules, such as cagA, to be delivered directly into the host cell.53,67 The cag PAI plays an important role in the pathogenesis of chronic Hp gastritis in humans.53,68 Hp bearing the cag PAI are associated with increased interleukin (IL)-8 expression, mucosal inflammation, peptic ulceration, and apoptosis compared to cag PAI-negative strains.69,70 Mongolian gerbils infected with mutated Hp strains lacking cagE exhibit less severe gastritis, fewer peptic ulcers, less intestinal metaplasia (IM), and less gastric cancer than gerbils infected with the wild-type strain.71 Different cagA proteins from distinct geographic Hp populations appear to be tyrosine phosphorylated by host cells in different manners, resulting in variable effects on intracellular signaling.78-85 Such heterogeneity in cagA may lead to different host responses that could account for some of the geographic differences seen in Hp-associated disease. Although tyrosine phosphorylation of the cagA protein may be important, it is not the only mechanism whereby this molecule regulates the host response.86,87 All strains of Hp possess the vacA gene, and more than half of strains produce a vacuolating cytotoxin (VacA).53,73 VacA attaches to host epithelial cells via an interaction with cellular protein-tyrosine phosphatases.72 Thus, mice deficient in a protein-tyrosine phosphatase do not develop gastric ulceration when exposed to Hp that secrete VacA.74 Different vacA alleles have been detected in the 5′ signal region (s-region) and in the middle region (m-region) of Hp’s vacA gene.75 The s-region is present as allele s1 (which can be further distinguished as s1a, s1b, s1c) or as allele s2, whereas the m-region is present as allele m1 or m2. Production of VacA is designated by the allelic combinations (e.g., s1/m1, s1/m2, s2/m1, s2/m2). Specific vacA alleles (s1 and m1) are associated with peptic ulceration75 and the induction of host epithelial cell apoptosis.76 Other bacterial virulence factors have also been associated with a putative increased risk of gastric adenocarcinoma. However, studies showing direct cancer causation for any of these bacterial factors in isolation have proved unfruitful. These findings support the notion that any bacterial or host factors that increase the host inflammatory response to infection may increase the risk of gastric cancer and that the degree of mucosal inflammation, cell injury, and gastric atrophy is the best determinant of cancer risk in an individual patient.77 Gastric epithelial cells play an integral part in the host response to Hp infection, in addition to being the target of infection. Epithelial cell responses to Hp include changes in their morphology,88 disruption of their tight junctional complexes,89 production of cytokines,67 increased proliferation, enhanced cell death via apoptosis, and induction of numerous host genes associated with the cellular stress that accompanies infection.23 Expression of genes by epithelial cells infected with Hp is regulated by transcription factors, particularly nuclear factor-kappa B (NF-κB). As discussed in Chapter 2, NF-κB regulates expression of a wide variety of proinflammatory cytokines and cellular adhesion molecules in response to infection or the local cytokine milieu. Enhanced gastric epithelial cell NF-κB activity correlates with the intensity of neutrophil infiltration and mucosal IL-8 levels.4867 This pathway is of particular interest given that certain polymorphisms in the IL-8 gene90 are linked to increased mucosal IL-8 expression, inflammation, and other premalignant changes associated with gastric cancer. Hp infection appears to activate NF-κB in gastric epithelial cell lines through various signaling mechanisms, including mitogen-activated protein kina ses.49,66,68,91 The mitogen-activated protein kinase cascades regulate a wide range of cell functions, including proliferation, inflammatory responses, and cell survival.69,92-94 Oxidative stress also regulates host gene expression during Hp infection.95,96 Oxidation of host DNA by reactive oxygen species such as hydroxyl radicals (•OH) are thought to play a causal role in malignant transformation through the induction of DNA damage. For this reason, there is growing interest in the role of

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antioxidants in cancer prevention or treatment, because Hp infection is associated with decreased levels of ascorbic acid, a tissue antioxidant scavenger. Moreover, there is evidence that diets high in antioxidants97 or “nutraceuticals” of the isothiocyanate group, such as sulforaphane,98 may antagonize oxidative stress and protect the host from gastric cancer, perhaps by decreasing inflammation and attenuating bacterial load. In vitro and in vivo studies in Mongolian gerbils show that an N-acetylcysteine, a precursor to the antioxidant compound glutathione, reduces Hp gastritis if administered early after infection,99 but whether this compound would reduce carcinogenesis is uncertain. Hp strains that express outer inflammatory protein A (OipA) are associated with increased bacterial density, higher mucosal IL-8 levels,100 and neutrophil infiltration, as well as more severe clinical consequences.101 Peptidoglycan (murein) from Hp’s cell wall can translocate into gastric epithelial cells via the cagE encoded by the cag PAI. Once inside the host cell, nucleotide-binding oligomerization domain-1 recognizes this murein, providing a novel mechanism of bacterial sensing.102 Binding of murein to nucleotide-binding oligomerization domain-1 can lead to activation of NF-κB and the subsequent expression of various host genes encoding proinflammatory molecules, as discussed earlier. Hp neutrophil-activating protein promotes neutrophil adhesion to endothelial cells and stimulates chemotaxis of neutrophils and monocytes, nicotinamide adenine dinucleotide phosphate hydrogen oxidase complex assembly at the plasma membrane, and the subsequent production of reactive oxygen intermediates.86,103 Within the inflammatory environment present in Hp gastritis, the effects of Hp neutrophil-activating protein on neutrophils can be potentiated by TNF-α and interferon (IFN)-γ. After epithelial cells undergo apoptosis, phagocytes remove the dead cells. Engulfment of necrotic epithelial cells by phagocytes may be another important mechanism by which Hp can activate a host response.23,2 Recruitment and activation of neutrophils and macrophages cause the release of other inflammatory mediators. Increased expression of inducible nitric oxide synthase occurs in the gastric mucosa during Hp infection.23 The nitric oxide (NO) produced reacts with superoxide anion (O2−) produced by infiltrating neutrophils to form peroxynitrite (ONOO−), a potent oxidizing and nitrating agent. NO and ONOO− have antimicrobial effects, but uncontrolled or inappropriate production could also play a role in the gastric mucosal cell damage observed during Hp infection. Furthermore, catabolism of urea by Hp urease produces NH3 and CO2, the latter of which can rapidly neutralize the bactericidal activity of the peroxynitrite by reacting with it to form the intermediate ONOOCO2− and then nitrate. Urease, thus, may favor Hp colonization by neutralizing some host cell responses, but this mechanism also enhances the nitration potential of ONOO− and may favor mutagenesis of host cell DNA. Cytokines induced in macrophages by bacterial urease include TNF-α and IL-6,89,104 and IL-6 is also induced by heat shock protein 60.9105 Cytokines secreted by epithelial cells complement those released by inflammatory cells in the lamina propria. Intact bacteria can induce the production of chemokines that recruit T cells,106,91 as well as IL-1292,93,107,108 and IL-18,94,109 cytokines that favor the selection of Th1 cells, with their characteristic patterns of cytokine secretion. Th1 cells promote cellmediated immune responses through the production of IFN-γ and TNF-α, whereas Th2 cells produce IL-4, IL-5, IL-10, and transforming growth factor-β (TGF-β). Th2 cells can promote mucosal IgA or IgE responses to helminths and other parasites, as well as diminish the inflammation caused by Th1 cytokines. Previous studies suggest that the Hp-infected gastric mucosa is preconditioned to favor Th1 development over Th2 cell development.92,107

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T cell (e.g., Th1 cell) activation by Hp infection may contribute to more severe inflammation and gastroduodenal diseases. Increased levels of IL-17, a cytokine produced by activated CD4+ T lymphocytes, are found in the mucosa of Hp-infected patients.110,111 IL-17, in turn, induces IL-8 expression by gastric epithelial cells, thereby enhancing neutrophil recruitment. Activation of transcription factors by IL-17 may also contribute to the increased levels of numerous other proinflammatory cytokines and enzymes observed during Hp infection, such as IL-1β, TNFα, and COX-2. IFN-γ and TNF-α produced by Th1 cells can increase the expression of many genes in the epithelium, including IL-8. These cytokines also enhance bacterial binding66 and they may also increase bacterial load.112 In animal models, Th1 cells increase epithelial cell apoptosis38 as well as inflammation, glandular atrophy, and a tendency toward dysplasia.113 TNF-α, IFN-γ, and IL-1β also up-regulate gastric epithelial cell Fas antigen expression.114 Because Th1 cells express higher levels of Fas ligand (FasL) than Th2 cells, the relative increase in Th1 cells during Hp infection may induce epithelial cell death through Fas-Fas ligand (FasL) interactions.114,115 This notion is substantiated by the observation that proton pump- (H+,K+-ATPase-) specific Th1 cells in the gastric mucosa kill target epithelial cells via Fas-FasL interactions and may act as effector cells in autoimmune gastritis (discussed later).116 IgA antibodies, normally produced in the GI tract (see Chapter 2), are highly adapted for mucosal protection, conferring protective immunity without activating the complement cascade and causing deleterious amounts of cell damage and inflammation. The number of IgA-producing plasma cells increases in Hp infection. However, increased numbers of IgG- and IgM-producing plasma cells are also detected, along with activated complement. Monoclonal antibodies that recognize Hp can cross-react with human and murine gastric epithelial cells.117,118 Transfer of these antibodies to recipient mice induces gastritis,117 as does the transfer of B cells that recognize heat shock proteins from individuals with MALToma.119 With few exceptions, infection with Hp persists for the life of the host unless there is some intervention with antibiotics. This observation has led to investigations as to whether immunologic tolerance impairs immunity. Several bacterial factors, including urease and catalase, thwart innate host responses to infection.22 Furthermore, production of arginase by Hp inhibits NO production and may favor bacterial survival,120 whereas virulent strains of Hp impair phagocytosis121 and mucus production.122 The VacA toxin can impair bacterial antigen presentation by macrophages by inhibiting the antigen presentation pathway.123 Moreover, Hp produce molecules that mimic host molecules, such as Lewis antigens, that theoretically could stimulate T cells to release cytokines that help avoid autoimmune reactions. However, as already discussed, the cytokine profile associated with Hp infection is not one that would be expected to occur in a tolerant environment. For example, IL-4, IL-10, and TGF-β (which could mediate an anti-inflammatory effect) are not expressed to the same levels as proinflammatory Th1 cytokines such as IFN-γ and TNF-α.23 Because the infected gastric mucosa is characterized by chronic active inflammation, tolerance, if it has occurred, may favor persistent infection even though it cannot prevent the chronic inflammatory response. Genetic heterogeneity in the regions of the host genome that controls the magnitude of inflammation is associated with gastric cancer development (Chapter 54).124 Polymorphisms in the regions controlling IL-1125 are associated with an increased incidence of hypochlorhydria and gastric cancer in Hp-infected individuals and decreases the incidence of DU recurrence.126 Increased IL-1 expression may not only drive inflammation but also lead to a physiologic change known to precede gastric cancer development, because IL-1 potently inhibits gastric acid secretion (see Chapter 51). Other genes that regulate the magnitude

BOX 52.1 Some Components of Hp That Are Involved in the Pathogenesis of Gastritis Cag pathogenicity island (PAI), including cag A and cag E Flagella HP-neutrophil activating protein (HP-NAP) Lipopolysaccharide Outer inflammatory protein A (Oip A) Peptidoglycan (murein) Urease Vacuolating toxin A (VacA)

of the inflammatory response to Hp, including IL-10, TNF-α, and IL-8, have also been associated with the sequence of events leading to cancer.127,128 Elevated fasting and meal-stimulated serum gastrin levels are well documented in individuals with Hp infection.3 The net effect of Hp infection on gastric acid secretion in an infected individual is variable, however, depending on the duration and distribution of Hp infection and presence or absence of atrophy of the oxyntic glandular mucosa (see Chapters 51 and 53). Hp infection also reduces gastric mucin secretion and mucosal hydrophobicity, abnormalities that can be reversed after eradication of infection. Epithelial barrier function is altered during Hp infection as a consequence of both direct effects of Hp infection and the accompanying inflammatory responses that collectively increase epithelial cell proliferation and programmed cell death.23 Bacterial (Hp)-related factors involved in the pathogenesis of Hp gastritis in the host discussed earlier are summarized in Box 52.1. Environmental factors can have a moderating role in the Hp-host interactions. Such factors as smoking, a high-salt diet, and various environmental mutagens can heavily influence both the degree and rate of progression of mucosal injury. In Japan, for example, the incidence of gastric cancer fell by 60% between 1965 and 1995 despite no change in the virulence of the most common strain of Hp. This dramatic drop has been attributed to societal changes such as refrigeration (vs. salt preservation), westernization of the diet, and smoking reduction.77 

Diagnosis There are endoscopic and nonendoscopic tests available to diagnose Hp infection. Such techniques may detect Hp directly (gastric histology, stool bacterial antigen, culture) or indirectly (urease detection or antibody response).129,130 The appropriate method to choose depends on the clinical situation, prevalence of infection in the population, pretest probability of infection, test availability, and cost. Recent use of antibiotics or PPIs can influence the results of certain tests.131 The commonly used diagnostic tests and their advantages and disadvantages are summarized in Table 52.1. Endoscopic tests. Performing EGD solely to obtain gastric biopsies for the diagnosis of Hp infection is not appropriate. When EGD is clinically indicated, there are 3 methods to identify Hp in a gastric biopsy specimen: biopsy urease testing, histology, and culture. The choice of method depends on the clinical situation, cost, availability, and test accuracy.125 For each method, either 1 or 2 biopsies are obtained from both the antrum and corpus. Biopsy urease testing is recommended initially because the method is efficient, relatively inexpensive, and generally accurate.131,132 Gastric biopsy material is tested for urease activity by placing tissue in a medium containing urea and a pH reagent such as phenolphthalein. Hp urease hydrolyzes urea, liberating ammonia, which produces an alkaline pH and a resultant color change of the phenolphthalein test medium.129 Test results can be positive

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TABLE 52.1  Tests for Hp Infection Endoscopic Tests

Advantages

Disadvantages

Biopsy urease

Rapid results Accurate in patients not using PPIs or antibiotics No added pathology cost Excellent sensitivity and specificity, especially with special immunostaining Provides additional information about gastric mucosa

Requires endoscopy Less accurate after treatment or in patients using PPIs Expensive (endoscopy and pathology costs) Some interobserver variability Accuracy affected by PPI and antibiotic use Difficult culture protocol Not widely available Expensive

Histology

Specificity ≈100% Allows antibiotic sensitivity testing

Culture

Nonendoscopic Tests Serology (qualitative or quantitative IgG) Urea breath (13C or 14C)

Stool antigen

Widely available Inexpensive Good NPV Identifies active infection Accuracy (PPV, NPV) not affected by Hp prevalence Useful both before and after treatment Identifies active infection Accuracy (PPV, NPV) not affected by Hp prevalence Useful both before and after treatment

A

Poor PPV if Hp prevalence is low Not useful after treatment Availability and reimbursement inconsistent Accuracy affected by PPI and antibiotic use Small radiation dose with14C test Fewer data available Accuracy affected by PPI and antibiotic use

B Fig. 52.4  Histopathology of Hp gastritis. A, Active chronic gastritis with diffuse lymphoplasmacytic inflammation and neutrophils infiltrating the gastric pit epithelium (H&E, ×400). B, Immunohistochemistry for Hp showing organisms along the gastric epithelial surfaces (arrows). (IHC, ×400).

within minutes to hours. Several urease test kits are commercially available, differing only regarding medium (agar gel or membrane pad) and testing reagents.129 These kits are generally inexpensive, but in western centers there may be added costs associated with obtaining gastric tissue samples (e.g., up-coding a diagnostic endoscopy). Nevertheless, biopsy urease testing is less expensive than histology. Sensitivity and specificity of biopsy urease tests are 90% to 95% and 95% to 100%, respectively.129,133 Accuracy can be negatively affected by blood in the stomach134 or by use of antibiotics, bismuth-containing compounds, or acid antisecretory drugs, especially PPIs.135 Therefore, a negative urease test does not exclude Hp infection in an individual taking antisecretory medication, a common scenario in patients referred for EGD. To improve sensitivity in such patients, stopping the potentially problematic medication and delaying EGD for 2 weeks (if possible) can be considered, and testing multiple (>2) biopsy samples from the antrum and corpus may be attempted. Gastric mucosal histology assessment is generally not necessary to diagnose Hp, but it can provide information regarding the severity of mucosal inflammation (see Fig. 52.3A) and for the detection of Hp-associated precancerous lesions such as metaplastic

(chronic) atrophic gastritis (discussed later) and dysplasia.129 Histologic examination had been considered the gold standard for identifying infection, with reported sensitivity and specificity as high as 95% and 98%, respectively.136 However, the distribution and density of organisms can vary within the stomach, with the potential for sampling error, particularly in patients taking antisecretory medications. Detection of organisms is common with standard H&E staining, but is improved with special stains such as Giemsa, silver, Genta, or specific immunohistochemical stains (Fig. 52.4).130,136,137 Culture of mucosal biopsies is difficult because Hp is fastidious and slow growing, requiring specialized media and growth environment.129,130 Culturing Hp is not routinely available in contemporary US practice. When culturing gastric mucosal biopsies for Hp, tissue should be obtained before biopsy forceps are exposed to formalin. Tissue is then placed in a container with only a few drops of saline or appropriate media to preserve the specimen during transport to a local or offsite microbiology facility.130 Although mucosal culture is not generally recommended, culture with antibiotic sensitivity testing can guide subsequent treatment in patients with refractory infection, with the understanding that in vitro sensitivity testing does not always predict clinical treatment outcome.130,138

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13C-urea 13CO 2 (µmol)

Positive urea breath test

NH2 H2O + 13C O 2NH3 + 13CO 2

NH2 Urease Breath 13CO 2

Negative urea breath test 2 1 Time (hour)

Blood Fig. 52.5  The urea breath test (see text for a more complete description). (From Walsh JH, Peterson WL. Drug therapy: the treatment of Hp infection in the management of peptic ulcer disease. N Engl J Med 1995;333:984-91.)

Nonendoscopic tests. Serology is the most popular noninvasive test in clinical practice and is used for its convenience and relatively low cost. As described earlier, infection incites a systemic immune response, and enzyme-linked immunosorbent assay technology can detect IgG serum antibodies to a variety of bacterial antigens.129,130 Tests for IgA and IgM antibodies are less reliable, and their use is discouraged.129 Office-based kits that test whole blood can provide results within 30 minutes and permit “point of service” testing. Although serology is relatively inexpensive, noninvasive, and ideally suited to a primary care setting, the prevalence of Hp in the population being tested influences its accuracy.131 The sensitivity of serology is generally quite high (90% to 100%), but its specificity is variable (76% to 96%). Therefore, in populations where infection is less common (including the USA), the negative predictive value of serology is high, but the positive predictive value is not, with many false positive results. Use of another test, such as a urea breath test or stool antigen (discussed later), is recommended in low-prevalence populations before embarking on therapy for Hp. Serology can remain positive for months or longer even after successful treatment of infection; thus, seroconversion (i.e., from a positive to negative result), though specific for treatment success, is not a practical way of testing for eradication.139 Urea breath testing (UBT) detects active Hp infection and is useful for making the diagnosis and for documenting successful treatment.131 UBT relies on bacterial hydrolysis of orally administered urea tagged with a carbon isotope, either nonradioactive 13C or radioactive 14C (Fig. 52.5). Hydrolysis of urea generates ammonia and tagged CO2 (13CO2 or 14CO2), which can be detected in breath samples.140 The nonradioactive 13C test is preferred for children and the rare cases in which pregnant women need testing, as opposed to delaying testing until after pregnancy, as treatment of Hp in pregnancy is rarely indicated. The radiation dose with the 14C test is low (1 μC), equivalent to 1 day of background radiation exposure. The specificity of the UBT exceeds 95%, making false-positive results uncommon. The sensitivity of the test is 88% to 95%, with false-negative results reported in patients taking antisecretory therapy such as PPIs, bismuth compounds, or antibiotics. To improve diagnostic accuracy, PPIs, bismuth salts, and antibiotics should ideally be stopped 1 to 2 weeks before UBT. UBT is not accurate in patients who have had a gastric resection. Stool antigen testing is an immunoassay that detects Hp antigens and is the other principal noninvasive modality to diagnose active Hp infection and confirm eradication following

treatment. Overall sensitivity and specificity of the stool antigen test are comparable to the UBT (94% and 97%, respectively). A rapid Hp stool antigen test is available that permits testing during a clinic visit, but it is slightly less accurate than a traditional laboratory-based stool test.141 The sensitivity of stool testing is also reduced by PPIs, bismuth salts, and antibiotics, which can decrease bacterial load; thus, similar precautions as described earlier for UBT are recommended when using stool antigen tests. PCR is a sensitive method to detect Hp and to detect antibiotic resistance genes, but it is not yet practical for routine clinical diagnosis.142 It is useful for research purposes to identify bacteria in gastric biopsies, stool, or drinking water in a community setting, to type organisms in epidemiologic or transmission studies, and for testing for antibiotic resistance genes. When clinically indicated, it is appropriate to confirm successful eradication of infection with either a UBT or stool antigen test. Current USA treatment guidelines (discussed later) suggest that all infected individuals should undergo testing to confirm successful eradication of infection.143,144 The European guidelines favor offering noninvasive tests to all individuals treated for Hp to confirm eradication. Post-treatment endoscopy with biopsy is only necessary if a repeat procedure is clinically indicated. In such patients, sampling multiple areas of the stomach is important to avoid missing persistent infection due to alteration of the bacterial density and distribution by prior antibiotics and antisecretory medications. These tests should not be performed sooner than 6 to 8 weeks after completion of treatment, because earlier testing might yield false-negative results. Also, medications that could affect test results, such as PPIs, should be discontinued for at least 1 to 2 weeks before testing to improve accuracy. The chronic inflammation associated with Hp infection may take months and sometimes over a year to subside following eradication of the organism, so its presence in biopsy material should not be interpreted as persistent infection.

Chronic Atrophic Gastritis (Gastric Atrophy) As discussed in Chapter 49, the gastric mucosa has a rapid rate of turnover, with new cells derived from progenitor (stem) cells replacing cells that are shed into the lumen or destroyed. This process maintains the thickness and the varied cell population of glands comprising the oxyntic and antral mucosa. During chronic inflammation of the stomach, the rate of cell loss may exceed the ability of the stem cells to replace lost cells, and the mucosa thins. This is often accompanied by metaplasia of this epithelium derived from isthmus-located stem cells.145 This thinning of the mucosa and accompanying metaplasia (most often intestinal, but sometimes pseudopyloric, pancreatic, squamous, or ciliated), if associated with chronic inflammation, is termed chronic atrophic gastritis, or gastric atrophy. Chronic atrophic gastritis may be regional or diffuse and is often patchy (see Fig. 52.2). It is an important risk factor for dysplasia and gastric cancer (see Chapter 54).146,147 In chronic atrophic gastritis (gastric atrophy),148-168 loss of specialized cells within gastric glands, such as parietal and chief cells, leads to a reduction or absence of their secreted products, such as intrinsic factor (IF) and hydrochloric acid (hypochlorhydria or achlorhydria) as well as pepsinogen, with an increased risk of adverse consequences such as vitamin B12 malabsorption, gastric bacterial overgrowth, and enteric infections. An international group of gastroenterologists and pathologists (the Operative Link for Gastritis Assessment [OLGA]) attempted to stage the risk of progression from chronic atrophic gastritis to gastric cancer.169 OLGA stages 0 through IV are recognized (Table 52.2). The OLGA system is based on the assumption that gastric cancer risk is related to the degree of gastric glandular atrophy.170-173 Others have proposed that IM, easier to recognize by pathologists than gastric atrophy, can be used in place

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TABLE 52.2  OLGA and OLGIM Classifications of Cancer Risk in Chronic Gastritis

52

OLGA Staging Corpus (Body, Fundus) ATROPHY ANTRUM*

None (0) Mid (1) Moderate (2)

None (0) STAGE 0 STAGE I STAGE II

Mid (1) STAGE I STAGE I STAGE II

Moderate (2) STAGE II STAGE II STAGE III

Severe (3) STAGE II STAGE III STAGE IV

Severe (3)

STAGE III

STAGE III

STAGE IV

STAGE IV

Moderate (2) STAGE II STAGE II STAGE III STAGE IV

Severe (3) STAGE II STAGE III STAGE IV STAGE IV

OLGIM Staging Corpus (Body, Fundus) ANTRUM

INTESTINAL METAPLASIA (IM) None (0) Mild (1) Moderate (2) Severe (3)

None (0) STAGE 0 STAGE I STAGE II STAGE III

Mild (1) STAGE I STAGE I STAGE II STAGE III

  

*Antrum includes the biopsy result from the incisura angularis. Modified from Rugge M, Correa P, Di Mario F, et al. OLGA staging for gastritis: a tutorial. Dig Liver Dis 2008;40:650-8; and Capelle LG, de Vries C, Haringsma J, et al. The staging of gastritis with the OLGA system by using intestinal metaplasia as an accurate alternative for atrophic gastritis. Gastrointestinal Endoscopy 2010;71:1150-8.

TABLE 52.3  Spectrum of AMAG and EMAG AMAG ↔ AMAG/EMAG

Overlap ↔ EMAG

Antibodies to intrinsic factor, parietal cell Other autoimmune disorders Antral sparing ↓Serum PGI and ↓PGI/PGII ratio Hypergastrinemia (can be marked) Gastric carcinoid tumors

Hp gastritis (Current, past) Potentially reversible (Hp Rx) Antral involvement Serum PG levels more variable Normal or slight increase in serum gastrin

  

PG, pepsinogen.   

of gastric atrophy (OLGIM).174,175 However, focusing on IM rather than the degree of gastric atrophy may be less sensitive in identifying patients at high gastric cancer risk.176 The Kyoto classification system is also used to assess cancer risk, especially in Japan.177 Subtyping of IM into complete (small intestinal) or incomplete (colonic) is of uncertain prognostic value, although a literature review suggested a higher cancer risk with the incomplete (colonic) type, especially if the intestinal goblet cells contain predominantly sulfomucins as opposed to sialomucins.178 Two types of chronic atrophic gastritis are recognized (Fig. 52.2, and Fig. 52.3B and C): an EMAG, also called multifocal atrophic gastritis, and an AMAG, also called diffuse corporal atrophic gastritis. At the 2 ends of the spectrum, these types can be distinguished using clinical, laboratory, endoscopic, and histologic features (Table 52.3). However, in many cases the distinction between EMAG (usually due to chronic Hp infection) and AMAG (usually due to autoreactive T and B/plasma cells against various antigens of the parietal cell) is blurred because of overlapping features. For example, in EMAG the Hp may disappear from the stomach over time as the gastric epithelium is replaced by metaplastic intestinal epithelium, although serum IgG antibodies to Hp as a marker of prior infection may persist. Likewise, it has been proposed that, through molecular mimicry, antibodies to Hp can cross react with parietal cell antigens such as the α and β chains of H+,K+-ATPase (the proton pump) to result in a form of AMAG.179,180 The sequence of IM, dysplasia, and gastric cancer, first popularized by Correa, is now well accepted and is discussed in Chapter 54. The role of endoscopic surveillance in

patients with gastric IM is controversial, but has been advocated by some.147,181 Gastric metaplasia and dysplasia may be visualized during gastroscopy, particularly if enhanced imaging methods, such as narrow band imaging and chromoendoscopy, are used (Fig. 52.6).147

EMAG EMAG is characterized by involvement of both the gastric antrum and corpus with glandular atrophy and IM (Fig. 52.3B). It is important for endoscopists to obtain at least 2 biopsies from the antrum, 1 from the incisura angularis, and 2 from the gastric body in order for the pathologist to be able to render a diagnosis of EMAG. Atrophic gastritis involving the corpus may be associated with pseudopyloric metaplasia, in which the mucosa resembles antral mucosa but stains for pepsinogen I (PGI), a proenzyme normally expressed in corpus mucosa. Other types of metaplasia (pancreatic, squamous, and ciliated) may also occur. Gastroscopy may show a pale mucosa, shiny surface, and prominent submucosal vessels due to mucosal thinning (see Fig. 52.6). However, endoscopy is neither sensitive nor specific in diagnosing chronic atrophic gastritis, especially in patients younger than age 50.148 Magnifying endoscopy and autofluorescence imaging video endoscopy may be more sensitive in detecting atrophy.146,147 The pathogenesis of EMAG is multifactorial, but Hp infection plays the most important role and has been incriminated in about 85% of patients. EMAG can occur early in life in Hp-infected individuals. Genetic and environmental factors, especially diet, are also important. Certain population groups are predisposed to EMAG, including African Americans, Scandinavians, Asians, Hispanics, Central and South Americans, Japanese, and Chinese. In China, a model has been developed based on gender, general health, family history of cancer, and diet/alcohol use to stratify the risk of gastric cancer in patients with EMAG and to determine the need for screening gastroscopy.149 IM is a risk factor for dysplasia and gastric cancer, usually the intestinal type (see Chapter 54). The incidence of gastric neoplasia (dysplasia, cancer) in intestinal metaplastic lesions of the stomach has been estimated to be 1% per year, although most of these incident neoplastic lesions were dysplastic lesions and not invasive cancers.151 IM of the gastric mucosa can be classified into 3 subtypes depending on the morphology of the epithelium and the types of mucins produced.178 

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A

B

C

D

E

F Fig. 52.6  EGDs in patients with metaplastic atrophic gastritis. Left, Note paucity of folds in the antrum (panel A), at the incisura (panel B), and along the lesser curvature in the gastric body (panel C). Biopsy sites are shown with local bleeding. Narrow-band imaging (panel D), which highlights the mucosal vascular pattern, did not suggest dysplasia, nor did 0.8% indigo carmine staining (not shown). Right, Note 2.5 cm area of dysplastic epithelium in the antrum (panel A); the dysplastic area has been marked in anticipation of endoscopic submucosal resection (panel B). (From Gomez JM, Wang AY. Gastric intestinal metaplasia and early gastric cancer in the west: a changing paradigm. Gastroenterol Hepatol 2014;10:369-78, with permission.)

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AMAG

Carditis

AMAG, also called diffuse corporal atrophic gastritis, is an autoimmune destruction of glands in the corpus of the stomach. AMAG is the pathologic process underlying pernicious anemia, an autoimmune disorder typically occurring in patients of northern European or Scandinavian background and in African Americans. It may be associated with other autoimmune disorders, especially autoimmune thyroiditis. Although some patients with AMAG are asymptomatic, many complain of dyspepsia with postprandial distress.182 Patients with AMAG exhibit achlorhydria or hypochlorhydria, hypergastrinemia with antral G-cell hyperplasia secondary to low or absent gastric acid, and low serum PGI concentrations with low ratios of serum PGI/PGII.183,184 Affected patients often have circulating antibodies to parietal cell antigens and to IF; the antibodies to IF are less sensitive for AMAG but more specific, whereas antibodies to parietal cell antigens are more sensitive but less specific. Autoreactive T cells and subsequent production of autoantibodies against the α and/or β chains of the H+, K+-ATPase (ATP4A and ATP4B) by B/plasma cells are thought to play a role in the pathogenesis of AMAG.185 Pseudopyloric metaplastic (sometimes called spasmolytic polypeptide-expressing metaplasia) and metaplastic pancreatic acinar cells are also a feature of AMAG.186 Histologically, atrophic glands with extensive IM are confined to the corpus mucosa (Fig. 52.3C).187 Atrophy is usually focal and the preserved islands of relatively normal oxyntic mucosa may appear polypoid endoscopically or radiologically (pseudopolyps). Rarely, AMAG progresses to diffuse (complete) gastric atrophy. Hypergastrinemia, a consequence of achlorhydria, is associated with enterochromaffin-like cell hyperplasia and gastric carcinoid tumors,152 discussed in more detail in Chapter 34. Antibodies to parietal cell antigens, most notably the H+, K+ATPase, are frequently present in patients with AMAG. These antibodies can also be detected in patients with various other autoimmune diseases, including type 1 diabetes mellitus154-156 and autoimmune thyroid diseases (Graves disease and Hashimoto thyroiditis),157,158 explaining the association of these conditions with pernicious anemia. The risk of AMAG is increased 3- to 5-fold in type 1 diabetic individuals, and some authors have suggested screening type 1 diabetics with gastroscopy and mucosal biopsy. AMAG has also been associated with autoimmune pancreatitis, as well as celiac disease/dermatitis herpetiformis.162,188 In patients with AMAG, a proportion of the CD4+ lymphocytes present in the chronic inflammatory infiltrate within the gastric mucosa proliferate in response to H+, K+-ATPase. Most CD4+ cells secrete Th1 cytokines such as IFN-γ and TNF-α, provide help for B cell immunoglobulin production, and enhance perforin-mediated cytotoxicity, as well as Fas-Fas ligand-mediated apoptosis. These factors in combination may contribute to gland destruction in AMAG. Many patients with AMAG have circulating antibodies to Hp and/or have Hp detectable in their gastric-oxyntic mucosa. Thus, Hp may play a role in the pathogenesis of AMAG.189 It appears Hp strains producing cagA and VacA are most likely to cause AMAG. These particular Hp are often the s1m1 VacA subtype that also express Lewis blood group antigens X and Y.190 Lewis antigens on the Hp may help camouflage the organism because these antigens are also present on human gastric epithelial cells. It has been suggested that when antibodies to Lewis antigens X and Y from Hp develop, they cross-react with similar antigens on epithelial cells resulting in AMAG (molecular mimicry). If chronic atrophic gastritis with IM develops in such patients over time, the prevalence of active Hp infection will then decrease. Immune checkpoint inhibitors that block programmed death receptors (e.g., PD-1) are being used more often in cancer patients, and one such agent, nivolumab, has been reported to cause an autoimmune hemorrhagic gastritis.191 

There is often a small rim of gastric glands in the cardia of the stomach just below the squamocolumnar junction of the esophageal and gastric mucosa (see Chapter 49). In an endoscopic study of normal volunteers, the majority had a cardiac-type mucosa in this region; the remainder had oxyntic mucosa with its specialized parietal and chief cells.192 Inflammation of a cardiac-type mucosa (carditis) has been attributed to both Hp and to GERD. Carditis occurring in healthy volunteers is mainly due to infection with Hp. However, in patients found to have carditis during a diagnostic endoscopy, Hp was present in only 11%. Severity of carditis in this diagnostic endoscopy population was more related to 24-hour acid exposure of the lower esophagus.193 Chronic atrophic carditis with IM has been proposed to be a precursor of adenocarcinoma of the gastroesophageal junction (see Chapters 46 to 48, and 54). 

OTHER INFECTIOUS GASTRITIDES Besides Hp-gastritis, the most common and important gastric infection, and acute phlegmonous gastritis which, though rare, is life threatening, there are many other infectious forms of gastritis that lead to morbidity.

Viral CMV CMV is a human herpesvirus (HHV5) that may infect the stomach. Although gastric CMV infection may occur in an immunocompetent host, infection usually occurs in the immunocompromised.194 Patients with solid organ or hematopoietic cell transplants (see Chapter 36), AIDS (see Chapter 35), cancer, or who are taking immunosuppressive drugs (especially glucocorticoids) are at increased risk. Patients with CMV infection of the stomach can experience epigastric pain with fever and atypical lymphocytosis.195 Gastric imaging may reveal marked thickening of gastric folds and a rigid and narrowed gastric antrum suggestive of an infiltrating antral neoplasm. Gastroscopy may reveal thickened hemorrhagic folds with a congested and edematous antral mucosa, covered with multiple ulcerations, suggestive of gastric malignancy, submucosal antral mass, or PUD. A hypertrophic and/or polypoid type of gastritis resembling Ménétrier’s disease (discussed later) with protein-losing gastropathy may occur, especially in children, including one case with CMV/Hp coinfection.196 Examination of mucosal biopsy specimens shows inflammatory debris, chronic active gastritis, and enlarged cells with CMV inclusion bodies indicative of an active infection (Fig. 52.7A). “Owl-eye” intranuclear inclusions are the hallmark of CMV infection in routine H&E histologic preparations and may be found in vascular endothelial cells, mucosal epithelial cells, and connective tissue stromal cells. Multiple granular, basophilic cytoplasmic inclusions may also be present (see Fig. 52.7B). When typical inclusions are hard to find in H&E-stained sections, immunohistochemical stain for CMV may be helpful. Usual treatment is with IV ganciclovir or foscarnet, along with reducing immunosuppression, if feasible. In patients with AIDS, antiretroviral therapy is required to prevent relapse of CMV infection. 

Other Herpesviruses Gastritis from HSV-1 (HHV1) or varicella-zoster virus (HHV3) is rare.197,198 Infected individuals typically experience the initial infection at an early age, and the virus then remains dormant until reactivation. Reactivation has been related to cancers (including lymphoma) and to radiation therapy and/or cancer

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B Fig. 52.7  Histopathology of CMV gastritis. A, gastric ulcer with granulation tissue containing several CMV inclusions (arrows) (H&E, ×600). B, Classic CMV infected cell with cytomegaly, well-formed Cowdry type A nuclear inclusion, and granular cytoplasmic inclusions (H&E, ×600).

chemotherapy agents. The typical immunocompromised patient with these herpesvirus gastritides may experience nausea, vomiting, abdominal pain, fever, chills, fatigue, and weight loss. Barium-air double-contrast radiographs show a cobblestone pattern, shallow ulcerations with a ragged contour, and an interlacing network of crevices filled with barium that corresponds to areas of ulceration. Gastroscopy reveals multiple, small, raised, ulcerated plaques or linear, superficial ulcers in a crisscrossing pattern, giving the stomach a cobblestone appearance. Brush cytology and biopsies should be performed at the time of endoscopy. Brush cytology has the advantage of sampling a wider area of mucosa. Grossly, the ulcers are multiple, small, and of uniform size. Microscopically, cytological smears and biopsy specimens show nonspecific active inflammation, containing scattered multinucleated cells with smudged (ground glass) intranuclear inclusions. HHV1 and HHV3 show identical histology in tissue. Immunohistochemistry, viral culture, or PCR of an appropriate swab or tissue specimen is required to differentiate these 2 infections.198 Treatment with acyclovir is reasonable but of unproved value. EBV (HHV4) is not present in normal gastric mucosa, but can be present in the stomach in almost half of the patients with gastritis.199 Whether EBV is a cause of the gastritis in these cases is uncertain. EBV infection has been linked to gastritis cystica profunda (GCP; discussed later) and with gastric cancer.200 Infectious mononucleosis due to acute EBV infection may lead to gastric lymphoid hyperplasia with atypical lymphocytes.201 

Measles Measles, caused by rubeola virus, has many GI manifestation, including, rarely, gastritis. The characteristic histologic pattern is of numerous multinucleated giant cells (Warthin-Finkeldey cells) within gastric epithelial and stromal cells, with background mild chronic inflammation. 202 

Bacterial Mycobacteria Gastric infection with Mycobacterium tuberculosis is rare.203 Patients typically present with abdominal pain, nausea and vomiting, GI bleeding from a tuberculous gastric ulcer, anemia, fever, and weight loss. Gastric TB may be associated with gastric outlet obstruction. Imaging studies reveal an enlarged stomach with a

narrowed, deformed antrum and pre-pyloric ulcerations. Upper endoscopy demonstrates ulcers, masses, or gastric outlet obstruction. Duodenal TB can also cause gastric outlet obstruction.204 Grossly, the stomach may demonstrate multiple small mucosal erosions, ulcers, an infiltrating mass (hypertrophic form), sclerosing inflammatory disease, or pyloric obstruction either by extension from peripyloric nodes or by invasion from other neighboring organs. Biopsies show caseating granulomas containing Langhan’s giant cells and rare tiny bacilli, visualized only with an acid-fast stain. Treatment is discussed in Chapter 84. Although infection with the Mycobacterium avium complex (M. avium, M. intracellulare, M. chimaera) is a common opportunistic infection among patients with AIDS (see Chapter 35), the stomach is rarely involved. Microscopically, the gastric mucosa demonstrates numerous foamy histiocytes containing many acid-fast bacilli. Treatment is with a macrolide (clarithromycin or azithromycin) plus rifampicin and ethambutol. 

Actinomycosis Primary gastric actinomycosis is a rare, chronic, progressive, suppurative disease characterized by formation of multiple abscesses, draining sinuses, and abundant granulation and dense fibrous tissue.205 The presenting symptoms of gastric actinomycosis include fever, epigastric pain, epigastric swelling, abdominal wall abscess with fistula, and UGI bleeding. Radiographic studies frequently suggest a malignant tumor or a peptic (gastric) ulcer. Endoscopy is suggestive of a circumscribed and ulcerated gastric carcinoma, and the diagnosis can be made with endoscopic biopsy. Grossly, the resected stomach demonstrates a large, illdefined, ulcerated mass in the wall of the stomach. Microscopically, multiple abscesses show the infective agent, Actinomyces israelii, a gram-positive filamentous anaerobic bacterium that normally resides in the mouth. A biopsy of a mass containing pus, or a biopsy of a draining sinus, may reveal actinomycosis. If the disease is recognized only by histologic examination, the prognosis is good. Prolonged (6- to 12-month) high-dose antibiotic treatment with penicillin or amoxicillin/clavulanic acid is recommended. 

Syphilis The incidence of primary and secondary syphilis is increasing in the USA, with over 27,000 cases reported in 2016, a 17.6% increase compared with 2015.206 Case reports and small case

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B

Fig. 52.8  Gastric syphilis (syphilitic gastritis). Film from an upper GI series (A) showing a stricture in the mid-stomach (hourglass stomach), with antral deformity. Endoscopic appearance before (B) and 4 weeks after (C) penicillin therapy in another patient with gastric syphilis. (Courtesy Mark Feldman, MD, Dallas, TX.)

C

A

series emphasize the importance of the gastroenterologist and pathologist remaining alert to the protean manifestations of syphilis and being familiar with the histopathologic pattern of the disease.207,208 Gastric involvement in secondary or tertiary syphilis is rarely recognized clinically, and its diagnosis by examination of endoscopic biopsy specimens has been reported infrequently. The features of syphilis in the stomach should be recognized because they can provide a window of opportunity for effective antibiotic therapy before the disease progresses and causes permanent disability. Syphilitic gastritis can occur in conjunction with hepatitis and proctitis.207 Gastric syphilis can occur in the setting of HIV infection. Patients typically present with symptoms of PUD, often with UGI bleeding. Diseases that may mimic gastric syphilis include PUD and gastric adenocarcinoma, lymphoma, TB, and Crohn disease. The acute gastritis of early secondary syphilis produces the earliest radiologically detectable signs of the disease, with diffusely thickened folds that may become nodular, with or without ulcers. Strictures in the mid-stomach (“hourglass” stomach) may be present (Fig. 52.8A). Endoscopy shows numerous shallow, irregular ulcers with overlying white exudate and surrounding erythema (see Fig. 52.8B). The surrounding mucosa may also demonstrate a nodular appearance. Gastroscopy may also demonstrate prominent, edematous gastric folds. Grossly, the stomach may be thickened and contracted and may show multiple serpiginous ulcers. Partial gastrectomy specimens may show compact, thick, mucosal folds and numerous small mucosal ulcers. Microscopically, biopsies show severe gastritis with dense plasma cell infiltrate in the lamina propria, varying numbers of neutrophils and lymphocytes, gland destruction, vasculitis, and granulomas. Warthin-Starry silver stain or modified Steiner silver impregnation stain reveals numerous spirochetes. Serum Venereal Disease Research Laboratory and Treponema immunofluorescence studies may be positive, and PCR may detect the Treponema pallidum gene. Treatment with penicillin is highly effective (see Fig. 52.8C). 

Other Bacteria Helicobacter heilmannii are spiral bacteria and an infrequent cause of chronic active gastritis; this infection may be a risk factor for gastric MALToma.209 These organisms, originally known as Gastrospirillum hominis, are longer than Hp and have multiple spirals. One of these H. heilmannii species, Helicobacter bizzozeronii, has been isolated from human gastric mucosa.210 Another organism that, like Hp, can stain with the Giemsa reagent is Campylobacter hyointestinalis.211 The clinical significance of these non-Hp curved bacilli remains to be established. 

Fungal Candidiasis Fungal colonization of gastric ulcers with Candida species is not uncommon.212 There is debate whether such colonization has any clinical significance or whether the organisms in fact aggravate and perpetuate gastric ulceration. Endoscopically, gastric ulcers associated with Candida albicans colonization tend to be larger in diameter and are more often suspected to be malignant than typical gastric ulcers. Diffuse superficial erosions may also be noted. Radiologic studies show tiny aphthoid erosions, which represent the earliest detectable radiographic change in gastric candidiasis. Aphthoid ulcers progress to deep linear ulcers. Fungal colonization of the GI tract, frequent in patients with underlying malignancy and in immunocompromised patients who have been treated with antibiotics or glucocorticoids, may occur also in immunocompetent patients. Massive growth of yeast organisms in the gastric lumen (yeast bezoar) is a potential complication of gastric surgical procedures, usually those for PUD. Candida infection of the stomach may also occur in alcoholic patients. Grossly, the gastric mucosa demonstrates tiny erosions, widespread punctate, linear ulcerations, or gastric ulcers. Microscopically,

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the layer of necrotic fibrinoid debris demonstrates yeasts or pseudohyphae. The organisms can be seen in the H&E stain; however, special stains such as periodic acid-Schiff-diastase stain or Gomori methenamine silver stain may be required. Treatment of the Candida species per se is usually not necessary, but if symptomatic candidiasis is suspected, fluconazole is reasonable but of unproved efficacy. 

Giardiasis

Histoplasmosis

The stomach is rarely affected by Strongyloides stercoralis.222 The organism may colonize the intact gastric mucosa and may also be associated with a bleeding peptic ulcer. Most patients are immunocompromised. Peripheral blood eosinophilia may be present. Diagnosis can be confirmed by endoscopic biopsy, examination of stools, or examination of a duodenal aspirate. Disseminated strongyloidiasis (hyperinfection) can be rapidly fatal. Treatment consists of ivermectin and reducing immunosuppression, if feasible (see Chapter 114). 

Progressive disseminated histoplasmosis is rare, occurring most frequently in the very young, the older adult, or in those with immunodeficiency. Disseminated histoplasmosis can involve any portion of the GI tract, although gastric involvement is uncommon.213 Hypertrophic gastric folds, a mass that mimics a gastric adenocarcinoma, or gastric ulceration may be associated with gastric histoplasmosis. Radiographic studies may demonstrate an annular infiltrating lesion of the stomach. Endoscopy may demonstrate enlarged and reddened gastric folds. Biopsy specimens show noncaseating granulomas within a mixed chronic inflammatory infiltrate. Gomori Methenamine Silver stains will highlight numerous small (2 to 5 μm) round-to-oval yeast forms with occasional budding, compatible with Histoplasma capsulatum. Treatment with IV liposomal amphotericin B followed by itraconazole for ≥12 months is appropriate.214 

Mucormycosis Gastric mucormycosis (also called zygomycosis or phycomycosis) is a rare and highly lethal fungal infection.215 Risk factors include malnutrition, immunosuppression, antibiotic therapy, and severe metabolic acidosis, usually diabetic ketoacidosis. Most patients present with UGI bleeding or gastric ulcers.216 Gastric mucormycosis can be classified as invasive or noninvasive (colonization). Deep invasion of the stomach and blood vessel walls by the fungus characterizes the former (see Acute Gastritis section earlier). Abdominal pain is the most frequent presenting complaint. In the noninvasive type, the fungus colonizes the superficial mucosa without causing an inflammatory response. Grossly, surgical specimens from affected patients reveal hemorrhagic necrosis involving the mucosa and gastric wall. Microscopically, nonseptate 10- to 20-μm hyphae branched at right angles are present in the tissue and they infiltrate into blood vessel walls. Treatment is resection of the affected necrotic portion of the stomach. Invasive gastric mucormycosis is almost always fatal. 

Aspergillosis Acute Aspergillus gastritis is rare and can be highly invasive.217 

Cryptococcosis The stomach and duodenum may be involved in immunocompromised hosts, including patients with AIDS in conjunction with cryptococcal meningitis.218 

Monascus Ruber This form of fungal gastritis acquired by eating dried, salted fish, and can result in invasive fungal infection.219 

Parasitic (see also Chapters 113 and 114) Cryptosporidiosis Cryptosporidiosis may rarely involve the stomach.220 

Giardia lamblia can rarely infect the stomach.221 An association of infection with trophozoites with chronic atrophic gastritis and its associated hypochlorhydria has been suggested. 

Strongyloidiasis

Anisakidosis Invasive anisakidosis (formerly, anisakiasis) may occur after the ingestion of raw marine fish containing nematode larvae of the genus Anisakis. Most cases of anisakidosis have been diagnosed in Japan. The parasite may migrate into the wall of the stomach, small intestine, or colon.223 Typically, patients present with sporadic epigastric pain or have no symptoms at all. Gastric perforation due to chronic gastric anisakidosis may occur. Some patients exhibit a mild peripheral blood eosinophilia. Endoscopy may show firm, yellowish submucosal masses with erosions. Imaging studies may reveal notched-shadow defects suggestive of a gastric tumor. Grossly, the stomach demonstrates multiple erosive foci with hemorrhage and small 5- to 10-mm gastric lesions in the stomach wall. Microscopically, sections of the stomach show a marked eosinophilic granulomatous inflammatory process with intramural abscess formation and granulation tissue. The eosinophilic abscess may contain a small worm measuring 0.3 mm in diameter, which is the larval form. If the larvae are not detectable by endoscopy, the diagnosis may be confirmed serologically. Treatment is endoscopic removal of the nematode, followed by albendazole. Successful relief of acute dyspeptic symptoms, which can be quite severe, has been reported with an over-the-counter medicine containing wood cresolate.224 

Ascariasis Although gastric ascariasis is rare, chronic, intermittent gastric outlet obstruction caused by Ascaris lumbricoides may occur.225 Gastric ascariasis has also been associated with UGI hemorrhage, with endoscopic examination showing several Ascaris worms in the stomach and duodenum. Treatment is endoscopic removal, followed by mebendazole or albendazole (see Chapter 114). 

Necatoriasis Endoscopic discovery, capture, and removal from the stomach of the hookworm Necator americanus has been reported.226 

Capillariasis Eosinophilic gastritis from capillariasis has been reported, perhaps linked to ingestion of raw fish.227 

GRANULOMATOUS GASTRITIDES A variety of granulomatous diseases can affect the stomach.228,229 In children, the most common of them is Crohn

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Glucocorticoid therapy is the cornerstone of treatment for gastric sarcoidosis (see Chapter 37). Subtotal gastric resection is reserved for patients with obstruction and severe hemorrhage. 

Xanthogranulomatous Gastritis XGG is a rare form of gastritis, with less than 15 reported cases worldwide. XGG is characterized by marked proliferation of foamy histiocytes mixed with acute and chronic inflammatory cells, multinucleated giant cells, and fibrosis. The destructive inflammatory and fibrotic process may extend into adjacent organs and simulate, or coexist with, a gastric neoplasm.233-235 An association of XGG with gastric actinomycosis has been reported.236 

DISTINCTIVE GASTRITIDES Fig. 52.9  Histopathology of granulomatous gastritis in a patient with Crohn disease. A noncaseating granuloma is present within the lamina propria (H&E, ×200).

disease (Fig. 52.9), discussed later and in Chapters 115 and 116. In adults, sarcoidosis (see Chapter 37) and Crohn are the most common diseases. Infections with spirochetes (e.g., T. pallidum), mycobacteria (e.g., M. tuberculosis), fungi, parasites, and the bacterium T. whipplei (see Chapter 109) can also cause granulomatous gastritis, as can xanthogranulomatous gastritis (XGG; discussed later), foreign bodies, lymphoma, Langerhans cell histiocytosis (gastric eosinophilic granuloma), eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss syndrome), chronic granulomatous disease of childhood, and, very rarely, granulomatosis with polyangiitis (see Chapter 37). An isolated idiopathic granulomatous gastritis also occurs. Some of these “idiopathic” cases may eventually evolve into Crohn disease or sarcoidosis. Other cases of “idiopathic” granulomatous gastritis appear to be due to Hp infection and may resolve slowly following appropriate antibiotic therapy, sometimes leaving a mucosal discoloration.230

Sarcoid Sarcoidosis is a systemic granulomatous disease, sometimes involving the GI tract, liver, and spleen (see Chapter 37). The gastric antrum is the most common portion of the GI tract affected in sarcoidosis, being involved in approximately 10% of cases.231 A diagnosis of sarcoid gastritis cannot be made with confidence in the absence of granulomatous disease in other organs. Affected patients, usually in the third to fifth decades of life, typically present with epigastric pain, nausea, vomiting, and weight loss. Occasionally they present with massive GI hemorrhage. Gastric sarcoidosis may result in pyloric outlet obstruction, achlorhydria, and pernicious anemia. Radiographically, gastric sarcoidosis may mimic the diffuse form of gastric adenocarcinoma (“linitis plastica”) or Ménétrier’s disease. Endoscopy may reveal a narrow distal stomach with multiple prepyloric ulcers or erosions, atrophy, thick gastric folds with a diffuse cobblestone appearance, or normal mucosa associated with microscopic granulomas. Surgical specimens from patients with gastric sarcoidosis show a thickened stomach wall with foci of erosions and ulcers. Microscopically, mucosal biopsies typically show multiple noncaseating granulomas, although granulomas may be necrotizing.232 As the presence of granulomas in GI tissue is a nonspecific finding, special stains should be performed to rule out granulomatous infections, particularly TB. In some cases, it may be difficult to differentiate gastric sarcoidosis from gastric Crohn disease or from isolated idiopathic granulomatous gastritis.

Collagenous Collagenous gastritis is rare, and can be associated with collagenous duodenitis, collagenous colitis, lymphocytic colitis, celiac disease, and/or autoimmune disorders.237-243 It has also been reported in children and adolescents, where it usually is an isolated phenomenon. In one series, 2 clinical patterns were identified. In the children and young adults, the presenting symptoms, anemia and epigastric pain, were attributed to the gastritis per se. In the older adults (ages 35 to 77), the presenting symptom was often diarrhea due to coexisting celiac disease or collagenous colitis.242 UGI barium radiography may demonstrate an abnormal mucosal surface with a mosaic-like pattern in the body of the stomach, corresponding to mucosal nodularity. Endoscopy may reveal multiple diffusely scattered, discrete submucosal hemorrhages, gastric erosions, and coarse folds of the body of the stomach along the greater curvature. Biopsy specimens from the body and antrum of the stomach reveal a patchy, chronic, superficial gastritis, focal atrophy, and irregular deposition of collagen 20 to 75 μm thick in the subepithelial region of the lamina propria often containing entrapped capillaries (Fig. 52.10). Tiny erosions of the surface epithelium are often present, and the inflammatory infiltrate consists of mainly plasma cells, intraepithelial lymphocytes, and eosinophils, together with marked hypertrophy of the muscularis mucosa. Little is known about the etiology, natural history, and proper treatment of this condition. 

Lymphocytic Lymphocytic gastritis244 is characterized by a dense lymphocytic infiltration of surface and pit gastric epithelium (Fig. 52.11A). Lymphocytic gastritis is related to an endoscopic form of gastritis known as varioliform gastritis, characterized by nodules, thickened folds, and erosions.245 Lymphocytic gastritis in adults is typically seen in patients with Hp infection. Hp eradication treatment in such patients causes significant improvement in the gastric intraepithelial lymphocytic infiltrate, corpus inflammation, and dyspeptic symptoms. The relationship between lymphocytic gastritis and gastric lymphoid hyperplasia, which also is associated with Hp infection, is not clear. Patients with gastric MALToma have a significantly increased prevalence of lymphocytic gastritis due to Hp infection. Thus, lymphocytic gastritis may be a precursor of gastric MALToma in patients with Hp infection (see Chapters 32 and 54 ). There is compelling evidence that lymphocytic gastritis may occur as a manifestation of celiac disease, and also be a marker of a more severe and earlier-onset form of celiac disease (see Chapter 107).245,246 Following institution of a gluten-free diet, the lymphocytic gastritis slowly resolves in these patients. Other

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etiologic associations of lymphocytic gastritis include celiac disease, HIV infection, Crohn disease, common variable immunodeficiency, and medication.247 Endoscopy in lymphocytic gastritis shows thick mucosal folds, nodularity, and aphthous erosion (varioliform gastritis).245,248 Gastric biopsies show expansion of the lamina propria by an infiltrate of plasma cells and lymphocytes, with rare neutrophils. These findings may be seen in the antral mucosa only, the body

mucosa only, or both. The surface and superficial pit epithelium shows a marked intraepithelial infiltrate with CD3+ T lymphocytes, with flattening of the epithelium and loss of apical mucin secretion. Lymphomatoid gastropathy249,250 is due to CD56+ natural killer lymphocytic infiltration of the stomach, simulating a gastric lymphoma. Most cases have been reported in Japan, where endoscopic screening of healthy individuals for cancer is common. In a series with 10 adults (ages 46 to 75), the lesions appeared as approximately 1-cm elevated nodules. Gastric symptoms were absent. Most lymphomatoid lesions resolved without therapy, although the lesions sometimes recurred. Deaths have not been reported. Chronic active gastritis can also occur in X-linked lymphoproliferative disease.251 

Eosinophilic Eosinophilic gastritis is a frequent component of eosinophilic gastroenteritis,252-254 a rare condition of unknown etiology characterized by eosinophilic infiltration of the GI tract, peripheral blood eosinophilia, and GI symptomatology in the absence of known causes for eosinophilia (e.g., parasitic infection, cow’s milk protein allergy) or another inflammatory GI disorder (e.g., IBD). Eosinophilic gastroenteritis is discussed in more detail in Chapter 30. Eosinophilic gastritis, like eosinophilic gastroenteritis, is classified according to the layer(s) of the stomach involved (i.e., mucosal disease, muscle disease, and subserosal disease). Gastric mucosal involvement may result in abdominal pain, nausea, vomiting, weight loss, anemia, and protein-losing gastropathy. Involvement of the muscular layer generally produces gastric outlet obstructive symptoms.253 Rare patients with subserosal eosinophilic disease may develop eosinophilic ascites. Radiographic studies of the stomach may demonstrate thickened mucosal folds, nodularity, or ulcerations. Gastroscopy may reveal a normal-appearing mucosa or a hyperemic, edematous mucosa with surface erosions or prominent gastric folds. Eosinophilic gastritis may simulate gastric cancer. Gastric mucosal biopsies are critical to the diagnosis and show marked eosinophilic infiltration, eosinophilic pit abscesses, necrosis with numerous neutrophils, and epithelial regeneration (see Fig. 52.11B). Abnormal eosinophilic infiltration, defined as at least 20 eosinophils per high-power field, can be either diffuse or multifocal. A diagnosis of eosinophilic gastritis has been proposed for cases in which

A

B Fig. 52.10  Histopathology of collagenous gastritis. (A, H&E, ×200; B, Masson trichrome, ×400.) The subepithelial thickening of the collagen band is apparent. (From Wang HL, Shah AG, Yerian LM, et al. Collagenous gastritis: an unusual association with profound weight loss. Arch Pathol Lab Med 2004;128:229-32.)

A

B Fig. 52.11 Histopathology of lymphocytic gastritis (A) and eosinophilic gastritis (B). A, High-power view of the antral mucosa shows numerous dark-staining mononuclear cells with striking intraepithelial lymphocytosis (H&E, ×400). B, Numerous eosinophils are noted within the lamina propria and within the walls and lumens of the gastric glands. The patient also had peripheral blood eosinophilia (H&E, ×400). (Courtesy Pamela Jensen, MD, Dallas, TX.)  

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eosinophils infiltrate the surface, foveolar epithelium, the deeper mucosa or submucosa, or are associated with other features of mucosal damage (e.g., foveolar hyperplasia or architectural distortion with significant chronic or active inflammation).252 A fullthickness biopsy of the stomach is necessary to diagnose muscle disease. Paracentesis can be performed to diagnose serosal disease. As discussed in Chapter 30, patients with disabling GI symptoms can be effectively treated with glucocorticoids after other systemic disorders associated with peripheral eosinophilia have been excluded (e.g., eosinophilic granulomatosis with polyangiitishypereosinophilic syndrome, parasitic infection). Endoscopic therapy (e.g., balloon dilation) or surgical intervention may be required in patients with gastric outlet obstruction. 

GASTRITIS IN INFLAMMATORY BOWEL DISEASE Gastritis is increasingly recognized in adults and, especially, pediatric patients with Crohn disease and UC.255-257 The 2 most common histologic abnormalities in IBD-associated gastritis are chronic inactive and chronic active gastritis. Focally enhanced gastritis and Hp gastritis are less common in these patients. Focally enhanced gastritis is characterized by tiny collections of lymphocytes and macrophages (histiocytes) surrounding gastric pits and glands, often with infiltrates of neutrophils as well (Fig. 52.12). Focally enhanced gastritis can sometimes be seen in Crohn, but not commonly in UC.

with Crohn disease are most commonly located in the antrum and the prepyloric region. In contrast to PUD, where the ulcers tend to be round or oval, the ulcerations and erosions of Crohn disease are frequently serpiginous or longitudinal. The microscopic features of mucosal biopsy or surgical specimens of gastric Crohn disease can be, but are not always, like those in the ileum or colon (see Chapters 115 and 116). They include granulomatous inflammation (see earlier section on granulomatous gastritis), transmural chronic inflammation, serpiginous or longitudinal ulcers, and marked submucosal fibrosis (see Fig. 52.9). Granulomas may be present in endoscopically normal antral mucosa. As mentioned earlier, focally enhanced gastritis is also common (see Fig. 52.12). Therapy of gastritis in Crohn disease should be driven by symptoms and not solely by demonstration of gastritis on mucosal biopsy. Double-blinded randomized controlled clinical trials of pharmacologic agents are lacking in gastric and duodenal Crohn disease. PPI therapy should be the first approach for symptomatic patients. The effectiveness of glucocorticoids, amino salicylates, immunosuppressive medications such as azathioprine, and biologic agents such as anti-TNF-α drugs has not yet been demonstrated in controlled clinical trials, but there are reports of success with infliximab.259 Gastric outlet obstruction refractory to medical and endoscopic therapy can be treated by gastroenterostomy, ideally performed laparoscopically. Treatment of Crohn disease is discussed in more detail in Chapters 115 and 116. 

UC

Crohn Disease Crohn disease involving the stomach is uncommon,258 and usually occurs together with intestinal disease (see Chapters 115 and 116). Although rare cases may be isolated to the stomach or to the stomach and duodenum, a diagnosis of isolated Crohn disease of the stomach should be made with caution.259 Close follow-up of such patients is indicated for the subsequent development of either Crohn disease in the lower GI tract or of other granulomatous diseases, such as sarcoidosis. Symptoms of gastric Crohn are nonspecific and include nausea and vomiting, epigastric pain, anorexia, and weight loss. Radiologic contrast studies of the stomach show antral fold thickening, antral narrowing, shallow ulcers (aphthae), or deeper ulcers. Involvement of the stomach from adjacent small intestinal or colonic disease segments is best visualized by radiologic examination. Endoscopy allows better visualization of mucosal defects and is characterized by reddened mucosa, irregularly shaped ulcers, and erosions in a disrupted mucosal pattern. Nodular lesions occur and often have erosions on the top of nodules. An atypical cobblestone pattern may be associated with the nodules surrounded by fissure-like ulceration. The swollen folds, traversed by linear furrows or erosive fissures, have been referred to as “bamboo-joint like.”260 Gastric ulcerations or erosions associated

Fig. 52.12  Histopathology of focally enhanced gastritis. A, Lowpower view of gastric mucosa showing ill-defined nodules of inflammatory cells (H&E, ×100). B, Higher-power view shows a mixed infiltrate of lymphocytes, eosinophils, and neutrophils focally impinging on the glandular epithelium (H&E, ×400). (Courtesy Jonathan Baker, MD, and Pamela Jensen, MD, Dallas, TX.)

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The prevalence of gastritis is lower in UC than in Crohn disease, particularly the prevalence of focally enhanced gastritis, but it is greater than in controls without IBD.255,256 In approximately 5% of cases of UC, the endoscopic appearance of the stomach is abnormal and similar to the appearance of the rectum and colon (see Chapters 115 and 116). Such UC patients with “ulcerative gastritis” are characterized by (1) gastric histopathology similar to colonic histopathology, (2) little or no response to acid-reducing medications (H2RAs or PPIs), and (3) response of the ulcerative gastritis to standard treatment of UC. All UC patients with ulcerative gastritis either had pancolitis or had had a proctocolectomy; many of the latter also had pouchitis.261,262,276 It has been speculated that anti-inflammatory drugs such as glucocorticoids, commonly used in UC, may treat and thus mask the ulcerative gastritis in some patients. 

GASTRITIS CYSTICA PROFUNDA GCP is a rare pseudotumor of the stomach characterized by cystically dilated gastric glands extending through the muscularis mucosa into the submucosa.263-270 This lesion can occur as a complication of partial gastrectomy with gastrojejunostomy for PUD, typically occurring at the site of the gastroenterostomy. GCP may

B

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Fig. 52.13  Histopathology of gastritis cystica profunda. Note the cystic dilatation of numerous gastric glands that extend through the muscularis mucosae (arrow), simulating a gastric carcinoma (H&E stain).

Fig. 52.14  Histopathology of foveolar hyperplasia, typically seen in reactive gastropathies. The gastric pits show an elongated, corkscrew appearance (H&E stain).

also develop in an unoperated stomach and be associated with Ménétrier’s disease263 and with gastric cancer.264-267 Inverted hyperplastic gastric polyp may be a variant of GCP. GCP may also be iatrogenic after attempted gastric polypectomy.268 Targeted deletion of the β subunit of the apical K+ efflux channel of the parietal cell leads to a GCP-like lesion in mice with invasive gastric cancer.269 It is generally believed that injury and inflammation within the mucosa leads to breaks in the muscularis mucosa and migration of epithelium into the submucosa.270 If present, gastric symptoms in GCP are nonspecific. Gastric imaging and endoscopy typically demonstrate multiple exophytic gastric masses that simulate a malignancy. EUS may assist in the diagnosis by demonstrating the cystic nature of the lesions. A diagnosis of GCP should lead to a thorough examination for a gastric cancer. Whether GCP patients without gastric cancer require endoscopic surveillance for subsequent cancer development is not clear. GCP can be removed by snare polypectomy after submucosal injection to elevate the lesion(s). Endoscopic submucosal dissection of GCP has also been reported, with removal of coexistent early gastric cancer.264 In some cases, surgical resection will be required. Grossly, the gastric mucosal surface demonstrates multiple nodules and exophytic masses. On section, the gastric wall is thick and multiple cysts are present. Microscopically, the mucosa shows foveolar hyperplasia with cystic glands extending through a disrupted muscularis mucosa into the submucosa and, rarely, into the muscularis propria (Fig. 52.13). There is associated chronic inflammation, and splayed muscle bundles lie between the dilated glands. 

open elimination challenge tests have no higher incidence of gastritis than children without food allergy.272 

ALLERGIC GASTRITIS (SEE ALSO CHAPTER 10) Infants allergic to cow’s milk protein may manifest hematemesis and melena with a wide spectrum of gastritis and gastropathy at gastroscopy.271 Gastric mucosal biopsy in such infants may show a neutrophilic and eosinophilic gastritis with mucosal hemorrhage. In contrast, children diagnosed with food allergies by an

REACTIVE GASTROPATHIES The epithelial cells of the gastric mucosa may be damaged by a variety of mechanisms that do not produce a significant inflammatory infiltrate. This injury leads to rapid epithelial restitution (resurfacing) and to cell regeneration with foveolar hyperplasia. Because of the paucity of inflammatory cells, the mentioned lesions are better referred to as reactive gastropathy, although the older term “acute erosive gastritis” is still sometimes used. Reactive gastropathy occurs in approximately 15% of endoscopic biopsies of the gastric mucosa. Its incidence increases with age and, ironically, with inflammatory conditions elsewhere in the GI tract.273 The endoscopic appearance of the gastric mucosa of patients who exhibit reactive gastropathy demonstrates a spectrum of reddish streaks,274 subepithelial hemorrhages, mucosal erosions, and even acute ulcers. Acute erosions and ulcers are frequently multiple, and the base of these lesions often stains dark brown owing to exposure of hemoglobin to gastric acid. Grossly, most gastric erosions and acute gastric ulcers appear as well-defined hemorrhagic lesions 1 to 2 mm in diameter. If the insult is severe, the mucosa between the lesions can be intensely hemorrhagic. Microscopically, an erosion demonstrates superficial lamina propria necrosis. An acute ulcer is an area of necrosis that extends to the muscularis mucosa. Foveolar hyperplasia, a sign of epithelial regeneration (Fig. 52.14), is often associated with glands that have atypical nuclei that can be misdiagnosed as dysplasia or even carcinoma. The diagnosis of neoplasia in a background of mucosal necrosis, cellular debris, and granulation tissue should be made with utmost caution. The biopsy procedure itself may induce tissue hemorrhage; thus, subepithelial hemorrhage should involve more than one fourth of a biopsy specimen to be considered significant. In some patients with reactive gastropathy, the stomach may “light up” during PET scanning.275 The most common causes of reactive gastropathy (acute erosive gastritis) are discussed later.

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TABLE 52.4  Some Medications, Toxins, and Illicit Drugs That May Cause Reactive Gastropathy Medications Aspirin, other NSAIDs, and COX-2 inhibitors Bisphosphonates (e.g., alendronate) Bromazepam (a schedule IV benzodiazepine) Cancer chemotherapy drugs Fluorides Iron supplements Sodium phosphate (bowel preps)

Toxins and Illicit Drugs Caustic/corrosive agents (see Chapter 28) Cocaine Ethyl alcohol Heavy metals (e.g., mercury sulfate) Ketamine (inhaled for recreational use) Selenium

Fig. 52.15  Histopathology of alcoholic gastropathy. Hemorrhage is confined to the superficial portion of the mucosa, with a paucity of inflammatory cells (H&E stain).

Medications, Toxins, and Illicit Drugs Ingestion of aspirin and/or nonaspirin NSAIDs, including COX-2–selective inhibitors, are very common causes of reactive gastropathy.276 The relationship between NSAID gastropathy and PUD is discussed in Chapter 53. Other medications that can injure the stomach are listed in Table 52.4.277-284 Lanthanum carbonate (Fosrenal) is a phosphate binder used in patients with end-stage renal disease; the lanthanum phosphate produced can deposit in the gastric mucosa, causing whitish spots and tissue histiocytosis.284 Numerous toxins and illicit drugs can damage the stomach, with ethanol being the most common toxin. After acute ethanol ingestion, subepithelial hemorrhages are seen frequently at endoscopy, typically without prominent mucosal inflammation on biopsy specimens (Fig. 52.15). The combined effect of alcohol and aspirin (or an NSAID) is associated with more gastric mucosal damage than that caused by either agent alone. Hemorrhage, gastric ulceration, and pyloric or prepyloric perforation due to crack cocaine use is well described.285 Some other causes of toxininduced reactive gastropathy are listed in Table 52.4. 

Bile Reflux Reflux of bile into the stomach is common after operations for PUD (see Chapter 53), gastric cancer, and obesity.286-288 Bile

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reflux gastropathy also may occur after cholecystectomy289 or biliary sphincterotomy, procedures that allow continuous exposure of the duodenum to bile with the potential for duodenogastric bile reflux. Bile reflux gastropathy can also be observed in adult or pediatric patients who have not had surgery.275,290 For example, adult patients with dyspeptic symptoms, reddish streaks seen at gastroscopy, and reactive gastropathy histologically often have bile in their stomachs.275 Children with proved bile reflux are characterized mainly as having foveolar hyperplasia.290 Bile reflux gastropathy may eventually result in IM.289 Diagnosis of bile reflux gastropathy can be challenging because many patients with bile in their stomach have no symptoms. Thus, a combination of clinical, endoscopic, and histologic findings is required. There are no universally agreed upon criteria for diagnosis. A bile reflux index has been proposed based on histology (the presence of IM and tissue edema and the absence of Hp and chronic inflammation). Using this index, patients with GERD were found to have a higher prevalence of bile reflux gastropathy than controls.291 A more direct approach has been to use a gastric probe to assess the bilirubin concentration in the stomach (Bilitec 2000),292 but this is a test for duodenogastric reflux rather than gastropathy. Endoscopy in patients with bile reflux gastropathy shows swelling, redness, erosions, and bile staining of the gastric mucosa. It is uncertain whether, in patients with prior gastrectomy, coexisting Hp gastritis worsens or lessens the endoscopic abnormalities.293,294 Biopsy specimens show foveolar hyperplasia, dilated cystic glands, atypical glands that may be misdiagnosed as dysplasia or carcinoma, and a paucity of acute and chronic inflammatory cells. IM289 and even gastric atrophy can result and may increase the risk of gastric carcinoma in the stomach remnant (see Chapter 54). Unfortunately, bile-diverting procedures performed because of severe bile gastropathy do not reverse IM or gastric atrophy. It may, therefore, be worthwhile, at the time of the original gastric surgery performed for gastric cancer or peptic ulcer, to construct a 30-cm Roux-en-Y limb or perform a 10- to 12-cm isoperistaltic jejunal interposition to try to prevent bile gastropathy and subsequent metaplastic and atrophic changes. Treatment of bile reflux gastropathy in the intact or operated stomach is also challenging and not based on a large number of controlled clinical trials.295-299 In one randomized trial of bile reflux gastropathy following cholecystectomy, both the PPI rabeprazole (20 mg daily), the antacid hydrotalcite (1 g 3 times daily), and especially their combination improved symptoms and gastric histopathologic abnormalities, as well as lessened bile reflux as assessed by Bilitec 2000 monitoring.299 Sucralfate has also been used successfully in some studies, but not others.296,298 In most clinical trials, placebo was not given; instead, medications were compared to observation alone. Other medical therapies for bile reflux gastropathy include ursodiol and cholestyramine.295,297 A recent nonrandomized study found that ursodiol appeared to be superior to a PPI.288 In patients who fail medical therapy, surgery is recommended if symptoms are severe. For patients with bile reflux gastropathy or esophagitis following a truncal vagotomy and gastrojejunostomy, it has been recommended that the gastrojejunostomy be dismantled. For patients with prior Billroth II gastrectomy and gastrojejunostomy, a Roux-en-Y diversion can be performed. Long-term results of Roux-en-Y biliary diversion in previously unoperated and in unoperated patients are good.300,301 

Stress Erosions and acute ulcers of the gastric mucosa may occur rapidly after major physical or thermal trauma, shock, sepsis, or head injury. These are often referred to as stress ulcers and are discussed in Chapter 53. 

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Radiation Injury to the stomach from external ionizing radiation can be classified as acute (1 year) (see Chapter 41).302,303 It is thought that the tolerance level for radiationinduced gastropathy is approximately 4500 cGy. With a gastric dose of ≥5500 cGy, most patients will develop clinical evidence of gastropathy and/or gastric ulcer formation. Selective internal radiation therapy with yttrium-90 microspheres infused into the hepatic artery to treat hepatocellular carcinoma (see Chapter 96) can also lead to reactive gastropathy. Radiation-induced gastric ulcers are usually solitary, 0.5 to 2 cm in diameter, and located in the antrum. Massive hemorrhagic gastropathy requiring endoscopic therapy to control the bleeding has been reported. 

Graft-Versus-Host Disease Graft-versus-host disease (GVHD) most often occurs after allogeneic bone marrow transplantation and is less common after solid organ transplantation (see Chapter 36). Acute GVHD occurs between post-transplant days 21 and 100, whereas chronic GVHD occurs after day 100. The GI tract (especially the intestine) is commonly affected in acute GVHD. Gastric GVHD is characterized by nausea, vomiting, and upper abdominal pain without diarrhea. EGD in GVHD may show mucosal loss, erosions, or edema. Gastric mucosal biopsies may be necessary to diagnose GVHD in patients without diarrhea and in patients with or without diarrhea but with normal rectosigmoid biopsy specimens, especially if these patients have UGI symptoms. In general, however, rectosigmoid biopsies are more sensitive than gastric (or duodenal) biopsies in diagnosing acute GVHD.304 The basic pathologic lesion of gastric GVHD consists of necrosis of single cells (apoptotic bodies) in the neck region of the gastric mucosa. The necrosis consists of an intraepithelial vacuole filled with karyorrhectic debris and fragments of cytoplasm. A 2014 NIH Conference recently updated the histopathologic diagnostic criteria for the major organ systems affected by acute and chronic GVHD. Within the stomach the diagnosis is confirmed with greater than or equal to one focus of apoptosis per biopsy piece. Longstanding GVHD is marked by gland destruction, ulceration, and/or submucosal fibrosis. Inflammation is typically minimal.305

Ischemia Histologic changes consistent with a reactive gastropathy may be demonstrated in patients with chronic mesenteric ischemia (see Chapter 38).306 Chronic ischemic reactive gastropathy as well as chronic ischemic gastric ulcers may occur secondary to chronic mesenteric insufficiency or in association with atheromatous embolization.307,308 Athletes involved in intense physical activity, especially long-distance running, may experience recurrent ischemic gastropathy and chronic GI bleeding with anemia.309 

Prolapse The mucosa of the gastric cardia may prolapse into the esophageal lumen during retching and vomiting and become injured.310 Barium studies and esophagoscopy may demonstrate the prolapsed gastric mucosa. The prolapsed, congested mucosa may show erosions and superficial ulcerations. One study showed a high incidence of pathologic gastroesophageal acid reflux in patients with prolapse gastropathy.311 

HYPERPLASTIC GASTROPATHIES, INCLUDING MÉNÉTRIER’S DISEASE Hyperplastic gastropathy is a rare condition characterized by giant gastric folds associated with epithelial hyperplasia.312 Two

clinical syndromes have been identified: ZE syndrome, which is discussed in Chapter 34, and Ménétrier’s disease and an even rarer variant of it referred to as hyperplastic, hypersecretory gastropathy. Figure 52.16A and B demonstrate enlarged gastric folds in these 2 conditions. The enlarged gastric folds in Ménétrier’s disease are due to foveolar cell hyperplasia, edema, and variable degrees of inflammation. Ménétrier’s disease is typically but not always associated with protein-losing gastropathy (see Chapter 31) and with hypochlorhydria, whereas its rare hyperplastic, hypersecretory variant is associated with increased or normal acid secretion and parietal and chief cell hyperplasia, with or without excessive gastric protein loss. Ménétrier’s disease has been associated with infection with Hp, CMV, and HIV.313-315 Other conditions more common than Ménétrier’s disease and ZE syndrome can also cause enlarged gastric folds,312 including gastric malignancy (adenocarcinoma, lymphoma), granulomatous gastritides, gastric varices, and eosinophilic gastritis. Furthermore, pachydermoperiostosis (primary hypertrophic osteoarthropathy) has been reported to cause a type of hypertrophic gastropathy akin to Ménétrier’s disease,316,317 as has primary Sjőgren syndrome.318 Patients with Ménétrier’s disease may present with weight loss, epigastric pain, vomiting, anorexia, dyspepsia, hematemesis, and positive fecal occult blood tests. Ménétrier’s disease may be self-limited and may completely resolve in patients younger than 10 years of age or when it occurs in the postpartum period. CMV infections can cause Ménétrier’s disease of childhood.196 The risk of gastric cancer appears to be increased in Ménétrier’s disease (see Chapter 54).319 A fibrosing variant of the disease can mimic linitis plastica gastric cancer.320 The mucosa of patients with Ménétrier’s disease demonstrates irregular hypertrophic folds that involve the entire gastric corpus. The mucosa also demonstrates a swollen, spongy appearance subdivided by creases, creating a picture like cerebral convolutions. Ménétrier’s disease can be suspected when EUS shows thickening in the second layer of the gastric wall (deep mucosa, normally hypoechoic) and can be confirmed histologically by endoscopic mucosal resection.321,322 A polypoid variant of Ménétrier’s disease that resembles multiple hyperplastic gastric polyps has been described. Gastric resection specimens from patients with Ménétrier’s disease typically show large polypoid gastric folds or large cerebriform gastric folds with antral sparing (see Fig. 52.16C). In the absence of a gastrectomy, a full-thickness gastric mucosal biopsy is required to adequately assess the gastric histology in patients with hyperplastic gastropathy. The predominant microscopic feature of Ménétrier’s disease and hyperplastic, hypersecretory gastropathy is foveolar hyperplasia with cystic dilation (see Fig. 52.16D). The parietal and chief cells may be decreased and replaced by mucous glands in typical Ménétrier’s disease. The etiology of Ménétrier’s disease is unknown, although some cases have undoubtedly been caused by gastric infections with CMV or Hp. Concurrence of the disorder in identical twin men, who presented at ages 29 and 35, suggests a genetic component.323 A germline mutation in SMAD4 associated with juvenile polyposis can lead to a mixed hypertrophic/polypoid gastropathy.324 Hyperplasia of surface mucous cells may be due to enhanced EGF signaling in the gastric mucosa due to local overproduction of TGF-α.325 A unifying working hypothesis for juvenile polyposis syndrome and Ménétrier’s disease has been proposed.324 The authors hypothesized a mechanism that involves TGF-β-SMAD4 pathway inactivation and TGF-α overexpression related to Hp infection.325 An association between UC and Ménétrier’s disease has been proposed.326 Ideal treatment of hyperplastic gastropathy is unclear because the condition is so rare and controlled trials are lacking. Spontaneous resolution may occur, especially in children. Ganciclovir can be used in children with Ménétrier’s disease associated with CMV gastritis. Hp infection should be sought and treated,

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B

A

C

D Fig. 52.16  Radiologic and histopathologic examples of hyperplastic gastropathy with giant gastric folds. A, Film from an upper GI series in a patient with ZES. B, Film from an upper GI series in a patient with Ménétrier’s disease. C, Total gastrectomy specimen in a patient with Ménétrier’s disease (right: body, revealing hyperplastic mucosa and cerebriform folds; left: antrum, with relative sparing). D, Histopathology of Ménétrier’s disease showing enlarged folds with foveolar hyperplasia, cystically dilated glands, and minimal gastritis.

if present. Symptoms may improve with antisecretory agents (H2RAs or PPIs),327 especially if the patient has ZE syndrome or the normogastrinemic hyperplastic, hypersecretory variant of Ménétrier’s disease. Gastric antisecretory drugs may reduce gastric protein loss by strengthening intercellular tight junctions. Some patients with Ménétrier’s disease have responded to infusions of cetuximab (Erbitux),326 a monoclonal antibody against the EGF receptor (Table 52.5). Others have responded to the somatostatin analog octreotide.328,329 Partial or total gastric resection is reserved for severe complications including refractory or recurrent bleeding, obstruction, severe hypoproteinemia, and dysplasia or cancer development. 

TABLE 52.5  Effect of Intravenous Cetuximab on the Course of Ménétrier’s Disease in 7 Patients Treated at One Institution326,341

PORTAL HYPERTENSIVE GASTROPATHY This condition represents an important cause of GI blood loss in patients with cirrhosis. Gastric mucosal biopsies show vascular ectasia and congestion without a significant degree of inflammatory infiltrate or reactive gastropathy (see Chapters 20 and 92). 

Duration of Cetuximab Most Recent Patient (Months or Cycles) Histology

Post-Treatment Status

1 2

18 15

Minimal FH Minimal FH

Off treatment Off treatment

3 4 5

40 9 24

Still on treatment Gastrectomy Gastrectomy

6 7

9 8

Minimal FH Normal Dysplastic lesion 12 mo after therapy stopped FH FH

  

FH, foveolar hyperplasia.   

Gastrectomy Gastrectomy

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TABLE 52.6  Antimicrobial Drug Resistance in 135 Hp Strains Isolated From Patients in Houston Antimicrobial Drug

% of Strains Resistant (95% CI)

Amoxicillin Clarithromycin Levofloxacin Metronidazole Tetracycline

0 16% (10%-23%) 31% (23%-39%) 20% (13%-27%) 1% (0%-2%)

the organism(s) infecting an individual patient. However, such information is generally unavailable in contemporary US practice because few laboratories offer culturing of the organism and assessment of its antibiotic sensitivities. Therefore, it is very important to know an individual patient’s personal antibiotic history and to have some understanding of local antibiotic resistance patterns.336 The growing problem of antibiotic resistance in some regions is driving the development of novel regimens for the future. 

  

From Shiota S, Reddy R, Alsarra A, et al. Antibiotic resistance of Helicobacter pylori among male United States veterans. Clin Gastro Hepatol 2015;13:1616-24.   

DIFFERENTIAL DIAGNOSIS The most important disorders that can simulate gastritis and gastropathy are gastric polyps (neoplastic and non-neoplastic) and gastric malignancy (see Chapters 32 and 54). Although CT criteria have been useful in distinguishing gastritis/gastropathy from gastric malignancy,330 endoscopy and gastric biopsy with review by an expert pathologist are the most useful diagnostic procedures. Increased fluoro-deoxyglucose uptake by the stomach, especially the proximal half of the stomach, is seen occasionally during PET scanning in patients with reactive gastropathy (acute erosive gastritis) and should not be confused with neoplasia.275 Demonstration of B cell clonality (e.g., by immunostaining) can also help distinguish gastric marginal zone lymphomas from chronic lymphocytic gastritis or lymphomatoid gastropathy. 

TREATMENT Hp Infection The most recent recommendations on treatment of Hp infection come from the Toronto consensus conference and an updated guideline from the ACG.143,144 Treatment of Hp infection varies around the world although certain principles of treatment are generally agreed. Specific recommendations in different parts of the world generally reflect availability and resistance patterns to antimicrobial agents and local concerns about certain Hp-related outcomes such as gastric cancer. Major guidelines for the management of Hp infection reflect general management concordance, with regional differences.331-361 Historically, recommended Hp treatment regimens generally included a PPI plus 2 antibiotics for 10 to 14 days. However, recent recommendations have moved toward a standard 14-day treatment duration, as shorter treatment durations are associated with reduced effectiveness. However, some flexibility in treatment duration is offered in view of insufficient evidence from randomized controlled trials to support a strong recommendation for a specific treatment duration. Furthermore, quadruple combinations of a PPI and 3 antibiotics or antimicrobial agents are now generally recommended.144 Adherence to treatment can be a problem because of the requirement of taking multiple medicines and the frequent occurrence of generally mild, medication-related side effects. Patients should be counseled about the minor adverse effects (e.g., diarrhea, taste disturbance, cramping) that they may experience and about the importance of taking all prescribed medicines together for the complete course. Treatment success rates vary among countries and regionally within countries, related to antibiotic resistance and local ecology.334,335 From a study in Houston, resistance rates to 5 antibiotics are shown in Table 52.6. The Hp strain was sensitive to all 5 antibiotics in less than 50% of cases.351 Ideally, a personalized treatment regimen would be guided by knowledge of the specific Hp antibiotic resistance pattern of

Primary Treatments The 2017 update of the ACG’s practice guideline included a number of regimens as possible primary treatments for Hp infection.143 The strength of recommendation and quality of evidence given to each regimen are summarized in Table 52.7. A variety of “primary” treatments were suggested so that clinicians would have some flexibility in choosing the best regimen for an individual patient, assuming some knowledge of the patient’s prior antibiotic history. Strong recommendations were made for only a small number of primary treatment regimens. Although not all currently available PPIs are approved by the U.S. FDA as part of treatment regimens for Hp infection, there is no evidence for any difference within this class of drugs with respect to efficacy. Clarithromycin triple therapy comprises the twice-daily combination of clarithromycin 500 mg, amoxicillin 1000 mg, and a PPI in standard dose taken for 14 days. Patients who are genuinely allergic to penicillin should receive metronidazole 500 mg 3 times daily in place of amoxicillin (see later for details on penicillin allergy testing). Although clarithromycin triple therapy was once the most frequent and most recommended treatment regimen for Hp infection, it has fallen into disfavor because of rising rates of clarithromycin resistance. However, retrospectively collected data from a single US center found eradication rates of around 79.5% over a 15-year period, with no obvious reduction in efficacy seen over time.143 Although still considered by the ACG as one of the “primary” treatment regimens, it should not be offered to patients who have previously received clarithromycin (or another macrolide such as azithromycin) for the treatment of Hp infection or for another indication. Furthermore, it is not recommended for use in regions where the local resistance rate of Hp to clarithromycin is estimated to be 15% or higher (e.g., see Table 52.8, from Houston). Clarithromycin resistance is best considered an absolute phenomenon that cannot be overcome by increasing the dose of clarithromycin. Bismuth-based quadruple therapy is another recommended primary treatment option. It consists of the combination of a bismuth salt (e.g., bismuth subsalicylate or bismuth subcitrate), tetracycline, metronidazole and a PPI for 10 to 14 days. Because this regimen contains neither clarithromycin nor amoxicillin, it is an appropriate choice for patients who have previously used macrolides, who reside in areas with high (≥15%) macrolide resistance, and for those who are truly penicillin-allergic. The recent lack of availability of generic tetracycline had limited the utility of this regimen. However, that issue should now have been resolved. The presence of clarithromycin resistance does not influence the effectiveness of bismuth-based quadruple therapy. A combination capsule containing bismuth subcitrate 140 mg, metronidazole 125 mg, and tetracycline 125 mg, may help to simplify bismuth-based quadruple therapy for patients. In 2 separate studies, patients treated with 3 of these combination capsules 4 times daily and a PPI twice daily for 10 days had comparable eradication rates compared with standard 10-day clarithromycin triple therapy (88% vs. 83%),345 and significantly higher efficacy when compared with 7-day clarithromycin triple therapy.346,347 Concomitant therapy (also known as nonbismuth-based quadruple therapy) is the quadruple combination of clarithromycin,

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TABLE 52.7  Summary of First-Line Treatment Regimens as Recommended in the 2017 ACG Clinical Guideline on the Treatment of Hp Infection First-line Regimen

Duration (days)

Components

Recommendation

Level of Evidence

Comments

PPI, clarithromycin 500 mg, and 14 amoxicillin 1000 mg, each twice daily (or, if penicillin allergic, metronidazole 500 mg 3 times daily in place of amoxicillin) Bismuth-based PPI twice daily, bismuth subcitrate 10-14 quadruple therapy or subsalicylate 4 times daily, tetracycline 500 mg 4 times daily, and metronidazole 250 to 500 mg 3 or 4 times daily

Conditional

Low (For duration, moderate)

Strong

Low

Avoid in patients with prior macrolide exposure. Avoid in areas where local clarithromycin resistance rate is ⬧15%. Particularly recommended for patients with prior macrolide exposure or proven penicillin allergy

Concomitant therapy PPI, clarithromycin 500 mg, and amoxicillin 1000 mg, and a nitroimidazole 500 mg, each twice daily

10-14

Strong

Very low

Nitroimidazole may be metronidazole or tinidazole

Sequential therapy

PPI and amoxicillin 1000 mg, both twice daily

5-7

Conditional

Nitroimidazole may be metronidazole or tinidazole

PPI, clarithromycin 500 mg, and a nitroimidazole 500 mg, each twice daily

5-7

Low (For duration, very low)

PPI and amoxicillin 1000 mg, both twice daily

7

Conditional

Low (For duration, very low)

Nitroimidazole may be metronidazole or tinidazole

10-14

Conditional

Low (For duration, very low)

—

5-7

Conditional

Low (For duration, very low)

Nitroimidazole may be metronidazole or tinidazole

Clarithromycin triple therapy

Hybrid therapy

PPI, clarithromycin 500 mg, amoxicillin 7 1000 mg, and a nitroimidazole 500 mg, each twice daily Levofloxacin triple therapy

PPI twice daily, levofloxacin 500 mg once daily, and amoxicillin 1000 mg twice daily.

Levofloxacin PPI and amoxicillin 1000 mg, each sequential therapy twice daily.

PPI and amoxicillin 1000 mg, each 5-7 twice daily, levofloxacin 500 mg once daily, and a nitroimidazole 500 mg twice daily   

Adapted from Checchi S, Montanaro A, Pasqui L, et al. L-thyroxine requirement in patients with autoimmune hypothyroidism and parietal cell antibodies. J Clin Endocrinol Metab 2008;93:465-9.   

TABLE 52.8  Summary of Rescue Treatment Regimens as Recommended in the 2017 ACG Clinical Guideline on the Treatment of Hp Infection Duration (days)

Recommendation

Level of Evidence

Comments

Bismuth-based quadruple therapy (see Table 52.7) Levofloxacin triple therapy (see Table 52.7) Concomitant therapy (see Table 52.7) Rifabutin triple therapy

14

Strong

Low

Appropriate for patients who failed initial treatment with a clarithromycin-based regimen

14

Strong

Moderate (For duration, low)

Appropriate for patients who failed initial treatment with a clarithromycin-based regimen

10-14

Conditional

Very low

10

Conditional

High-dose dual therapy

14

Conditional

Moderate (For duration, very low) Low (For duration, very low)

Rescue Regimen

PPI twice daily, rifabutin 300 mg once daily, and amoxicillin 1000 mg twice daily PPI and amoxicillin 750 mg, each 4 times daily

  

Adapted from Checchi S, Montanaro A, Pasqui L, et al. L-thyroxine requirement in patients with autoimmune hypothyroidism and parietal cell antibodies. J Clin Endocrinol Metab 2008;93:465-9.   

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amoxicillin, metronidazole (or tinidazole) and a PPI. Although it is one of the recommended primary treatments in the 2017 ACG guideline, there have been no recent US-based clinical trials assessing its effectiveness. Optimal duration of treatment is uncertain; various studies have used it for between 3 and 14 days. Current recommendations are that it should be given for between 10 and 14 days. Sequential therapy involves a 2-step regimen, each of 5 to 7 days in duration. In the first step, a PPI is given with amoxicillin alone. In the second step, the PPI is given with clarithromycin and a nitroimidazole (typically tinidazole but possibly also metronidazole). This approach was developed in Europe where it had been widely adopted. It has not been extensively evaluated in trials conducted within North America but has not been found to be superior to other regimens. Despite its use of clarithromycin, it was initially thought to have limited effectiveness in the treatment of clarithromycin-resistant strains of Hp; in an early meta-analysis,362 sequential therapy eradicated 76.9% of clarithromycin-resistant strains, compared to 40.6% with clarithromycin triple therapy. More recently, however, an updated meta-analysis found no significant advantage of sequential therapy over 14 days of standard triple therapy or 10 to 14 days of bismuth-based quadruple therapy.363 Its relative complexity compared to other treatments and the limited evidence from North American trials regarding its lack of superiority over other treatments limit its utility and attractiveness as a first-line treatment option. Various “hybrid” regimens have also been developed, which essentially comprise a combination of some of the elements of sequential and concomitant treatment with corresponding increases in complexity. For example, one approach consists of giving a PPI and amoxicillin for 7 days, followed by the PPI, amoxicillin, a nitroimidazole, and clarithromycin for the next 7 days. There have been no trials in North America comparing this approach with other regimens, although studies in Asia suggest it is both efficacious and associated with high levels of treatment adherence. Except for bismuth-based quadruple therapy, all the regimens listed earlier include clarithromycin. In view of the problem of clarithromycin resistance, regimens that replace clarithromycin with an alternative antimicrobial have been developed for first-line treatment. The most frequently evaluated alternative to clarithromycin has been levofloxacin. Regimens that include this fluoroquinolone antibiotic have usually combined it with a PPI and amoxicillin. Levofloxacin triple therapy has not been formally evaluated as a first-line treatment in North America. However, studies from around the world indicate that it has similar efficacy as clarithromycin triple therapy but that local rates of antimicrobial resistance limit its effectiveness. Levofloxacin has also been studied in various sequential regimens in which it has essentially taken the place of clarithromycin. However, these have not been evaluated in trials conducted in North America. A combination of levofloxacin, omeprazole, nitazoxanide (“Alinia”) and doxycycline (referred to as “LOAD”) was found to be superior to clarithromycin-based triple therapy in a US randomized controlled trial.364 No further trials have been reported with this regimen. Treatment-related adverse effects can occur in as many as 50% of patients taking one of the treatment regimens described in Table 52.7, but generally these are mild and do not require discontinuation of therapy. Some of the more common adverse effects include taste alteration and GI upset with metronidazole and clarithromycin, and allergic reactions and diarrhea with amoxicillin. In addition, tetracycline should not be prescribed to children or women of childbearing potential. Adverse effects of Hp treatment have been extensively reviewed.337,338 Counseling patients to expect minor adverse effects is likely to improve adherence rates.340 

Rescue Treatments Initial treatment of Hp infection fails in up to 25% of patients. The most important predictors of failure of treatment are antibiotic resistance and poor adherence to treatment. Because patients’ upper GI symptoms after treatment are an unreliable guide to success or failure of eradication, it is recommended that all patients be re-tested after treatment.143 Post-treatment testing should be with a test of active infection such as the urea breath test or fecal antigen test; serologic testing should always be avoided after treatment of the infection. Only by the implementation of a program of routine post-treatment testing can clinicians get some understanding of the success rates of eradication treatments in practice. Patients who fail treatment with a first-line regimen should be re-treated with a rescue regimen. In general, patients should not be treated with a previously used combination, particularly those containing clarithromycin or levofloxacin. For patients with persistent infection following treatment with a clarithromycin-based primary regimen, re-treatment with either bismuth-based quadruple therapy or levofloxacin-based triple therapy is recommended. Table 52.8 summarizes recommendations about rescue treatment regimens. Primary resistance to antibiotics used to treat Hp varies widely throughout the world. In the USA, resistance to metronidazole and clarithromycin have been detected in up to 40% and in approximately 11% of strains, respectively. However, reliable recent data about Hp antimicrobial resistance from within the US remain scarce. Metronidazole and clarithromycin resistance increase with patient age and are more common in women than in men; there are also regional and racial differences in resistance rates. Hp resistance to tetracycline and amoxicillin remains extremely unusual (A) polymorphism in children and teenagers with Helicobacter pylori infection. J Venomous Animals and Toxins including Tropical Diseases 2017;23:23. 91. Maeda S, Yoshida H, Ogura KH, et al. Pylori activates NF-kappaB through a signaling pathway involving IkappaB kinases, NF-kappaB-inducing kinase, TRAF2, and TRAF6 in gastric cancer cells. Gastroenterology 2000;119:97–108. 92. Keates S, Keates AC, Warny M, et al. Differential activation of mitogen-activated protein kinases in AGS gastric epithelial cells by cag+ and cag- Helicobacter pylori. J Immunol 1999;163:5552–9. 93. Naumann M, Wessler S, Bartsch C, et al. Activation of activator protein 1 and stress response kinases in epithelial cells colonized by Helicobacter pylori encoding the cag pathogenicity island. J Biol Chem 1999;274:31655–62. 94. Takahashi S, Keto Y, Fujita T, et al. FR167653, a p38 mitogenactivated protein kinase inhibitor, prevents Helicobacter pylori– induced gastritis in Mongolian gerbils. J Pharmacol Exp Ther 2001;296:48–56. 95. Ding SZ, O’Hara AM, Denning TL, et al. Helicobacter pylori and H2O2 increases AP endonuclease-1/redox factor-1 expression in human gastric epithelial cells. Gastroenterology 2004;127:845–58. 96. O’Hara AM, Bhattacharyya A, Mifflin RC, et al. Interleukin-8 induction by Helicobacter pylori in human gastric epithelial cells is dependent on apurinic/apyrimidinic endonuclease-2/redox factor-1. J Immuol 2006;177:7990–9. 97. Serafini M, Bellocco R, Wolk A, Ekstrom AM. Total antioxidant potential of fruit and vegetables and risk of gastric cancer. Gastroenterology 2002;123:985–91. 98. Fahey JW, Haristoy X, Dolan PM, et al. Sulforaphane inhibits extracellular, intracellular, and antibiotic-resistant strains of Helicobacter pylori and prevents benzo[a]pyrene-induced stomach tumors. Proc Natl Acad Sci U S A 2002;99:7610–5. 99. Jang S, Bak E-J, Cha J-H. N-acetylcysteine prevents the development of gastritis induced by Helicobacter pylori. J. Micobiology 2017;55:396–402. 100. Yamaoka Y, Kwon DH, Graham DY. A M(r) 34,000 proinflammatory outer membrane protein (oipA) of Helicobacter pylori. Proc Natl Acad Sci U S A 2000;97:7533–8.

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345. Laine L, Hunt R, El-Zimaity H, et al. Bismuth-based quadruple therapy using a single capsule of bismuth biskalcitrate, metronidazole, and tetracycline given with omeprazole versus omeprazole, amoxicillin, and clarithromycin for eradication of Helicobacter pylori in duodenal ulcer patients: a prospective, randomized, multicenter, North American trial. Am J Gastroenterol 2003;98:562–7. 346. Malfertheiner P, Bazzoli F, Delchier JC, et al. Helicobacter pylori eradication with a capsule containing bismuth subcitrate potassium, metronidazole, and tetracycline given with omeprazole versus clarithromycin-based triple therapy: a randomised, open-label, non-inferiority, phase 3 trial. Lancet 2011;377:905–13. 347. Lara LF, Cisneros G, Gurney M, et al. One-day quadruple therapy compared with 7-day triple therapy for Helicobacter pylori infection. Arch Intern Med 2003;163:2079–84. 348. Gisbert JP, Calvet X. Review article: Rifabutin in the treatment of refractory Helicobacter pylori infection. Aliment Pharmacol Ther 2012;35:209–21. 349. Broutet N, Tchamgoue S, Pereira E, et al. Risk factors for failure of Helicobacter pylori therapy—results of an individual data analysis of 2751 patients. Aliment Pharmacol Ther 2003;17:99–109. 350. Suzuki T, Matsuo K, Ito H, et al. Smoking increases the treatment failure for Helicobacter pylori eradication. Am J Med 2006;119:217– 24. 351. Greenberg ER, Chey WD. Defining the role of sequential therapy for H. pylori infection. Lancet 2013;381:180–2. 352. Kearney DJ. Retreatment of Helicobacter pylori infection after initial treatment failure. Am J Gastroenterol 2001;96:1335–9. 353. Luther J, Chey WD, Saad RJ. A clinician’s guide to salvage therapy for persistent Helicobacter pylori infection. Hosp Pract 2011;39:133– 40. 354. Fiorini G, Vakil N, Zullo A, et al. Culture-based selection therapy for patients who did not respond to previous treatment for Helicobacter pylori infection. Clin Gastroenterol Hepatol 2013;11:507–10. 355. Gisbert JP, Calvet X. Update on non-bismuth quadruple (concomitant) therapy for eradication of Helicobacter pylori. Clin Exp Gastroenterol 2012;5:23–34. 356. Osato MS, Reddy R, Reddy SG, et al. Pattern of primary resistance of Helicobacter pylori to metronidazole or clarithromycin in the United States. Arch Intern Med 2001;161:1217–20. 357. Meyer JM, Silliman NP, Wang W, et al. Risk factors for Helicobacter pylori resistance in the United States: the surveillance of Hp antimicrobial resistance partnership (SHARP) study, 1993-1999. Ann Intern Med 2002;136:13–24. 358. Gisbert JP. The recurrence of Helicobacter pylori infection: incidence and variables influencing it. A critical review. Am J Gastroenterol 2005;100:2083–99. 359. Gisbert JP, González L, Calvet X, et al. Proton pump inhibitor, clarithromycin and either amoxycillin or nitroimidazole: a metaanalysis of eradication of Helicobacter pylori. Aliment Pharmacol Ther 2000;14:1319–28.

360. Morgan DR, Torres J, Sexton R, et al. Risk of recurrent Helicobacter pylori infection 1 year after initial eradication therapy in 7 Latin American communities. J Am Med Assoc 2013;309:578–86. 361. Gisbert JP, Castro-Fernandez M, Bermejo F, et al. Third-line rescue therapy with levofloxacin after two H. pylori treatment failures. Am J Gastroenterol 2006;101:243–7. 362. Jafri NS, Hornung CA, Howden CW. Meta-analysis: sequential therapy appears superior to standard therapy for Helicobacter pylori infection in patients naïve to treatment. Ann Int Med 2008;148:922–31. 363. Gatta L, Vakil N, Vaira D, et al. Global eradication rates for Helicobacter pylori infection: systematic review and meta-analysis of sequential therapy. Br Med J 2013;347:f4587. 364. Basu PP, Rayapudi K, Pacana T, et al. A randomized study comparing levofloxacin, omeprazole, nitazoxanide and doxycycline versus triple therapy for the eradication of Helicobacter pylori. Amer J Gastroenterol 2011;106:1970–5. 365. Macy E. Penicillin allergy: optimizing diagnostic protocols, public health implications, and future research needs. Curr Opin Allergy Clin Immunol 2015;15:308–13. 366. Goodman KJ, Joyce SL, Ismond KP. Extragastric diseases associated with Helicobacter pylori infection. Curr Gastroenterol Rep 2006;8:458–64. 367. Franchini M, Veneri D. Helicobacter pylori–associated immune thrombocytopenia. Platelets 2006;17:71–7. 368. Asahi A, Nishimoto T, Okazaki Y, et al. Helicobacter pylori eradication shifts monocyte Fcgamma receptor balance toward inhibitory FcgammaRIIB in immune thrombocytopenia purpura patients. J Clin Invest 2008;118:2939–49. 369. DuBois S, Kearney DJ. Iron-deficiency anemia and Helicobacter pylori infection: a review of the evidence. Am J Gastroenterol 2005;100:453–9. 370. Zeng M, Mao XH, Li JX, et al. Efficacy, safety and immunogenicity of an oral recombinant Helicobacter pylori vaccine in children in Chia: a randomized, double-blind, placebo-controlled, phase 3 trial. Lancet 2015;386:1457–64. 371. Setiawan VW, Zhang ZF, Yu GP, et al. Protective effect of green tea on the risks of chronic gastritis and stomach cancer. Int J Cancer 2001;92:600–4. 372. Du Y, Hao J, Wang B, et al. Gastro-protecting effect of gefarnate on chronic erosive gastritis with dyspeptic symptoms. Chin Med J 2012;125:2878–84. 373. Chitapanarux T, Praisontarangkul O, Lertprasertsuke N. An openlabeled study of rebamipide treatment in chronic gastritis patients with dyspeptic symptoms refractory to proton pump inhibitors. Dig Dis Sci 2008;53:2896–903.

53

Peptic Ulcer Disease Francis K.L. Chan, James Y.W. Lau

CHAPTER OUTLINE EPIDEMIOLOGY����������������������������������������������������������������806 ETIOLOGY AND PATHOGENESIS����������������������������������������806 Hp Infection��������������������������������������������������������������������807 Use of Aspirin and Other NSAIDs������������������������������������807 Other Causes of Ulcers and Idiopathic Ulcers������������������808 CLINICAL FEATURES AND DIAGNOSIS������������������������������808 MEDICAL THERAPY OF ACTIVE PEPTIC ULCER DISEASE����������������������������������������������������������������������������810 Pharmaceutical Agents��������������������������������������������������810 Hp-associated Ulcers ����������������������������������������������������811 NSAID Ulcers������������������������������������������������������������������812 Other Causes of Ulcers and Idiopathic Ulcers������������������812 REFRACTORY ULCERS������������������������������������������������������812 PREVENTION OF ULCER DISEASE������������������������������������812 Antacids������������������������������������������������������������������������812 H2RAs����������������������������������������������������������������������������813 Misoprostol��������������������������������������������������������������������813 PPIs ������������������������������������������������������������������������������813 COX-2 Inhibitors (In Place of NSAIDs)������������������������������813 Assessing Risk and Choice of Agent(s)����������������������������814 COMPLICATIONS AND THEIR TREATMENT ����������������������815 Bleeding������������������������������������������������������������������������815 Perforation ��������������������������������������������������������������������817 Obstruction��������������������������������������������������������������������818 STRESS ULCERS ��������������������������������������������������������������819

An ulcer in the GI tract can be defined as a 5 mm or larger break in the lining of the mucosa, with appreciable depth at endoscopy or with histologic evidence of submucosal extension. An erosion is a break less than 5 mm. The distinction between an ulcer and an erosion is somewhat arbitrary. The term PUD is used to include ulcerations and erosions in the stomach and duodenum from a number of causes. These lesions are called “peptic” because the enzyme pepsin, proteolytic at an acidic pH (see Chapter 51), plays a major role in causing the mucosal breaks, regardless of the inciting agent. Decades of research focused on the role of gastric acid secretion and the effects of stress, personality type, and genetics in the pathogenesis of PUD. The discovery of the histamine-2 (H2) receptor and development of H2RAs,1 and subsequently PPIs, led to major changes in the management of PUD. The discovery of Hp and its role in PUD (see Chapter 52) transformed PUD from a chronic, recurrent disease to a curable one.2 Hp infection remains an important cause of PUD in the world. In developed countries, frequent use of NSAIDs, including low-dose aspirin for cardiovascular indications, has emerged as a leading cause of PUD, especially among the aging population.

806

EPIDEMIOLOGY The epidemiology of PUD has undergone remarkable changes in the past 2 centuries. The risk of developing PUD, and dying from PUD, increased in successive cohorts born between 1840 and 1890, and then declined thereafter.3 There was a peak in the incidence of GU in the first half of the 19th century and a subsequent peak in the incidence of DU in the second half of the 19th century. Sonnenberg proposed a birth-cohort effect to explain the peaks in the incidence of, and mortality from, peptic ulcers. Hp infection acquired during childhood or adolescence became manifested as peptic diseases in later years. As Hp infection gradually declined in the population over time, the prevalence of infection also gradually shifted from a younger toward older age groups. The incidence of DU and GU has declined in parallel with the decline in the prevalence of Hp infection, likely a result of improved sanitary conditions and a safer food and water supply. Based on physicians’ diagnoses, the annual incidence of PUD ranges from 0.14% to 0.19% in developed countries. Based on hospital diagnoses, the incidence is lower: 0.03% to 0.17%. The prevalence of PUD ranges from 0.12% to 4.7% for physiciandiagnosed, and from 0.1% to 2.6% for hospital-diagnosed case series.4 There is a wide geographic variation in the prevalence of PUD. In an endoscopic series involving 1022 volunteers from Shanghai, China (average age, 48 years), the prevalence of PUD was 17.2%, of whom 93% were infected with Hp.5 The most frequent complication from PUD is bleeding; the reported annual incidence of bleeding among populations varies from 19 to 57 per 100,000 individuals (≈0.02% to 0.06%). Peptic ulcer perforation (PULP), less frequent than bleeding, has reported incidences of 4 to 14 per 100,000 individuals (0.004% to 0.014%).6 Along with a decline in uncomplicated PUD cases, there is a similar decline in incidence of ulcer complications in recent years. Laine and colleagues7 used a national inpatient database to calculate the annual incidence of, and mortality from, GI complications during 2001 to 2009. During this time period, the incidence of peptic ulcer bleeding fell from 48.7 to 32.1 per 100,000. Over the same period, the ageand sex-adjusted case fatality rates from UGI bleeding decreased from 3.8% to 2.7%. In 2009, the case fatality rate for UGI bleeding (2.45%) was considerably lower than for UGI perforation (10.7%). In a nationwide population-based cohort study of 403,567 Taiwanese patients, hospitalizations for complicated peptic ulcers decreased significantly over a 10 year period8; thus the annual incidence of hospitalizations for bleeding DU or for perforated DU fell from 108 to 40 and from 9.8 to 5.8 per 100,000, respectively. A similar decline was evident for bleeding and perforated GUs (from 117 to 61 and from 11 to 6 per 100,000, respectively). 

ETIOLOGY AND PATHOGENESIS The principal risk factors of PUD are Hp infection and NSAID use (Fig. 53.1) and as will be discussed, many patients with PUD have both of these risk factors. On the other hand, PUD patients may have neither of these risk factors (Hp-negative, NSAIDnegative ulcers); some of these latter patients will have another cause of ulcer such as gastrinoma (ZES; see Chapter 34), whereas others will have ulcers that are idiopathic.

CHAPTER 53  Peptic Ulcer Disease None known

None known

ZES, other NSAID use

ZES, other NSAID use

Hp infection

Hp infection

Duodenal

Gastric

Fig. 53.1  Pie charts depicting conditions associated with PUD. The percentages shown are rough approximations based on studies from Western countries. The relative contributions of Hp infection and NSAID use to peptic ulcer vary considerably among different populations and, within populations, vary with age and socioeconomic status. Also, the separation depicted in this figure is somewhat artificial because NSAID use and Hp infection often coexist.

Hp Infection The prevalence of Hp infection varies widely among countries in the world (see Chapter 52). In series reported between 2009 and 2011, the prevalence of infection ranged from 7% to 87%, depending on the methods of diagnosis and the population that was sampled. The lowest prevalence was observed in the USA and European countries (7% to 33%).9 Those reported from Japan and China ranged from 56% to 72%. In general, the rate of Hp infection is declining. Feinstein and colleagues studied hospital discharge records for PUD in the USA between 1998 and 2005.10 In parallel with a decline in annual hospitalization rates for PUD, from 71.1 to 56.5 per 100,000, there was a decrease in hospitalization due to Hp-related disease, from 35.9 to 19.2 per 100,000. The prevalence of Hp infection in patients with bleeding ulcers remains high. Sanchez-Delgado and colleagues compiled 71 studies containing 8496 patients with bleeding peptic ulcers and found an Hp infection rate of 72%. The use of an Hp diagnostic test after the index bleed was associated with high Hp prevalence.11 As discussed in Chapters 51 and 52, Hp causes an antrumpredominant gastritis in 10% to 20% of infected patients, which results in high gastric acid secretion and an increased risk of DU. The increased acid output from the stomach results in increased acid load to the duodenum that can result in gastric metaplasia in the duodenal bulb.12 Some believe that the metaplastic epithelium then becomes infected with Hp from the stomach, resulting in focal “duodenitis” (technically, gastritis), sometimes followed by erosion and ulcer formation. Most patients with Hp infection have a pan-gastritis involving both the antral and fundic mucosa that lowers gastric acid secretion13 and predisposes to GU formation. In these individuals, it is proposed that weakened mucosal defense mechanisms (see Chapter 51), rather than high acid secretion, are what predisposes to gastric ulceration. The role of Hp’s genes and their protein products in the pathogenesis of PUD is discussed in Chapter 52. 

Use of Aspirin and Other NSAIDs Aspirin is increasingly used on a regular basis for the prevention of cardiovascular events, either alone or in combination with a platelet adenosine diphosphate inhibitor such as clopidogrel (dual antiplatelet therapy). NSAIDs are used on a regular basis by approximately 11% of the U.S. population. Regular use of NSAIDs increases the odds of GI bleeding up to 5- to 6-fold.14

807

Serious ulcer-related complications often leading to hospitalization occur in 1% to 4% of NSAID users.15 NSAID users who also take aspirin are at an especially high risk for complications. In a population-based study from Denmark, the odds ratio for GI bleeding in people taking low-dose aspirin alone was 2.6, and this ratio increased to 5.6 in patients who were also taking an NSAID.16 In a national study of mortality associated with a hospital admission for adverse GI events related to NSAID use in Spain, the death rate attributed to NSAID/aspirin use was 15.3 per 100,000 population compared to 2.5 per 100,000 of the general population.17 The gastric and duodenal mucosa have several defense mechanisms protecting them from digestion by acid and pepsin (see Chapter 51). NSAIDs cause mucosal damage through disruption of mucus phospholipids, cell membranes and by uncoupling mitochondrial oxidative phosphorylation, but most evidence suggests that NSAIDs damage the gastric and duodenal mucosa by suppression of prostaglandin synthesis.18 COX isoforms COX-1 and COX-2 are responsible for the synthesis of prostaglandins. COX-1 is expressed in the stomach and helps maintain the integrity of gastric epithelium and the mucous barrier. COX-2 is not expressed in the healthy stomach but is rapidly expressed in response to the cytokines generated by inflammatory processes. Conventional NSAIDs such as ibuprofen inhibit the COX-1 and the COX-2 isoenzymes more or less equally. COX-1 inhibition reduces prostaglandin synthesis, which leads to a reduction in mucosal defense. Animal experiments have found that neutrophil adherence to the gastric microcirculation plays a critical role in initiating NSAID injury. Neutrophil adherence liberates oxygen-free radicals, releases proteases, and obstructs capillary blood flow. Inhibition of neutrophil adherence has been shown to reduce NSAID-induced damage. In addition, 2 gaseous mediators, nitric oxide (NO) and hydrogen sulfide (H2S), contribute to maintaining the gastric mucosal barrier. NO and H2S increase mucosal blood flow, stimulate mucus secretion, and inhibit neutrophil adherence.19 NO-releasing and H2S-releasing derivatives of NSAIDs have been shown to protect against gastric damage when compared to the parent drugs. Gastric acid plays a secondary but important role by turning superficial mucosal lesions into deeper injury, interfering with platelet aggregation, and impairing ulcer healing.20 Hp infection appears to influence the risk of PUD in patients receiving NSAIDs. A meta-analysis showed that Hp infection raised the risk of peptic ulcer bleeding more than 6-fold in patients receiving long-term NSAIDs, whereas Hp alone and NSAID use alone raised the risk by 1.79-fold and 4.85-fold, respectively.21 An updated meta-analysis showed similar findings.22 Among patients who are about to start NSAID therapy, eradication of Hp reduces the subsequent risk of ulcer development.23,24 A systematic review has shown that testing for (and eradication of) Hp lowers the risk of peptic ulcers among NSAID users;25 however, eradication of Hp infection alone is insufficient to prevent peptic ulcer bleeding in NSAID users at high ulcer risk.26,27 There is also evidence that Hp infection increases the risk of PUD in patients receiving low-dose aspirin. Among Hp-infected patients with recent ulcer bleeding who continued to take lowdose aspirin, successful eradication of Hp infection resulted in a very low risk of recurrent ulcer bleeding, similar to that seen with aspirin/omeprazole co-therapy.26 This low risk of ulcer rebleeding after eradication of Hp was not seen in patients with bleeding ulcers who continued to take NSAIDs. In a long-term prospective cohort study,28 Hp-infected low-dose aspirin users (≤160 mg/day) with bleeding ulcers who resumed their aspirin had a low risk of recurrent ulcer bleeding after eradication of Hp, a risk that was not significantly different from the risk in new aspirin users with no history of ulcer disease (5 bleeds per 100 patient-years). 

Other Causes of Ulcers and Idiopathic Ulcers Deep ulcers and perforations of the stomach and duodenum have been described in cocaine and methamphetamine users, presumably due to mucosal ischemia.29 Bisphosphonate therapy has also been associated with gastroduodenal ulceration,30 although esophageal injury with bisphosphonates is clinically more of a concern. There is little, if any, risk for PUD in patients taking glucocorticoids.31 In combination with NSAIDs, however, glucocorticoids increase the risk of PUD above the risk with NSAIDs alone.32 There is also a weak association between use of selective serotonin reuptake inhibitor antidepressants and PUD, especially in those with concurrent NSAID use. Smoking, stress, type A personality, and excessive alcohol use are some of the risk factors implicated for PUD. Although these factors can contribute to PUD, none has emerged as a sole cause of the disease. Hp infection is a confounder that was not addressed in earlier studies. An uncommon cause of PUD is gastrinoma (ZES) (see Chapter 34).33 Systemic mastocytosis (see Chapter 37) is another uncommon condition in which multiple ulcers may occur in the stomach or duodenum.34 Secretion of histamine by the mast cells is thought to result in the excessive stimulation of acid production through the histamine receptor. Associations between PUD and α1-antitrypsin deficiency, chronic obstructive lung disease, and chronic kidney disease have been described. Several other diseases (e.g., gastric cancer, gastric lymphoma, Crohn disease) can cause ulcers that can mimic peptic ulcers. Rarer causes of peptic ulcers include eosinophilic gastroenteritis, viral infections (e.g., cytomegalovirus), Behcet disease in immunocompromised patients, Helicobacter heilmannii infection, and ulcers in a Meckel diverticulum with heterotopic gastric mucosa. With a global decline in the prevalence of Hp infection, the proportion of patients with idiopathic ulcers has been increasing. Studies in North America have shown that more than 10% of peptic ulcers are not associated with Hp infection or the use of NSAIDs.

Whether the incidence of idiopathic ulcers is increasing or not is controversial. It has been argued that only the relative proportion, but not the true incidence, of idiopathic ulcers has increased as a result of a falling incidence of Hp ulcers. However, there are prospective data showing that the absolute incidence of idiopathic bleeding ulcers has increased by 4-fold. Importantly, patients with a history of idiopathic bleeding ulcers have a 4-fold increased risk of recurrent ulcer bleeding and more than 2-fold increase in mortality compared to patients with history of Hp ulcers.35 

CLINICAL FEATURES AND DIAGNOSIS The predominant symptom of patients with uncomplicated PUD is epigastric pain. Pain is typically associated with hunger, occurs at night, and is often relieved by food and antacids. Often patients complain of dyspeptic symptoms such as a bloated sensation and fullness. Some patients complain of heartburn that may or may not be accompanied by erosive esophagitis. Chronic NSAID users, typically older adult patients, can present with ulcer bleeding or perforation without prior ulcer symptoms. EGD is the procedure of choice for diagnosis of uncomplicated PUD (Fig. 53.2A and B). EGD is more sensitive and specific than radiologic studies, such as UGI series with barium. Nevertheless, endoscopy is expensive and has the potential for complications (see Chapter 42). Therefore, the decision to perform endoscopy in a patient suspected of having PUD is based on a number of factors. As discussed later in this chapter and in Chapter 20, patients presenting with acute GI bleeding need endoscopic evaluation to allow an accurate diagnosis and for the administration of endoscopic therapy. Furthermore, patients with epigastric pain suggestive of PUD but also with “alarm” features such as weight loss or recurrent vomiting may prompt concern for gastric malignancy as well as require EGD (Box 53.1). If a DU or GU is found during EGD, gastric mucosal biopsies should be obtained for a rapid urease test to diagnose Hp infection (see Chapter 52). Biopsies should also be taken from the edges of GUs because of risk of gastric cancer. Customarily, if the GU biopsies are benign, EGD is repeated 8 weeks later to confirm healing of the GU, because up to 4% of apparently benign GUs at initial endoscopy are subsequently found to be malignant.36,37

CHAPTER 53  Peptic Ulcer Disease

Dyspeptic upper abdominal symptoms consisting of pain or discomfort in the upper abdomen are common in clinical practice, accounting for 2% to 5% of visits to family practitioners (see Chapter 14).38 Owing to the high cost and impracticality of subjecting all dyspeptic individuals to prompt endoscopy, 2 other nonendoscopic strategies (besides UGI series, with its inherent lower sensitivity and specificity for PUD) have been proposed as an initial step in the

BOX 53.1 Alarm Features in Patients With UGI Symptoms* Age older than 55 years with new-onset dyspepsia Family history of UGI cancer GI bleeding, acute or chronic, including unexplained iron deficiency Jaundice Left supraclavicular lymphadenopathy (Virchow node) Palpable abdominal mass Persistent vomiting Progressive dysphagia Unintended weight loss   

*These features should prompt EGD and often other testing to establish a definitive diagnosis (see Chapter 14).

≥ 60 years of age

management of suspected PUD (Fig. 53.3). The strategies are (1) “test-and-treat,” based on a noninvasive diagnosis of Hp infection and subsequent eradication therapy when Hp is detected, and (2) empirical antisecretory therapy, usually with a PPI. Gisbert and Calvet39 reviewed the literature and concluded that the Hp test-and-treat strategy will cure most cases of PUD and prevent most cases of gastroduodenal disease. A small proportion of patients with Hp-related functional dyspepsia would also improve in their symptoms. The test-and-treat strategy has been compared with endoscopy-directed diagnosis in 8 randomized controlled trials (RCTs). These trials differed in how Hp was diagnosed, and the upper age cutoff varied from 45 to 55 years. In some studies, serology was used for diagnosis of infection, which is less specific than 13C urea breath testing (see Chapter 52). The background Hp prevalence in the study populations ranged from 23% to 53%. After a 12-month follow-up, the prevalence of dyspeptic symptoms was similar in the 2 groups. In 7 of the 8 trials, cost data were reported, and the test-and-treat strategy was less expensive because of the many endoscopies avoided. Ford and colleagues performed a meta-analysis of 5 RCTs involving 1924 patients and found a slight benefit at 12 months of prompt EGD on dyspeptic symptoms over test-and-treat (risk ratio, 0.95; 95% confidence index [CI], 0.92 to 0.99), possibly because a normal EGD may have had a reassuring effect in some patients.40

Adult dyspepsia patient

< 60 years of age

Hp test and treat

Endoscopy Organic pathology

Normal

Manage according to relevant guideline

809

Positive

Manage according to Chapter 14

No response

Hp eradication

Response

Response

Response

Success

Response

Negative

PPI

No Response

TCA or prokinetic

No Response

Consider psychotherapy

Fig. 53.3 ACG and Canadian Association of Gastroenterology (CAG) guideline algorithm for the management of undiagnosed PUD. This is also the current management approach for patients with suspected PUD. TCA, tricyclic antidepressant. (Adapted from Moayyedi P, Lacy BE, Andrews CN, et al. ACG and CAG clinical guideline: management of dyspepsia. Am J Gastroenterol 2017; 112:988-1013.)  

 

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PART VI  Stomach and Duodenum

According to a joint ACG/Canadian Association of Gastroenterology guidelines, it was recommended that patients with uninvestigated dyspepsia who are below 60 years of age should have a noninvasive test H and treatment if positive. Those with a negative test or do not respond to this approach should receive a trial of PPI therapy. Tricyclic antidepressants or prokinetic therapies can be tried if they are not responsive to PPI therapy. The incidence of UGI malignancies including gastric cancer rises with age and, thus, current nonendoscopic management strategies are generally reserved for younger patients with upper abdominal symptoms. The age after which prompt EGD should become routine is debated and, to a substantial degree, depends on the epidemiology of UGI cancer in the population under consideration. In Western populations, UGI cancer is uncommon in young individuals, and therefore an age cutoff of 50 or 55 years is often used. Patients older than age 60 presenting with new-onset upper abdominal symptoms suggestive of PUD should therefore be referred for EGD. In Asia and Eastern Europe, where the incidence of gastric cancer is substantially higher than in Western nations, a younger age cutoff may be reasonable. The Joint ACG/Canadian Association of Gastroenterology guidelines on dyspepsia in 2017 recommended that patients with uninvestigated dyspepsia who are less than 60 years of age should have a noninvasive Hp test and treatment if positive.39,41 Those with a negative Hp test or who do not respond to this approach should receive a trial of a PPI therapy. Tricyclic antidepressants or prokinetic therapies can be tried if the patients are not responsive to PPI therapy (see Chapter 14 and Fig. 53.3). In areas of moderate- to- high Hp prevalence, the test-and-treat strategy is preferred. The Maastricht Consensus Conference Report in 2017 recommended a test-and-treat strategy for uninvestigated dyspepsia. This approach is subject to regional Hp prevalence and cost-benefit considerations.40,42 The test-and-treat strategy is, however, not applicable to patients with alarm symptoms or to older patients. The ability of alarm features (see Box 53.1) to accurately predict malignancy (as opposed to PUD or nonulcer dyspepsia) has, however, been questioned in a review of 15 studies.43 The sensitivity of alarm symptoms in the diagnosis of malignancy varied from 0% to 83% across studies. 

MEDICAL THERAPY OF ACTIVE PEPTIC ULCER DISEASE Several pharmaceutical agents are available to attempt to heal active DUs and GUs.

Pharmaceutical Agents Antacids Antacids neutralize gastric acid but their ability to heal ulcers is poor. Most physicians do not use antacids as primary therapy to heal ulcers but instead recommend their use to relieve dyspeptic symptoms. The most common adverse effect of magnesium-containing antacids is diarrhea. In contrast, aluminum- and calciumcontaining antacids may cause constipation. All antacids must be used with caution, if at all, in patients who have chronic kidney disease, in whom magnesium-containing agents can cause hypermagnesemia, calcium-containing antacids hypercalcemia, and aluminum-containing antacid neurotoxicity.44 

Antisecretory Agents Antisecretory therapy is not routinely required for patients with uncomplicated Hp ulcers in whom ulcers heal after successful eradication of Hp even without antisecretory therapy; however, antisecretory drugs play an important role in the management of

patients with PUD not associated with Hp. The role of antisecretory drugs in the management of gastrinoma (ZES) is discussed in Chapter 34. H2Ras H2RAs are competitive inhibitors of histamine-stimulated acid secretion (see Chapter 51) and markedly suppress basal and mealstimulated acid secretion.45 When administered in the evening, H2RAs are effective in suppressing nocturnal acid output.46 H2RAs are well absorbed after oral dosing, and their absorption is not affected by food. Peak blood levels are achieved within 1 to 3 hours after an oral dose. H2RAs cross the blood-brain barrier and the placenta.47,48 After oral administration, several H2RAs (cimetidine, ranitidine, and famotidine) undergo first-pass hepatic metabolism, which reduces their bioavailability by 35% to 60%. In contrast, the H2RA nizatidine does not undergo first-pass metabolism, and its bioavailability approaches 100% with oral dosing. H2RAs are eliminated by a combination of renal excretion and hepatic metabolism. Dose reductions are recommended when the creatinine clearance is below 50 mL/min. Dialysis does not remove substantial amounts of H2RAs; thus, dose adjustments are not necessary for dialysis patients. Dose reductions are generally not required for patients with hepatic failure unless it is accompanied by chronic kidney disease. Tolerance to the antisecretory effects of H2RAs develops quickly and frequently,49 although the mechanism for tolerance is not clear. H2RAs are safe and well tolerated. One meta-analysis of randomized clinical trials concluded that the overall rate of adverse effects reported for H2RAs did not differ significantly from placebo treatment.50 Nevertheless, a number of untoward effects have been described, primarily in anecdotal reports and uncontrolled series. Cimetidine has weak antiandrogenic activity that can occasionally cause gynecomastia and impotence.51 Both cimetidine and ranitidine bind to the hepatic cytochrome P-450 (CYP) mixed-function oxidase system. This binding can inhibit the elimination of other drugs that are metabolized through the same system, including warfarin, theophylline, phenytoin, lidocaine, and quinidine.52 In contrast, famotidine and nizatidine have no significant avidity for the CYP system.  PPIs. PPIs decrease gastric acid secretion through inhibition of H+, K+-ATPase, the proton pump of the parietal cell (see Chapter 51). These agents are prodrugs that must be activated by acid to inhibit the H+, K+-ATPase. Interestingly, prodrug PPIs are also acid-labile compounds that must be protected from degradation by gastric acid after oral administration by enteric coating or an antacid.53 Absorption of the enteric-coated PPIs may be erratic, and peak serum concentrations are not achieved until 2 to 5 hours after oral administration. Although the plasma half-life of PPIs is short (≈2 hours), the duration of acid inhibition is long as a result of covalent binding of the active metabolite of the prodrug to the H+, K+-ATPase. PPIs undergo significant hepatic metabolism, but dose adjustments are not required in patients with significant renal or hepatic impairment. There is genetic polymorphism in CYP2C19, one of the isoenzymes involved in PPI metabolism. Approximately 25% of Asians and 3% of white persons have deficient CYP2C19 activity. This polymorphism leads to substantially higher plasma levels of omeprazole, lansoprazole, and pantoprazole, but not rabeprazole.36,37,54 PPIs, as a result of their requirement for concentration and activation in acidic compartments, bind predominantly to those proton pumps that are actively secreting acid. With meal stimulation, 60% to 70% of the proton pumps actively secrete acid; thus, PPIs are most effective if they are administered immediately before meals. For once-daily dosing, it is recommended that PPIs be taken immediately before breakfast.55 Unlike H2RAs, tolerance to the antisecretory effects of PPI therapy has not been seen.

CHAPTER 53  Peptic Ulcer Disease

PPIs, by raising the gastric pH, can affect the absorption of a number of drugs. However, this pH effect rarely has clinically important effects, except when the PPIs are given with ketoconazole or digoxin.55-57 Ketoconazole requires gastric acid for absorption, and this antifungal drug may not be absorbed effectively if PPIs have also been prescribed. If a patient requires both a PPI and antifungal therapy, it is recommended that an agent other than ketoconazole be chosen. Conversely, an elevated gastric pH facilitates absorption of digoxin, resulting in higher plasma digoxin levels. For patients treated concomitantly with PPIs and digoxin, clinicians should consider monitoring plasma digoxin levels. Because PPIs are metabolized by the CYP system, they have the potential to alter the metabolism of other drugs that are eliminated by CYP enzymes. The potential interaction between PPIs and clopidogrel has drawn widespread attention. Clopidogrel, a nonaspirin antiplatelet prodrug, is activated by hepatic CYP2C19 and other CYPs to its active metabolite. PPIs reduce the antiplatelet effect of clopidogrel through competitive inhibition of CYP2C19. Meta-analysis of observational studies reported a significant increase in major adverse cardiovascular events including cardiovascular deaths among patients receiving concomitant PPIs and clopidogrel.58,59 However, an association between PPI and clopidogrel use has not been confirmed by prospective studies and a large-scale RCT.60,61 Despite the inconsistent findings, regulatory authorities in the USA and Europe have issued warnings against the use of certain PPIs in patients receiving concomitant clopidogrel. There are other concerns about the safety of long-term use of PPIs. To date, PPI use has been implicated in many conditions, including osteoporosis, hypomagnesaemia, gastric cancer, enteric infections, interstitial nephritis, pneumonia, dementia, and NSAID-enteropathy. Currently, there is no definite evidence to suggest that these conditions are attributable to PPI use.62 It is possible that a new evidence will emerge to indicate a causal relationship. In the meantime, long-term use of PPI without a strong indication should be discouraged.  Potassium-Competitive Acid Blocker Potassium-competitive acid blocker (P-CAB) therapy competes with potassium to inhibit H+, K+-ATPase in parietal cells at the final stage of the acid secretory pathway (see Chapter 51).63 Unlike PPIs, a P-CAB is acid stable and does not require an acidic environment for activation (i.e., a prodrug is not required). To date, vonoprazan is the only P-CAB commercially available in Japan and some other countries. Vonoprazan exerts a near-maximum inhibitory effect from the first dose and its effect lasts for 24 hours.63 In 2 phase 3 RCTs, vonoprazan (20 mg once daily) was not inferior to lansoprazole (30 mg once daily) for the healing of GUs and DUs. RCTs.64,65 Two other randomized trials showed that vonoprazan (10 and 20 mg) was as effective as lansoprazole (15 mg) in preventing ulcer recurrence associated with long-term use of NSAIDs and low-dose aspirin.66 

Mucosal Protective Agents Sucralfate is a complex aluminum salt of sulfated sucrose. When exposed to gastric acid, the sulfate anions can bind electrostatically to positively charged proteins in damaged tissue.67,68 Sucralfate (1g 4 times daily) is equally effective to H2RAs in healing DUs and is approved by the FDA in the USA for this indication. Very little (2 cm) probably should not be considered refractory until it has persisted beyond 12 weeks of antisecretory therapy. • Is there evidence of a hyper-secretory condition? A family history of gastrinoma or MEN type I or a personal history of chronic diarrhea, hypercalcemia caused by hyperparathyroidism, or ulcers involving the postbulbar duodenum or proximal jejunum suggest a diagnosis of ZES (see Chapter 34). • Finally, is the ulcer indeed peptic? Primary or metastatic neoplasms, infections (e.g., cytomegalovirus), cocaine use, eosinophilic gastroenteritis, and Crohn disease can cause ulcerations of the stomach and duodenum that can mimic peptic ulcers. These disorders should be considered and excluded appropriately.   

Treatment options for truly refractory peptic ulcers include a more prolonged course of antisecretory therapy, often at double the prior PPI dose. Although uncommon nowadays, elective ulcer surgery may be necessary to attempt to heal a symptomatic refractory or penetrating ulcer. Surgical options are discussed later in this chapter. 

PREVENTION OF ULCER DISEASE Most studies of ulcer prophylaxis have used endoscopy endpoints (rather than clinical endpoints) to assess the effectiveness of various regimens. An “endoscopic ulcer” has been arbitrarily defined as a circumscribed mucosal defect having a diameter of 5 mm or more with a perceivable depth.83 However, many studies have loosened this criterion to include flat mucosal breaks with a diameter of 3 mm or more as ulcers. The distinction between small ulcers and erosions is arbitrary and is prone to interobserver bias. The clinical relevance of these minor endoscopic lesions is uncertain. It is assumed that endoscopic findings roughly correlate with clinical outcomes in subjects at low-to-average risk for ulcer complications. It is unclear if results of endoscopic studies can be generalized to high-risk patients. Because there are few prospective outcome trials to evaluate the true clinical efficacy of ulcer prophylactic agents, clinical judgment relies on data largely using endoscopic endpoints. Hp ulcers do not require ulcer prophylaxis if the organism can be eradicated from the stomach (see earlier and Chapter 52). Most use of ulcer prophylaxis regimens is, therefore, related to prevention of NSAID ulcers in patients at moderate-to-high ulcer risk. The risk factors for NSAID-induced ulcers are listed in Table 53.1. Pharmaceutical agents that may reduce the development of NSAID-induced ulcers are discussed later. Ulcer prophylaxis is also frequently used in patients with idiopathic ulcers. Among the agents listed, only the antisecretory agents are commonly used in the prevention of idiopathic ulcers.

Antacids Many clinicians prescribe antacids as co-therapy for patients taking NSAIDs, both to relieve dyspeptic symptoms and to (hopefully) prevent ulcers; however, antacids have no proved efficacy

CHAPTER 53  Peptic Ulcer Disease

TABLE 53.1  Risk Factors for NSAID Ulcers* Risk factor

Risk ratio

History of complicated ulcer

13.5

Use of multiple NSAIDs (including aspirin, COX-2 inhibitors)

9

Use of high doses of NSAIDs

7

Use of an anticoagulant

6.4

History of an uncomplicated ulcer

6.1

Age >70 years

5.6

Hp infection

3.5

Use of a glucocorticoid

2.2

  

*Not all NSAIDs pose the same risk.   

in the prevention of NSAID-induced ulcers. Antacids may mask dyspeptic symptoms, thereby creating a false sense of ulcer protection and increasing the risk of silent ulcer complications with prolonged NSAID therapy. Co-prescription of antacids in patients taking NSAIDs who are at risk for ulcer should be discouraged. 

H2RAs Using standard doses of H2RAs is not effective in preventing NSAID-induced GUs,84,85 and, as already mentioned, may be harmful. A systematic review85 of randomized trials in NSAID users concluded that using twice the standard daily dose of H2RA significantly reduces the risk of endoscopic NSAID-induced DUs and GUs. However, whether high-dose H2RAs prevent NSAID-induced ulcer complications is unknown. In contrast, H2RAs appear to be more effective for prevention of ulcers associated with low-dose aspirin than with NSAIDs. In a 12 month, multi-center randomized trial of low-dose aspirin users at risk for recurrent ulcer bleeding, there was no significant difference in the incidence rates of recurrent bleeding between patients receiving a PPI and patients receiving an H2RA.89 

Misoprostol The efficacy of misoprostol in preventing NSAID-induced ulcers has been assessed in RCTs.86,87 A systematic review of these trials indicated that all doses of misoprostol studied (400 to 800 μg/day) reduce the risk of NSAID-induced endoscopic ulcers.85 However, only full-dose misoprostol (800 μg/day) reduces ulcer complications.86 In a randomized double-blind trial in patients with rheumatoid arthritis who received NSAIDs, misoprostol (200 μg 4 times daily) lowered the rate of GI complications by 40% (from 0.95% in the placebo group to 0.57% in the misoprostol group). However, up to 30% of misoprostol-treated patients in this trial experienced GI upset, thereby limiting its clinical use. Even though endoscopic studies had suggested that lower doses of misoprostol, such as 200 μg 2 or 3 times daily, can prevent NSAIDinduced ulcers with fewer adverse effects than the full dose,86 such low doses of misoprostol fail to prevent ulcer complications.88 

PPIs PPIs significantly reduce the risk of endoscopic duodenal and GUs.85 The efficacy of PPIs has been compared with that of H2RAs and with misoprostol in patients who received NSAIDs. Two 6-month studies compared omeprazole 20 mg once daily with either standard-dose ranitidine (150 mg twice daily) and half-dose misoprostol (200 μg twice daily).76,80 Omeprazole was more effective than standard-dose ranitidine and comparable with half-dose

813

misoprostol in preventing endoscopic ulcers. The superiority of omeprazole over ranitidine in preventing NSAID-related ulcer was due to a greater reduction in endoscopic DUs. A posthoc analysis revealed that most of the added protection attributable to omeprazole over ranitidine occurred among those with Hp infection. Another endoscopic study compared high-dose misoprostol (200 μg 4 times daily) with 2 doses of lansoprazole (15 and 30 mg daily) for the prevention of ulcers in long-term NSAID users without Hp infection and with a history of GU.88 Misoprostol was more effective than either dose of lansoprazole in preventing GU, but there was no practical advantage of misoprostol over lansoprazole because of the high withdrawal rate in the misoprostol group. In a head-to-head endoscopic ulcer prevention study comparing 2 doses of pantoprazole with 20 mg/day of omeprazole in patients with rheumatoid arthritis receiving NSAIDs, the 6-month probabilities of remaining ulcer free were 91%, 95%, and 93% for pantoprazole 20 mg, pantoprazole 40 mg, and omeprazole 20 mg, respectively.89 Two identical multicenter randomized clinical trials compared esomeprazole (20 or 40 mg) with placebo in the prevention of ulcers in patients taking NSAIDs or COX-2 inhibitors over a 6 month period. Patients in both studies were Hp negative, older than age 60, and had a history of GU or DU. Overall, the rates of ulcers were 17.0%, 5.2%, and 4.6% in the groups receiving placebo, esomeprazole 20 mg, and esomeprazole 40 mg, respectively.90 Whether PPIs can reduce the risk of NSAID-associated peptic ulcer bleeding is largely based on observational studies and 1 randomized trial in high-risk patients. A large-scale, case-control study found that PPI therapy was associated with a significant reduction in risk of UGI bleeding among chronic NSAID users (relative risk, 0.13; 95% CI, 0.09 to 0.19).91 The randomized trial compared long-term (6 months) omeprazole therapy to 1 week of Hp eradication therapy for the prevention of recurrent ulcer bleeding in Hp-infected patients with a recent history of NSAID-related ulcer bleeding who continued to use naproxen.92 Recurrent ulcer bleeding occurred in 18.8% of patients undergoing eradication therapy compared with only 4.4% of patients receiving omeprazole. 

COX-2 Inhibitors (In Place of NSAIDs) COX-2 inhibitors offer the hope of minimizing GI toxicity of NSAIDs while preserving their therapeutic effects.93-97 In a systematic review of randomized trials, when compared with nonselective NSAIDs the COX-2 inhibitors led to significantly fewer gastroduodenal ulcers (relative risk, 0.26; 95% CI, 0.23 to 0.30) and ulcer complications (relative risk, 0.39; 95% CI, 0.31 to 0.5), as well as fewer withdrawals caused by GI symptoms94; however, the sparing effect of COX-2 inhibitors on ulcer development is negated by concomitant use of low-dose aspirin.59 Current evidence indicates that COX-2 inhibitors are as effective as a combination of nonselective NSAIDs combined with a PPI in patients at risk for ulcers. In a randomized comparison of the NSAID diclofenac plus omeprazole versus celecoxib for secondary prevention of ulcer bleeding in patients who either were Hp negative or had undergone Hp eradication,95 a similar proportion of patients had recurrent bleeding in 6 months (6.4% in the diclofenac/omeprazole group and 4.9% of patients in the celecoxib group). Although the 2 treatments were comparable in terms of the incidence of ulcer bleeding, a subsequent follow-up endoscopic study showed that 20% to 25% of patients receiving either treatment developed recurrent endoscopic ulcers at 6 months. These findings suggest that neither treatment can eliminate the risk of recurrent bleeding in very high-risk patients. In a 13-month, double-blind randomized trial comparing celecoxib alone with celecoxib/esomeprazole in patients with a history of NSAID-associated ulcer bleeding, 8.9% of the celecoxib-alone group had recurrent ulcer bleeding compared with none of the combined therapy group (P = 0.0004).96

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TABLE 53.2  Recommendations for Reducing the Risk of NSAID Ulcers as a Function of GI and Cardiovascular Risk GI Risk* Low

Moderate

High

Low CV risk

NSAID at the lowest effective dose

NSAID plus a PPI, or celecoxib alone

Celecoxib plus a PPI

High CV risk†

Naproxen or celecoxib, plus a PPI

Naproxen or celecoxib, plus a PPI

Celecoxib plus a PPI if simple analgesics failed

  

*Low GI risk denotes no risk factors (see Table 53.1); moderate GI risk denotes 1 or 2 risk factors; high GI risk denotes ≥3 risk factors, prior complicated ulcer, or concomitant use of low-dose aspirin or anticoagulants. All patients with a history of ulcer who require NSAIDs should be tested for Hp, and if infection is present, eradication therapy should be given (see Chapter 52). †High CV risk denotes the requirement for prophylactic low-dose aspirin for primary or secondary prevention of serious CV events. CV, cardiovascular.   

Despite the improved gastric safety profile of COX-2 inhibitors, the cardiovascular risk associated with this new class of NSAIDs has been a subject of much concern. In the VIGOR study,97 the incidence of acute myocardial events, although low, was 4 times higher among patients receiving rofecoxib than among patients receiving naproxen. Whether this observed difference in myocardial infarction rates was related to an antiplatelet property of naproxen or to a pro-thrombotic effect of rofecoxib was debated. Further data regarding the cardiovascular hazards of COX-2 inhibitors were derived from 2 long-term studies of colon polyp prevention, using either rofecoxib (the Adenomatous Polyp Prevention on Vioxx [APPROVE] study)98 and celecoxib (the Adenoma Prevention with Celecoxib [APC] study).99 In APPROVE, interim data at 18 months indicated that patients who had received 25 mg rofecoxib a day had twice the risk of serious cardiovascular events compared with patients who received placebo. In 2004, rofecoxib was voluntarily withdrawn from worldwide markets in light of this unexpected finding. In the APC study, interim data at 33 months showed that serious cardiovascular events were significantly more frequent with celecoxib at the high dose of 400 mg twice a day (hazard ratio, 1.9; 95% CI, 1 to 3.3). The MEDAL program was a pre-specified pooled analysis of cardiothrombotic events from 3 trials in which patients with osteoarthritis or rheumatoid arthritis were randomly assigned to etoricoxib (60 mg or 90 mg daily) or diclofenac (150 mg daily). After an average treatment of 18 months, rates of cardiothrombotic events were similar between the 2 treatment groups.100 Current evidence suggests that not only COX-2 inhibitors but also nonselective NSAIDs, with the exception of full-dose naproxen (1000 mg/day), increase cardiothrombotic risk. In a meta-analysis of randomized trials of COX-2 inhibitors (data mostly derived from rofecoxib and celecoxib), all COX-2 inhibitors increased the cardiothrombotic risk compared with placebo (risk ratio, 1.42; 95% CI, 1.13 to 1.78). This was largely attributable to an increased risk of myocardial infarction, with little difference in other vascular outcomes. A dose-dependent increase in cardiothrombotic events was observed with celecoxib. Importantly, there was no significant difference in cardiothrombotic risk between COX-2 inhibitors and nonselective NSAIDs, with naproxen (500 mg twice daily) the only exception. In a meta-analysis of observational studies, high-dose rofecoxib (≥25 mg a day), diclofenac, and indomethacin were associated with an increase in cardiothrombotic events, whereas celecoxib did not significantly increase the cardiothrombotic risk, although an increased risk could not be excluded with doses greater than 200 mg/day.101 In a large-scale, randomized, noninferiority trial of celecoxib versus naproxen and ibuprofen in patients with arthritis (mostly osteoarthritis) and with increased cardiovascular risk,102 more than 24,000 patients were recruited with a mean treatment duration of 20 months and a mean follow-up period of 34 months. Celecoxib (on average approximately 200 mg/day) was found to be noninferior to ibuprofen (approximately 2000 mg/day) or naproxen

(approximately 850 mg/day) with regard to cardiovascular safety. Patients treated with celecoxib had a significantly lower risk of adverse GI events than with naproxen or ibuprofen. The risk of adverse renal events was also significantly lower with celecoxib than with ibuprofen; however, the proportion of patients continued on concomitant low-dose aspirin during the study period was unclear and very few patients had a history of GI bleeding. It is, therefore, unclear whether the advantage of celecoxib over naproxen or ibuprofen can be extrapolated to patients on concomitant aspirin with high risk of GI bleeding. In another 18-month randomized trial of patients at high risk of both cardiovascular and GI adverse events who required concomitant lowdose aspirin and an NSAID, celecoxib plus a PPI was found to be superior to naproxen plus a PPI in reducing the risk of recurrent ulcer bleeding.103, 108 

Assessing Risk and Choice of Agent(s) Safe prescription of NSAIDs should be based on assessment of an individual patient’s GI and cardiovascular risks. In patients with low cardiovascular risk, the therapeutic approach can be stratified according to their levels of GI risk as follows (Table 53.2):   

• L  ow ulcer risk: no risk factors. Patients without risk factors (see Table 53.1) are at very low risk of ulcer complications with NSAID use (≈1% per year). Rational use of NSAIDs, including avoidance of high doses of NSAIDs and use of a less ulcerogenic NSAID (e.g., ibuprofen, diclofenac) at the lowest effective dose is a cost-effective approach. • Moderate ulcer risk: 1 or 2 risk factors. These patients should receive combination therapy with an antiulcer agent (a PPI or misoprostol) and an NSAID. Alternatively, substitution with celecoxib alone is as effective as the combination therapy mentioned earlier.   

High ulcer risk: 3 or more risk factors, history of ulcer complications, or concomitant use of low-dose aspirin, glucocorticoids, or anticoagulant therapy. In general, NSAIDs should be avoided in these patients, not only because of the high risk of ulcer complications but also owing to the serious consequences of ulcer complications in the presence of comorbidities. Glucocorticoid therapy (without NSAID) can be considered if short-term antiinflammatory therapy is required for acute, self-limiting arthritis (e.g., gout), because glucocorticoids alone do not increase the risk of ulcer. If regular anti-inflammatory therapy is required for chronic arthritis, the combination of celecoxib and a PPI offers the best GI protection. Defining patients with high cardiovascular risk remains arbitrary. The American Heart Association recommends that aspirin should be considered in all apparently healthy men and women whose 10-year risk for a cardiovascular event is 10% or above.104 We consider patients with arthritis to have significant cardiovascular risk if they are already on aspirin for secondary prophylaxis or if they require aspirin for primary prophylaxis according to

CHAPTER 53  Peptic Ulcer Disease

the American Heart Association guidelines. Because the potential cardiovascular hazards of COX-2 inhibitors and most nonselective NSAIDs, patients with high cardiovascular risk should avoid using these drugs, if possible. Ibuprofen can attenuate the cardioprotective effect of aspirin, possibly through competitive binding to platelet COX-1, and concomitant use of ibuprofen and low-dose aspirin, therefore, should be avoided. If an NSAID is deemed necessary in patients at high cardiovascular risk, current evidence suggests that either celecoxib at moderate dose (200 mg/ day) or naproxen can be considered. One major drawback of concomitant use of NSAIDs such as naproxen and low-dose aspirin is that the combination will markedly increase the risk of ulcer complications; thus, combination of celecoxib and low-dose aspirin may be the best available option for patients with high GI and high cardiovascular risk who require NSAIDs for long term. Because Hp infection increases the risk of ulcer complications in NSAID users, patients with a history of PUD who require NSAIDs for long term should be tested for Hp and, if present, the infection should be eradicated. 

COMPLICATIONS AND THEIR TREATMENT Bleeding Acute UGI bleeding, the most common complication of PUD, is discussed in detail in Chapter 20. PUD remains the leading cause of acute UGI bleeding.105 Consensus groups have recommended a multidisciplinary approach to the care of patients presenting with UGI bleeding.106 Patients with acute UGI bleeding should be assessed promptly on presentation. Volume resuscitation should take priority and precede endoscopy. Features of liver disease should call attention to the possibility of bleeding from esophagogastric varices rather than an ulcer. This distinction has prognostic as well as management implications. Variceal hemorrhage carries a higher death rate than ulcer bleeding. The possibility of variceal hemorrhage calls for specific measures prior to endoscopy, such as the use of vasoactive drugs (e.g., octreotide) and antibiotics (e.g., cefotaxime) as prophylaxis against infective complications such as spontaneous bacterial peritonitis (see Chapters 92 and 93).

Endoscopic Therapy Early endoscopy is generally defined as EGD performed within 24 hours of the patient’s admission. In patients with signs of active UGI bleeding, urgent endoscopy establishes a diagnosis and offers a possible intervention. RCTs demonstrated that early endoscopy in patients at low risk for rebleeding allowed early hospital discharge, reduced resource utilization, and facilitated management as outpatients.107-109 Meta-analysis of 18 clinical trials that compared endoscopic therapy to pharmacotherapy alone showed that endoscopic therapy was superior with regard to the rates of further bleeding (odds ratio [OR] 0.35; 95% CI, 0.27 to 0.46), surgery (OR 0.57; 95% CI, 0.41 to 0.81), and, importantly, mortality (OR 0.57; 95% CI, 0.37 to 0.89).110 An International Consensus group104 recommended the use of a prognostic score to guide patient management. The Rockall scoring system is a composite score using pre- and postendoscopy clinical parameters to predict mortality. The score was derived from data gathered from the first National UK Audit.109 The Glasgow Blatchford score (GBS), on the other hand, uses only clinical parameters to predict the need for intervention and is calculated from patient’s Hgb level and blood urea concentration, pulse and systolic blood pressure on admission, the presence or absence of melena or syncope, as well as evidence of cardiac or hepatic failure.110 The GBS has been the most widely validated score and correlates with clinical outcomes. In a multicentre prospective study111 of 3012 patients, the GBS score was the best of the 4 at predicting the need for

815

intervention or death with an area under the receiver operating curve (AUROC) of 0.86. A GBS score of 1 appears to be the threshold for outpatient management. The GBS score, however, does not define a cutoff value above which urgent endoscopy becomes mandatory. A significant proportion of patients at lowto-median scores require endoscopic treatment. At the time of EGD, endoscopic stigmata of bleeding in a ulcer not only pinpoint PUD as the source of bleeding but are themselves prognostic for patient outcomes (see Chapter 20). The commonly used nomenclature is a version modified from Forrest and Finlayson’s112 original description. Laine and Jensen113 summarized rates of further bleeding, surgery, and mortality associated with stigmata of bleeding in prospective trials without endoscopic therapy.   

• T  ype I: Active bleeding: Ia: Spurting hemorrhage (Fig. 53.4) Ib: Oozing hemorrhage (see Fig. 53.4) • Type II: Stigmata of recent hemorrhage: IIa: Nonbleeding visible vessel (see Fig. 53.4) IIb: Adherent clot (see Fig. 53.4) IIc: Flat pigmentation (see Fig. 53.4) • Type III: Clean-base ulcers   

Actively bleeding ulcers and ulcers with nonbleeding visible vessels (“protuberant discoloration” or a “sentinel clot”) warrant endoscopic therapy (see Chapter 20). Endoscopic therapy of ulcers with “adherent clots” had been controversial. The definition of adherent clot varies with the vigor in endoscopic washing. Two randomized controlled studies114,115 and a meta-analysis116 compared medical therapy to endoscopic treatment in ulcer patients with “adherent clots” and concluded that clot removal followed by endoscopic treatment of the vessel underneath lowers the risk of recurrent bleeding from 30% to 5%. The term sentinel clot, is often used synonymously with visible vessel.117 It represents a fibrin clot, which plugs the rent in an eroded artery. As the ulcer begins to heal, the clot resolves leaving a flat pigmentation to the ulcer base, which eventually disappears from the ulcer floor. This evolution of a bleeding vessel usually takes less than 72 hours. Ulcers with a flat pigmentation or a clean base do not warrant endoscopic therapy. Recently, a group from UCLA reported their experience with the use of an endoscopic Doppler probe to interrogate the ulcer base. In a prospective cohort of 163 patients with bleeding ulcers and varying endoscopic stigmata or recent hemorrhage, Doppler signals were found in ulcers with minor stigmata (adherent clots, 68.4%, and flat pigmentations, 40.5%).118 In a subsequent RCT of 148 patients with bleeding peptic ulcers, Jensen and associates119 compared Doppler endoscopic probe–guided hemostasis to standard endoscopic hemostasis. The 30 day re-bleeding rate was lower with the use of a Doppler probe to guide the treatment endpoint (11.1% vs. 26.3%, P =.02). Endoscopic therapeutic modalities are discussed in more detail in Chapter 20, and the methods used are discussed briefly here.  Injection Methods Endoscopic injection of diluted epinephrine into a bleeding peptic ulcer works by volume tamponade and local vasoconstriction. The technique is easy to learn and is not damaging to tissues. Diluted epinephrine, however, does not induce vessel thrombosis. Recurrent bleeding after injection with diluted epinephrine alone occurs in 20% to 30% of patients. Injection with diluted epinephrine allows a clear view of the bleeding vessel and should then be combined with application of either thermal-coagulation or clips. In a meta-analysis,120 addition of a second modality after epinephrine injection significantly reduced the rate of recurrent

53

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PART VI  Stomach and Duodenum

Spurting (Ia)

A visible vessel IIa

Flat pigmentation IIc

Oozing (Ib)

An adherent clot (IIb)

Clean base (III)

Fig. 53.4  Endoscopic appearances of bleeding peptic ulcers using the Forrest classification.139

bleeding (RR 0.57, 0.43 to 0.76), emergency surgery (RR 0.68, 0.5 to 0.93), and mortality (RR 0.64, 0.39 to 1.06). Improved outcomes seem to be more evident in ulcers with active bleeding (Forrest type I ulcers). Injection with diluted epinephrine alone should no longer be considered an adequate treatment. A second treatment to induce arterial thrombosis should be added.  Thermal Methods Thermal methods include contact and noncontact methods. Contact thermal methods are more often used. Commonly used contact thermal probes are the heater probe and bipolar probes. The term coaptive thermal-coagulation emphasizes the need for firm mechanical compression of the vessel. Cessation of blood flow by compression reduces the “heat-sink” effect when heat energy is generated, welding the arterial lumen. The main noncontact method is argon plasma coagulation (see Chapter 20).  Mechanical Methods The mechanical method of hemoclipping is widely used. Tangential applications of clips in treating bleeding posterior duodenal bulbar or lesser curvature ulcers with the endoscope in a retroflexed position can be technically difficult. In meta-analyses comparing endoscopic treatment modalities, hemoclips was superior to injection alone in rate of hemostasis and comparable to thermal coagulation.108,121 Recently, a multicenter RCT compared the use of over-thescope-clips (OTSC) to standard through-the-scope clips and thermal methods in 66 patients with refractory bleeding ulcers.122 The use of OTSC was associated with a reduced rate of further bleeding (15.2% vs. 57.6%). OTSC are made of shape memory nitinol of up to 13 mm in diameter capable of strong tissue compression over a wider area. The current standard is the use of

either through-the-scope hemo-clips or thermal-coagulation with or without pre-injection of epinephrine. OTSC appears to be a useful rescue when other modalities fail. 

Antisecretory Therapy The rationale for antisecretory therapy in bleeding PUD is based on the fact that both pepsin activity and platelet aggregation are pH dependent. An ulcer stops bleeding when a fibrin or platelet plug blocks the rent in a bleeding artery. When gastric pH exceeds 4, pepsin is inactivated, preventing enzymatic digestion of blood clots. A gastric pH of 6 or greater is critical for clot stability and hemostasis. Labenz and associates123 studied gastric pH in patients with GU or DU who were receiving either a high dose of omeprazole (IV bolus 80 mg, followed by 8 mg/hr) or a high dose of ranitidine (IV bolus 50 mg, followed by 0.25 mg/kg/hr). The gastric pH exceeded 6 with omeprazole 99.9% of the time, but less than 50% of the time in patients receiving ranitidine (46% of the time in GU patients and 20% of the time in DU patients). The PUB study was an international multicenter study that enrolled 764 patients with ulcer bleeding. It evaluated use of high-dose esomeprazole after endoscopic hemostasis in bleeding peptic ulcers. The PPI reduced the rate of recurrent bleeding over 30 days from 11.6% to 6.4%. In addition, fewer patients given the PPI needed further endoscopic therapy, blood transfusion, and surgery.124 A Cochrane Systematic Review of randomized trials that compared PPI use to placebo or a H2RA concluded that the use of PPI therapy significantly reduces rates of recurrent bleeding and surgery but not overall mortality.125 In a subgroup analysis among patients with active bleeding or with a nonbleeding visible vessel, a significant reduction in mortality was observed with use of PPI (OR 0.53; 95% CI, 0.31 to 0.91).

CHAPTER 53  Peptic Ulcer Disease

The optimal PPI dose to use and the routine of PPI administration continue to be controversial. A meta-analysis of RCTs that compared low- to high-dose PPI use after endoscopic hemostasis consisted of trials that included bleeding ulcers with minor stigmata of bleeding and clean-based ulcers.126 The majority of studies were underpowered to declare equivalence between lowand high-dose PPI. An international consensus group has continued to endorse the use of a high-dose PPI, especially in high-risk patients.104 Pre-emptive use of an IV PPI infusion prior to endoscopy was studied in a large-scale randomized study.127 Patients with overt signs of UGI bleeding were randomized to receive either a highdose PPI infusion or placebo. Most (60%) of the patients in this cohort were found at EGD to be bleeding from a peptic ulcer. The study demonstrated that early PPI infusion down-staged endoscopic bleeding stigmata in patients with peptic ulcers and thereby reduced the need for endoscopic therapy; thus, there were fewer ulcers with active bleeding or with major stigmata of recent hemorrhage observed during the following morning’s EGD in the PPI group. PPI infusion starts ulcer healing, and significantly more clean-based ulcers are seen the next day. The study has cost-saving implications, with less endoscopic therapy required with the preemptive use of an IV PPI. In patients awaiting endoscopy, it is reasonable to start PPI therapy. 

Surgical Therapy Effective endoscopic intervention and improved pharmacotherapy have greatly reduced the need for emergency ulcer surgery. In the USA, the incidence of surgery to control ulcer bleeding has continued to decline (from 13.1% in 1993 to 9.7% in 2006), while there was an increase in the use of endoscopic treatment (12.9% to 22.2%).128 In an UK National Audit in 2006, only 2.3% of 4478 patients who presented with UGI bleeding required surgery. Mortality after surgery was 29%.129 Surgery is indicated in patients with bleeding not controlled during endoscopy or with further bleeding refractory to endoscopic therapy. Independent predictors to recurrent bleeding after endoscopic hemostatic therapy include hemodynamic instability, comorbid illnesses, active bleeding at endoscopy, large ulcer size, posterior DU, or lesser curvature ulcer.130 Often, an attempt at further endoscopic control is indicated. A RCT that compared endoscopic re-treatment to surgery suggested that the former can secure bleeding in 75% of cases and is associated with less procedure-related morbidities.131 The type of emergency operation to be performed for ulcer bleeding is controversial. Some surgeons maintain that oversewing of ulcers alone, combined with acid-suppression therapy, is safer than “definitive” surgery using either gastrectomy or vagotomy. Hp eradication and PPIs have provided incentives for surgeons to perform the minimum operation. Two RCTs that compared minimal with definitive surgery were published before the era of endoscopic hemostasis and PPI infusion.132,133 A UK multicenter study compared minimal surgery (oversewing the vessel or ulcer excision alone plus IV H2RA therapy) with a definitive ulcer operation (vagotomy and pyloroplasty or partial gastrectomy) in patients with bleeding GUs or DUs. The trial was aborted because of the high rate of fatal recurrent bleeding in those assigned to minimal surgery (7 in 62 patients, with 6 deaths). Of the 67 patients who received definitive ulcer surgery, 4 re-bled and none died.132 In a trial conducted by the French Association of Surgical Research, patients with DU were randomized to receive oversewing plus vagotomy and drainage or partial gastrectomy.133 After oversewing and vagotomy, recurrent bleeding occurred in 10 of 60 patients (17%); conversion to a Billroth II gastrectomy was required in 6 of the 10 patients with recurrent bleeding. In the group of 60 patients assigned to undergo partial gastrectomy, only 2 (3%) had rebleeding, and both recovered with conservative treatment. With

817

an intention-to-treat analysis, no differences in overall mortality rates or duodenal leak rates were seen. These 2 RCTs suggest that simple oversewing with or without vagotomy is associated with a higher rate of recurrent bleeding. Exclusion of an ulcer or, in the case of GUs, ulcer excision is important in preventing recurrent bleeding. In a review of data from the American College Surgeons National Surgical Quality Improvement Program, 30 day mortality was higher in patients who underwent a simple oversewing or ulcer excision (106/498, 21.3%) when compared to that after vagotomy with resection or drainage (39/283, 13.8%). There was obvious bias in this retrospective analysis.134 

Angiographic Therapy Angiographic embolization of bleeding arteries is a nonoperative alternative to surgery in patients with bleeding peptic ulcer. In a pooled analysis of 6 retrospective studies comparing angiography and surgery, a higher re-bleeding rate was observed after angiographic treatment (51/178, or 29% vs. 36/241, or 15%; RR 1.82; 95% CI, 1.20 to 2.67).135 Mortality was not significantly different (17% vs. 23%). When radiology skills are available, angiography is often attempted before surgery. A recent RCT that compared added embolization to standard treatment after endoscopic hemostasis did not confirm a mortality benefit of prophylactic embolization.136 In a per protocol analysis, rate of further bleeding was lower after added embolization (6/96, or 6.2% vs. 14/123, or 11.4%). In a subgroup analysis of ulcers of 15 mm or more in size, embolization reduced bleeding from 23.1% to 4.5%. The authors suggested that for larger ulcers with significant bleeding, angiographic embolization should be considered after endoscopic hemostasis. 

Perforation Perforation of a GU or DU (Fig. 53.5) is a surgical emergency that may be the initial manifestation of PUD, especially in patients using NSAIDs. Ulcer perforation is associated with a mortality approaching 30%. Older adults with significant comorbid illnesses and a delay in performing surgery have the worst prognosis. The clinical presentation is one of peritonitis but clinical signs can be obscured in older and immunocompromised patients (see Chapter 39).

Medical Therapy It has been suggested that a standardized peri-operative management protocol can improve outcomes. In a Danish multicenter study (n = 2619),137 the PULP trial group showed that with aggressive and specific treatment of sepsis and, importantly,

Fig. 53.5  Laparoscopic view of a perforated DU (arrow) with fibrinous exudate on the adjacent peritoneum.

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PART VI  Stomach and Duodenum

surgery within 6 hours, mortality was 17% in 117 hospitals with strict management protocols and was 27% in 512 hospitals without protocols. Other measures include goal-directed fluid therapy, general respiratory and circulatory support, intravenous broad-spectrum antibiotics, and insertion of a double-barreled NG tube, and a urinary catheter. An intravenous PPI is given routinely after surgery. Nonoperative management of ulcer perforation should seldom be practiced. It involves NG suctioning, parenteral antibiotics, and IV fluids. In a RCT, Crofts and associates138 assigned patients with the presumptive diagnosis of perforated peptic ulcers to either conservative treatment or prompt surgery. Overall morbidity and mortality rates (5%) were low and similar in the medical and surgical groups. Of the 40 patients assigned to conservative treatment, 11 showed no improvement within 12 hours and underwent operation. Three of these 11 patients were found to have perforated carcinomas (2 gastric and 1 sigmoid colon). Findings of the study highlight common objections to the use of non-operative management: uncertainty of the site of perforation, the possibility of a perforated GI tumor, and atrophic momentum making spontaneous sealing unlikely. Older adults tolerate sepsis poorly. Any delay in definitive treatment leads to poor outcomes. 

Surgical Therapy Perforated gastroduodenal ulcer carries a high mortality rate. In a review of surgery for perforated ulcers between 2011 and 2013 in Denmark, the 90-day mortality was 25.5% among 726 patients. Re-operation was required in 124 patients (17.1%), approximately one third of them caused by persistent leaks.139 Boey and associates140 identified preoperative shock, major medical illnesses, and perforation longer than 12 hours as important adverse prognostic factors. The PULP score was recently developed from a cohort of 2668 patients who received surgery in 11 hospitals across Denmark. Variables included were age greater than 65 years, active malignant disease or acquired immunodeficiency, cirrhosis, glucocorticoid use, perforation more than 24 hours, shock, raised serum creatinine level, and American Society of Anesthesiologists (ASA) score greater than 1. The PULP score was accurate in predicting mortality from ulcer perforation (AUROC of 0.83).141 The score, however, has not been validated in centers outside Denmark. The controversies in the operative management of perforated peptic ulcers have revolved around the choice between laparoscopic and open repair and the need for a definitive ulcer operation after closure of the perforation (and which definitive operation to perform). Treatment also differs for duodenal and gastric perforations. Simple closure of a perforated duodenal or a juxta-pyloric ulcer with the use of an omental patch is widely practiced. Meta-analyses of 3 RCTs (2 from Hong Kong and the Dutch LAMA Study) that compared laparoscopic to open surgical treatment of perforated peptic ulcers tends to favor laparoscopic repair with respect to rates of abdominal septic complications (OR 0.66; 95% CI, 0.3 to 1.47), and pulmonary complications (OR 0.43; 95% CI, 0.17 to 1.12)142; thus, laparoscopic repair should, at the least, be considered not inferior to open repair. There may, however, have been selection bias in these RCTs. Poor risk patients (those with delayed presentations, shock, and with significant comorbidities) may be better suited for a laparotomy. Large perforations (>10 mm) suggest sizable ulcerations and should also be managed by laparotomy; often, gastric resections are required in such patients. GU accounts for approximately 20% of perforated peptic ulcers. Epidemiologic data suggest a rising proportion of GUs among perforated ulcers, especially in older adult patients who use NSAIDs. Patients with perforated GUs are more likely to be older and to have significant comorbid illnesses, making their

prognosis less favorable. As with perforated DUs, there has been a debate regarding the choice of surgery for perforated GUs. Simple closure should be offered to small perforations at the prepyloric area. The optimal treatment of an angular notch GU along the lesser curvature should entail an antrectomy and lesser curve ulcer excision, followed by either a Billroth type I or II reconstruction. The role of vagotomy is unclear. The advocates for primary resection in perforated GUs argue that mortality rates after gastrectomy are not increased and that the rate of postoperative ulcer-related complications is reduced. The arguments for primary resection also include the possibility that the ulcer is malignant. Malignancy is seen in approximately 6% of perforated GUs.143 In a retrospective series comprising 287 perforated GUs, death occurred in 21.5% of patients who underwent patch closure alone and in 24.3% of those who underwent gastric resections.144 In Hp-associated ulcers, Hp eradication reduces the relapse of ulceration after patch repair. In a RCT from Hong Kong, 99 patients after patch repairs for perforated ulcers, were assigned to Hp eradication or a course of PPI. At 1 year, there were fewer relapses in those given Hp eradication (4.8% vs. 38.1%).145 A meta-analysis of 5 RCTs that compared simple closure plus Hp eradication to closure alone in patients with perforated DU showed that the pooled incidence of ulcer relapse in the year after Hp eradication was 5.2% compared to 35.2% in those without eradication. These data support the use of simple closure in the majority of perforated DUs.146 

Obstruction Gastric outlet obstruction is now an infrequent complication of PUD. Its clinical manifestations—nausea and postprandial vomiting, abdominal fullness, pain, and early satiety—are discussed in Chapters 15 and 50, as is the diagnostic approach to patients presenting with possible gastric outlet obstruction. Gastric outlet obstruction should alert clinicians to possible malignancy (see Chapter 54).

Medical Therapy Patients with obstructing peptic ulcers are often volume depleted. The loss of fluid, hydrogen ions, and chloride ions in the vomitus leads to hypochloremic, hypokalemic metabolic alkalosis. The patient should be volume resuscitated with normal saline followed by potassium replacement once urine output is adequate. In severely malnourished patients, parenteral nutrition should be considered. Decompression of the stomach by a large-bore NG tube relieves vomiting, helps to monitor fluid loss, and allows the stomach to regain its tone. A high-volume, non–bile-stained aspirate can help distinguish gastric outlet obstruction from a high small bowel obstruction. Use of an IV PPI reduces gastric acid output, making fluid and electrolyte management easier. PPI therapy also initiates ulcer healing, ameliorates inflammatory edema, and assists in resolving obstruction. Approximately half of patients respond to this management. Improvement is especially noticeable in patients with active ulceration and edema. Surgery is, therefore, deferred until after an adequate trial of conservative management. Other factors that may influence the decision to proceed to surgery are chronicity, a history of previous ulcer complication, and the patient’s age and general medical condition. Furthermore, many authorities argue for initial endoscopic dilation before surgery. 

Endoscopic Therapy Endoscopic balloon dilation has been used successfully in patients with gastric outlet obstruction from PUD (Fig. 53.6).147-149 During endoscopic examination, the stenosis is traversed by means of a biliary-type guidewire with a flexible tip. A low-compliance

CHAPTER 53  Peptic Ulcer Disease

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Fig. 53.6  A through-the-scope dilation of an obstructed pylorus caused by an ulcer. The procedure was performed under fluoroscopic guidance. A dual-channel endoscope with a 3.7 mm therapeutic channel was used. A, The stricture was first traversed with a biliary-type guidewire (arrowhead). A through-the-scope balloon was passed over the guidewire across the stricture. B, A waist, representing the stricture (arrow), was observed and was nearly abolished on balloon inflation (C).

A

through-the-scope balloon is then passed over the guidewire, and dilation can be seen through the endoscope. The use of a balloon is preferred because its inflation produces a uniform radial force, which has a theoretical advantage over the longitudinal shearing force associated with the use of conventional dilators. The procedure is typically performed with fluoroscopic guidance. A regimen of gradual dilation over 2 or 3 sessions seems sensible. The targeted diameter is unclear; many authorities recommend dilation to 15 mm, which is often associated with relief of symptoms. The presence of gastric atony also contributes to symptoms. The risk of perforation increases with the size of balloon. Endoscopic series reported immediate relief of obstruction in 78% to 100% of cases. In a small series of Hp-infected patients, balloon dilation followed by Hp eradication led to sustained symptom relief.150 

Surgical Therapy A variety of operations have been described for obstructing DUs, pyloric channel ulcers, and pre-pyloric ulcers. They include vagotomy with either a drainage procedure (gastrojejunostomy or pyloroplasty) or an antrectomy. In the unusual event of an obstructing prepyloric GU, an antrectomy followed by a Billroth type I gastroduodenostomy is the procedure of choice. 

STRESS ULCERS Stress-related gastric and duodenal mucosal injury (stress ulcers) is an illness of the critically ill who are typically cared for in an ICU. The etiology of stress ulceration is probably related to mucosal ischemia and splanchnic hypo-perfusion from shock or low cardiac output. Fortunately, only a small proportion of patients with stress-related mucosal lesions have

B

C

clinically overt GI bleeding. In a cohort study151 of 2252 ICU patients, only 1.5% developed clinically important bleeding. Respiratory failure (OR 15.6) and coagulopathy (OR 4.3) were independent predictive factors for bleeding stress ulcers. In 2015, a prospective study152 of 1034 patients admitted to ICUs was published; clinically important GI bleeding occurred in 2.6% of patients. Those with 3 or more comorbid illnesses, liver disease, receiving renal replacement therapy, and with a high organ failure score were at risk. Patients in the ICU with traumatic brain injuries and burns also belong to a highrisk group of developing GI bleeding. Across different studies, there appears to be different candidate predictors for bleeding. The use of enteral nutrients buffers acid and protects against bleeding. PPI, H2RA and sucralfate are drugs used for stress ulcer prophylaxis. In a network meta-analysis of 57 RCTs (n = 7293), Alhazzani and associates153 showed that PPIs were more effective for preventing clinically important bleeding than H2RA (OR 0.38), sucralfate (OR 0.30), or placebo (OR 0.24). PPIs, however, increased the risk of nosocomial pneumonia compared with H2RA (OR 1.27), sucralfate (OR 1.65), and placebo (OR 1.52). There is concern that acid suppression predisposes patients to nosocomial infection probably linked to gut dysbiosis.154 A European multicenter study randomized 3298 ICU patients to receive 40 mg of intravenous PPI or placebo and found that deaths by 90 days were similar between groups (31.1% vs. 30.4%). The rate of composite adverse events (gastrointestinal bleeding, Clostridium difficile infection, pneumonia, or myocardial ischemia) were comparable (21.9 vs. 22.6%). There were fewer clinically important bleeding events in the PPI group (2.5 vs. 4.2%).155 Full references for this chapter can be found onwww.expertconsult.com

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73. Malfertheiner P, Kirchner T, Kist M, et al. Helicobacter pylori eradication and gastric ulcer healing—comparison of three pantoprazolebased triple therapies. BYK Advanced Gastric Ulcer Study Group. Aliment Pharmacol Ther 2003;17:1125–35. 74. Higuchi K, Fujiwara Y, Tominaga K, et al. Is eradication sufficient to heal gastric ulcers in patients infected with Helicobacter pylori? A randomized, controlled, prospective study. Aliment Pharmacol Ther 2003;17:111–7. 75. Yeomans ND, Tulassay Z, Juhasz L, et al. A comparison of omeprazole with ranitidine for ulcers associated with non-steroidal antiinflammatory drugs. Acid Suppression Trial: ranitidine versus Omeprazole for NSAID-Associated Ulcer Treatment (ASTRONAUT) study group. N Engl J Med 1998;338:719–26. 76. Agrawal NM, Campbell DR, Safdi MA, et al. Superiority of lansoprazole versus ranitidine in healing nonsteroidal antiinflammatory drug-associated gastric ulcers: results of a double-blind, randomized, multicenter study. NSAID-Associated Gastric Ulcer Study Group. Arch Intern Med 2000;160:1455–61. 77. Goldstein JL, Johanson JF, Hawkey CJ, et al. Clinical trial: healing of NSAID-associated gastric ulcers in patients continuing NSAID therapy—a randomized study comparing ranitidine with esomeprazole. Aliment Pharmacol Ther 2007;26:1101–11. 78. Roth S, Agrawal N, Mahowald M, et al. Misoprostol heals gastroduodenal injury in patients with rheumatoid arthritis receiving aspirin. Arch Intern Med 1989;149:775–9. 79. Hawkey CJ, Karrasch JA, Szezepanski L, et al. Omeprazole compared with misoprostol for ulcers associated with non-steroidal antiinflammatory drugs: omeprazole versus Misoprostol for NSAIDInduced Ulcer Management (OMNIUM) Study Group. N Engl J Med 1998;338:727–34. 80. Kyaw MH, Otani K, Ching JYL, et al. Misoprostol heals small bowel ulcers in aspirin users with small bowel bleeding. Gastroenterology 2018;S0016–5085(18)34698–5. 81. Taha AS, McCloskey C, McSkimming P, McConnachie A. Misoprostol for small bowel ulcers in patients with obscure bleeding taking aspirin and non-steroidal anti-inflammatory drugs (MASTERS): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Gastroenterol Hepatol 2018;3:469–76. 82. Lancaster-Smith MJ, Jaderberg ME, Jackson DA. Ranitidine in the treatment of nonsteroidal anti-inflammatory drug associated gastric and duodenal ulcers. Gut 1991;32:252–5. 83. Singh G, Triadafilopoulus G. Epidemiology of NSAID-induced GI complications. J Rheumatol 1999;26:18–24. 84. Rostom A, Wells G, Tugwell P, et al. Prevention of NSAID-induced gastroduodenal ulcers (Cochrane review). Cochrane Database Syst Rev 2000;4:CD002296. 85. Chan FK, Kyaw M, Tanigawa T, et al. Similar efficacy of protonpump inhibitors vs H2-receptor antagonists in reducing risk of upper gastrointestinal bleeding or ulcers in high-risk users of low-dose aspirin. Gastroenterology 2017;152:105–10. 86. Chan FK, Sung JJ, Ching JY, et al. Randomized trial of low-dose misoprostol and naproxen vs. nabumetone to prevent recurrent upper gastrointestinal haemorrhage in users of non-steroidal antiinflammatory drugs. Aliment Pharmacol Ther 2001;15:19–24. 87. Graham DY, Agrawal NM, Campbell DR, et al. Ulcer prevention in long-term users of nonsteroidal anti-inflammatory drugs: results of a double-blind, randomized, multicenter, active- and placebo-controlled study of misoprostol vs lansoprazole. Arch Intern Med 2002;62:169–75. 88. Regula J, Butruk E, Dekkers CP, et al. Prevention of NSAID-associated gastrointestinal lesions: a comparison study pantoprazole versus omeprazole. Am J Gastroenterol 2006;101:1747–55. 89. Lanas A, Garcia-Rodriguez LA, Arroyo MT, et al. Effect of antisecretory drugs and nitrates on the risk of ulcer bleeding associated with nonsteroidal anti-inflammatory drugs, antiplatelet agents, and anticoagulants. Am J Gastroenterol 2007;102:507–15. 90. Chan FK, To KF, Wu JC, et al. Eradication of Helicobacter pylori and risk of peptic ulcers in patients starting long term treatment with non-steroidal anti-inflammatory drugs: a randomized trial. Lancet 2002;359:9–13. 91. Chan FK, Hung LC, Suen BY, et al. Celecoxib versus diclofenac and omeprazole in reducing the risk of recurrent ulcer bleeding in patients with arthritis. N Engl J Med 2002;347:2104–10. 92. Rostom A, Muir K, Dube C, et al. Gastrointestinal safety of cyclooxygenase-2 inhibitors: a Cochrane collaboration systematic review. Clin Gastroenterol Hepatol 2007;5:818–28.

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114. Jensen DM, Kovacs TO, Jutabha R, et al. Randomized trial of medical or endoscopic therapy to prevent recurrent ulcer hemorrhage in patients with adherent clots. Gastroenterology 2002;123:407–13. 115. 115. Bleau BL, Gostout CJ, Shearman KE, et al. Recurrent bleeding from peptic ulcer associated with adherent clot: a randomized study comparing endoscopic treatment with medical therapy. Gastrointest Endosc 2002;56:1–6. 116. Kahi CJ, Jensen DM, Sung JJ, et al. Endoscopic therapy versus medical therapy for bleeding peptic ulcer with adherent clot: a metaanalysis. Gastroenterology 2005;129:855–62. 117. Johnston JH. The sentinel clot and invisible vessel: pathologic anatomy of bleeding peptic ulcer. Gastrointest Endosc 1984;30:313–5. 118. Jensen DM, Ohning GV, Kovacs TOG, et al. Doppler endoscopic probe as a guide to risk stratification an definitive hemostasis of peptic ulcer bleeding. Gastrontest Endosc 2016;83:129–36. 119. Jensen DM, Kovacs TOG, Ohning GV, et al. Doppler endoscopic probe monitoring of blood flow improves risk stratification and outcomes of patients with severe nonvariceal upper gastrointestinal hemorrhage. Gastroenterology 2017;152:1310–8. 120. Vergara M, Bennett C, Calvet X, Gisbert JP. Epinephrine injection versus epinephrine injection and a second endoscopic method in high risk bleeding ulcers. Cochrane Database Syst Rev 2014;(10):CD005584. 121. Sung JJ, Tsoi KK, Lai LH, et al. Endoscopic clipping versus injection and thermocoagulation in the treatment of non-variceal upper gastrointestinal bleeding: a meta-analysis. Gut 2007;56:1364–73. 122. Schmidt A, Golder S, Goetz M, et al. Over-the-scope clips are more effective than standard endoscopic therapy for patients with recurrent bleeding of peptic ulcers. Gastroenterology 2018;05:037. [Epub ahead of print]. 123. Labenz J, Peitz U, Leusing C, et al. Efficacy of primed infusions with high-dose ranitidine and omeprazole to maintain high intragastric pH in patients with peptic ulcer bleeding: a prospective randomised controlled study. Gut 1997;40:36–41. 124. Sung JJY, Barkum A, Kuipers EJ, et al. Intravenous esomeprazole for prevention of recurrent peptic ulcer bleeding. Ann Int Med 2009;150:455–64. 125. Leontiadis GI, Sharma VK, Howden CW. Proton pump inhibitor treatment for acute peptic ulcer bleeding. Cochrane Database Syst Rev 2006;25:CD902094. 126. Neumann I, Letelier LM, Rada G, et al. Comparison of different regimens of proton pump inhibitors for acute peptic ulcer bleeding. Cochrane Database Syst Rev 2013;60:CD007999. 127. Lau JY, Leung WK, Wu JC, et al. Omeprazole before endoscopy in patients with gastrointestinal bleeding. N Engl J Med 2007;356:1631–40. 128. Wang YR, Richter JE, Dempsey DT. Trends and outcomes of hospitalizations for peptic ulcer disease in the united states, 1993 to 2006. Ann Surg 2010;251:51–8. 129. Jairath V, Kahan BC, Logan RF, et al. National audit of the use of surgery and radiological embolization after failed endoscopic hemostasis for non-variceal upper gastrointestinal bleeding. Br J Surg 2012;99:1672–80. 130. Elmunzer BJ, Young SD, Inadomi JM, et al. Systematic review of the predictors of recurrent hemorrhage after endoscopic hemostatic therapy for bleeding peptic ulcer. Am J Gastroenterol 2008;103:2625–32. 131. Lau JY, Sung JJY, Lam YH, et al. Endoscopic re-treatment compared with surgery in patients with recurrent bleeding after initial endoscopic control of bleeding ulcers. N Engl J Med 1999;340:751– 6. 132. Poxon VA, Keighley MRB, Dykes PW, et al. Comparison of minimal and conventional surgery in patients with bleeding ulcer: A multicentre trial. Br J Surg 1991;78:1344–5. 133. Millat B, Hay JM, Valleur P, et al. Emergency surgical treatment for bleeding duodenal ulcer: oversewing plus vagotomy versus gastric resection, a controlled randomized trial french associations for surgical research. World J Surg 1993;17:568–74. 134. Schroder VT, Pappas T, Vaslef S, et al. Vagotomy/Drainage is superior to local oversew in patients who require emergency surgery for bleeding peptic ulcers. Ann Surg 2014;259:1111–8.

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135. Kyaw M, Tse Y, Ang D, et al. Embolization versus surgery for peptic ulcer bleeding after failed endoscopic hemostasis: a meta-analysis. Endosc Int Open 2014;02:6–14. 136. Lau JY, Pittayanon R, Wong KT, Pinjaroen N, Chiu PWY, Rerknimitr R, et al. Prophylactic angiographic embolisation after endoscopic control of bleeding to high-risk peptic ulcers: a randomized controlled trial. Gut 2018;0:1–8. 137. Moller MH, Adamsen S, Thomsen RW, Moller AM. Peptic Ulcer Perforation (PULP) trial group Multicentre trial of a perioperative protocol to reduce mortality in patients with peptic ulcer perforations. Br J Surg 2011;98:802–10. 138. Crofts TJ, Park KGM, Steele RJC, et al. A randomized trial of nonoperative treatment for perforated peptic ulcer. N Engl J Med 1989;320:970–3. 139. Wilhelmsen M, Moller MH, Rosenstock S. Surgical complications after open and laparoscopic surgery for perforated peptic ulcer in a nationwide cohort. Br J Surg 2015;102:382–7. 140. Boey J, Choi SKY, Alagaratnam TT, Poon A. Risk stratification in perforated duodenal ulcers: a prospective validation of predictive factors. Ann Surg 1987;205:22. 141. Moller MH, Engebjerg MC, Adamsen S, et al. The Peptic Ulcer Perforation (PULP) score: a predictor of mortality following peptic ulcer perforation a cohort study. Acta Anaesthesiol Scand 2012;56:655–62. 142. Sanabria A, Villegas MI, Morales Uribe CH. Laparoscopic repair for perforated peptic ulcer disease. Cochrane Database Syst Rev 2013;28:CD004778. 143. McGee GS, Sawyers JL. Perforated gastric ulcers: a plea for management by primary gastric resection. Arch Surg 1987;122:555–61. 144. Lanng C, Hansen CP, Christensen A, et al. Perforated gastric ulcer. Br J Surg 1988;75:758–9. 145. Ng EK, Lam YH, Sung JJ, Yung MY, et al. Eradication of Helicobacter pylori prevents recurrence of ulcer after simple closure of

duodenal ulcer perforation randomized controlled trial. Ann Surg 2000;231:153–8. 146. Tomtitchong P, Siribumrungwong B, Vilaichone RK, et al. Systemic review and meta-analysis: helicobacter pylori eradication therapy after simple closure of perforated duodenal ulcer. Helicobacter 2012;17:148–52. 147. Lau JY, Chung SC, Sung JY, et al. Through-the-scope balloon dilation for pyloric stenosis: long term results. Gastrointest Endosc 1996;43:98–101. 148. Griffin SM, Chung SC, Leung JW, Li AK. Peptic pyloric stenosis treated by endoscopic balloon dilatation. Br J Surg 1989;76:1147–8. 149. Craig PI, Gillespie PE. Through the endoscope balloon dilatation of benign gastric outlet obstruction. BMJ 1988;297:396. 150. Lam YH, Lau JY, Fung TM, et al. Endoscopic balloon dilation for benign gastric outlet obstruction with or without Helicobacter pylori infection. Gastrointest Endosc 2004;60:229–33. 151. Cook DJ, Fuller HD, Guyatt GH, et al. Risk factors for gastrointestinal bleeding in critically ill patients. Canadian Critical Care Trials Group. N Engl J Med 1994;330:377–81. 152. Krag M, Perner A, Wetterslev J, et al. Prevalence and outcome of gastrointestinal bleeding and use of acid suppressants in acutely ill adult intensive care patients. Intensive Care Med 2015;41:833–45. 153. Alhazzani W, Alshamsi F, Belley-Cote E, et al. Efficacy and safety of stress ulcer prophylaxis in critically ill patients: a network metaanalysis of randomized trials. Intensive Care Med 2018;44:1–11. 154. Cook D, Guyatt G. Prophylaxis against upper gastrointestinal bleeding in hospitalized patients. N Engl J Med 2018;378:2506–16. 155. Krag M, Marker S, Perner A, Wetterslev J, Wise MP,Schefold JC et al. Pantoprazole in patients at risk for gastrointestinal bleeding in the ICU. N Engl J Med 2018;379:2199–208.

54

A denocarcinoma of the Stomach and Other Gastric Tumors Michael Quante, Jan Bornschein

CHAPTER OUTLINE EPIDEMIOLOGY����������������������������������������������������������������820 ETIOLOGY AND PATHOGENESIS����������������������������������������820 Hp Infection��������������������������������������������������������������������823 Dietary Risk Factors ������������������������������������������������������825 Cigarette Smoking����������������������������������������������������������825 Alcohol��������������������������������������������������������������������������825 Obesity��������������������������������������������������������������������������825 Genetic Factors��������������������������������������������������������������826 TUMOR GENETICS������������������������������������������������������������827 PREMALIGNANT CONDITIONS������������������������������������������829 Chronic Atrophic Gastritis ����������������������������������������������829 Intestinal Metaplasia and Dysplasia��������������������������������830 Gastric Polyps����������������������������������������������������������������831 Previous Gastrectomy����������������������������������������������������831 PUD��������������������������������������������������������������������������������831 Ménétrier Disease����������������������������������������������������������832 SCREENING AND SURVEILLANCE ������������������������������������832 PREVENTION ��������������������������������������������������������������������832 Eradication of Hp������������������������������������������������������������832 Aspirin and other NSAIDs, Including COX-2 Inhibitors������833 Statins ��������������������������������������������������������������������������833 Antioxidants ������������������������������������������������������������������833 Other Dietary Factors ����������������������������������������������������834 CLINICAL FEATURES��������������������������������������������������������834 DIAGNOSIS������������������������������������������������������������������������834 Endoscopy ��������������������������������������������������������������������834 CT Gastrography������������������������������������������������������������834 Serum Markers��������������������������������������������������������������835 CLASSIFICATION AND STAGING ��������������������������������������835 EUS��������������������������������������������������������������������������������836 CT and PET��������������������������������������������������������������������836 Laparoscopy with Peritoneal Lavage������������������������������837 Other Imaging Modalities�����������������������������������������������837 Restaging after Neoadjuvant Treatment��������������������������837 PROGNOSIS AND TREATMENT������������������������������������������837 Surgery��������������������������������������������������������������������������837 Endoscopic Mucosal Resection and Submucosal Dissection������������������������������������������������������������������838 Chemotherapy����������������������������������������������������������������838 Chemoradiation��������������������������������������������������������������839 Intraperitoneal Chemotherapy����������������������������������������840 Unresectable Disease����������������������������������������������������840 MISCELLANEOUS GASTRIC TUMORS��������������������������������841 Gastric cancer remains a major cause of cancer-related mortality in the world, despite declining rates of incidence in many industrialized countries. In this chapter, we mainly discuss

820

gastric adenocarcinoma, which makes up most of gastric malignancies.

EPIDEMIOLOGY Gastric cancer is the third leading cause of cancer mortality in the world,1 although the overall incidence is declining.2 In Western countries, the incidence of gastric cancer has decreased dramatically over the past century; in the USA, gastric cancer mortality has decreased 87% since 1950 with a similar trend being reported in Europe.3 In the USA, the incidence of gastric cancer has diminished to approximately 7.6 cases per 100,000 people,4 whereas as recently as 1945, gastric cancer was the leading cause of cancer mortality in men.5 There is great geographic variation in gastric cancer incidence, with the highest incidence rates in the Far East (Fig. 54.1). Eastern Europe and Central and South America also have high incidence rates, with the lowest incidence rates observed in North America, North Africa, South Asia, and Australia.6 Although gastric cancer was common in industrialized countries in the past, the latest epidemiologic data indicate that more than 70% of new cases of gastric cancer are in developing countries, reflecting a more rapid decline in developed countries.1 In the USA, the median age of diagnosis is 70 years.4 In Japan, a country with a high incidence of gastric cancer, the mean age of diagnosis is roughly a decade earlier, perhaps reflecting lead-time bias due to widespread screening. The incidence of gastric cancer in males is approximately twice that in females (Table 54.1).1 The incidence of gastric cancer in blacks in the USA is nearly double that in whites. Native Americans and Hispanics also have a higher risk of developing gastric cancer than whites. In contrast to the pattern seen with nonjunctional gastric cancers, the incidence rates of adenocarcinomas at the esophagogastric junction (EGJ, formerly “cardia cancer”) are rising,2 According to the US Surveillance, Epidemiology, and Ends Results (SEER) database, these junctional cancers now represent 27% of gastric cancers in the USA, up from just 10% in 1975.4 There are numerous dietary, environmental, and genetic risk factors for gastric adenocarcinoma (Box 54.1). The dominant risk factor remains, however, infection with Hp and the associated chronic-active inflammation of the gastric mucosa (see Chapter 52). 

ETIOLOGY AND PATHOGENESIS Gastric cancer can be subdivided using the Laurén classification into 2 distinct histologic subtypes with different epidemiologic and prognostic features (Fig. 54.2).7 The intestinal type of cancer is characterized by the formation of gland-like tubular structures with features reminiscent of intestinal glands. This type of gastric cancer is more closely linked to environmental and dietary risk factors, tends to be the predominant form in regions with a high incidence of gastric cancer, and is the form of cancer that is now declining worldwide. The diffuse type of cancer lacks glandular structure and consists of poorly cohesive cells that infiltrate the wall of the stomach. It is found at the same frequency throughout the world, occurs at a younger age, and is associated with a

CHAPTER 54  Adenocarcinoma of the Stomach and Other Gastric Tumors

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54

Fig. 54.1  Worldwide incidence per 100,000 population of gastric cancer in men in 2012. (WHO).

TABLE 54.1  Gastric Cancer Incidence and Mortality Rates per 100,000 Population (Age-Adjusted) in 2012 Incidence

Mortality

Male

Female Male

Female

Developed countries

15.6

6.7

9.2

4.2

Developing countries

18.1

7.8

14.4

6.5

  

Data from Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA Cancer J Clin [Internet]. 2015; 65:87-108. Available from http://www .ncbi.nlm.nih.gov/pubmed/25651787   

worse prognosis than the intestinal form. Extensive involvement of the stomach by the diffuse type can result in a rigid and thickened stomach, a condition referred to as linitis plastic (Video 54.1). Another key feature of diffuse type cancers are signet-ring cells, special mucin-filled cells that are not present in intestinal type adenocarcinomas. There are also mixed phenotypes that contain heterogenous areas that feature predominantly either intestinalor diffuse-type characteristics. Adenocarcinoma of the stomach is also classified into proximal tumors (EGJ and gastric cardia) and distal or nonjunctional tumors (fundus, body, and antrum of the stomach). Junctional cancers can be further classified according to the Siewert classification by the location of the main tumor mass into Type I (1 to 5 cm above the EGJ), Type II (from 1 cm above to 2 cm below the junction), and Type III (2 to 5 cm below the junction) tumors.8 There is no clear distinction between the genetic and cellular origin of adenocarcinomas of the distal esophagus, the EGJ, and a subgroup of nonjunctional distal gastric cancers.9 Interestingly, with the decreasing incidence of Hp infection, nonjunctional tumors have been declining while more proximal tumors have been increasing. In a mouse model, it has even been postulated that Barrett esophagus-related esophageal cancer and cancer of the EGJ have their origins in the gastric cardia.10 Emerging data from gene expression profiling suggest that differences in pathologic appearance and clinical behavior may be due to the presence of unique molecular phenotypes. Characterization of the gastric

cancer genomic landscape reveals the presence of multiple alterations in the expression of tyrosine kinase receptors, which in conjunction with their ligands and downstream effector molecules represent potential pathways for future drug development. The Cancer Genome Atlas (TCGA) consortium suggested4 gastric cancer subtypes based on the genomic profile of about 300 gastric cancers.11 This classification correlated well with the clustering of high throughput data of different platforms including epigenome, transcriptome, and proteome analysis. So far, there are only little data to support the biological relevance of this proposed classification. Previous transcriptome analyses of gastric cancers, on the other hand, have demonstrated phenotypic clusters with either distinct prognostic outcomes or different response to systemic treatment.12,13 It is believed that the development of intestinal-type gastric cancer occurs through a multistep process in which the normal mucosa is sequentially transformed into a hyperproliferative epithelium, followed by metaplastic processes leading to glandular atrophy, dysplasia, and then carcinoma. In colon cancer, the evidence is strong that each step in the transition is associated with a specific gene mutation,14 but the evidence that gastric cancer follows a comparable sequence of genetic events has been lacking. However, in both the intestinal-type gastric cancer and colorectal cancer, it does appear that DNA mutations are established over time in stem cells in the normal human stomach, and that in intestinal metaplasia these mutations spread through the stomach through a process involving crypt fission and monoclonal conversion of glands.15 The contention that the pathogenesis of intestinal-type gastric cancer is a multistep process is supported mainly by the observation that both chronic atrophic gastritis and intestinal metaplasia are found in higher incidences in patients with intestinal-type cancer and in countries with a high incidence of gastric cancer (see Chapter 52).16,17 This multistep model of intestinal-type gastric cancer, developed in large part by Pelayo Correa and colleagues,18 postulates that there is a temporal sequence of preneoplastic changes that eventually lead to the development of gastric cancer. A common feature of the initiation and progression to intestinal-type gastric cancer is chronic inflammation of the gastric mucosa. Hp infection is the

822

PART VI  Stomach and Duodenum

BOX 54.1 Risk Factors for Gastric Adenocarcinoma DEFINITE Adenomatous gastric polyps* Chronic atrophic gastritis Cigarette smoking Dysplasia* EBV History of gastric surgery (esp. Billroth II)* Hp infection Intestinal metaplasia  GENETIC FACTORS Family history of gastric cancer (first-degree relative)* Familial adenomatous polyposis (with fundic gland polyps)* Hereditary nonpolyposis colorectal cancer* Juvenile polyposis* Peutz-Jeghers syndrome*  PROBABLE High salt intake History of gastric ulcer Obesity (adenocarcinoma of the cardia only) Pernicious anemia* Regular aspirin or other NSAID use (protective) Snuff tobacco use  POSSIBLE Diet high in nitrates Heavy alcohol use High ascorbate intake (protective)  High intake of fresh fruits and vegetables (protective) Low socioeconomic status Ménétrier disease Statin use (protective) QUESTIONABLE High green tea consumption (protective) Hyperplastic and fundic gland polyps   

*Surveillance for cancer is recommended in patients with this risk factor.

A

B

primary cause of gastric inflammation and the leading etiologic agent for gastric cancer (see Chapter 52). In a subset of patients, the inflammatory process leads to the development of atrophic gastritis (with loss of glandular tissue) followed by progression to intestinal metaplasia, dysplasia, early gastric cancer, and, eventually, advanced gastric cancer (Fig. 54.3). Although animal models suggested that all stages prior to the development of high-grade dysplasia are potentially reversible, there is still ongoing debate what defines the “point of no return” for humans from which further progression of neoplasia can no longer be prevented.19,20 Eradication of Hp has the potential to prevent gastric cancer as shown in recent metaanalyses.21,22 The preventive effect of eradication is more evident if there are no preneoplastic conditions of the gastric mucosa (glandular atrophy, intestinal metaplasia) at the time of intervention.23 Hp eradication can prevent further progression of preneoplastic conditions, and even a certain degree of regression can be documented.24 Although it is currently assumed that presence of intestinal metaplasia is most likely to mark the point of no return, there is even an effect of Hp eradication if advanced lesions are present (e.g., after endoscopic resection of an early gastric cancer).25 Unlike the situation observed with colon cancer, the precise genes involved in each step of this progression are still not defined. Nevertheless, next-generation sequencing techniques have shown that there is more heterogeneity in genetic alterations in gastric cancer and cancer of the EGJ than in colon cancer.26,27 Furthermore, the premalignant stages of gastric cancer are not as readily identifiable during endoscopy as those of colon cancer, and many gastric carcinomas are very heterogeneous, containing a large percentage of stromal cells. These stromal cells, which also include cancer-associated fibroblasts known to promote tumor growth, have been reported to show distinct genetic and epigenetic changes that may confound tumor analysis.28,29 This feature makes characterization of the timing of specific gene mutations in gastric cancer difficult at best. Currently, the role of chronic inflammation in the diffuse type of gastric cancer, as well as the similarities if any to the proposed pathway in Fig. 54.3 for the intestinal type of cancer, remain to be clarified. One common factor that is related to both histological subtypes is a strong association with Hp infection, which has shown to directly modify genes involved in DNA damage repair (DDR) pathways.30 Modifications of DDR-related genes are a common event in gastric carcinogenesis.31

Fig. 54.2  Histopathology of the 2 types of gastric cancer. A, The intestinal type of gastric adenocarcinoma is characterized by the formation of gland-like tubular structures mimicking intestinal glands. B, The diffuse type of gastric cancer contains singly invasive tumor cells that frequently contain abundant mucin and that lack any glandular structure. H&E stains. (Courtesy Rhonda K. Yantiss, MD, Boston, Mass.)

CHAPTER 54  Adenocarcinoma of the Stomach and Other Gastric Tumors

Normal gastric mucosa

Superficial gastritis

H. pylori Diet, salt?

Chronic inflammation

Recruitment of BM cells that form a tumor microenvironment Higher gastric pH

Atrophic gastritis

Bacterial overgrowth and nitrate reduction

Metaplasia

Barrier defect

Dysplasia

Salt? N-nitroso carcinogens Chronic inflammation and ROS

Carcinoma

Fig. 54.3  Proposed Correa pathway of pathologic events in gastric adenocarcinoma. In well-differentiated, intestinal-type gastric cancer, histopathologic studies indicated that chronic Hp infection progresses over decades through stages of chronic gastritis, atrophic gastritis, intestinal metaplasia, dysplasia, and cancer. The development of cancer has been attributed to alterations in DNA caused by chronic inflammation, which is associated with the recruitment and of bone marrow-derived immune and mesenchymal cells (BM cells) that form a microenvironment that favors tumorigenesis. An imbalance between epithelial cell proliferation and apoptosis and, in a milieu of atrophy and achlorhydria, gastric colonization by enteric bacteria with nitrate reductase activity facilitating formation of carcinogenic nitrosamines allow the accumulation of oncogenic genetic alterations. Corpus-predominant atrophy, or the loss of specialized glandular cell types such as parietal and chief cells, appears to be the critical initiating step in the progression toward cancer. (From Fox JG, Wang TC. Inflammation, atrophy, and gastric cancer. J Clin Invest 2007; 117:60-9.) ROS, Reactive oxygen species.

Hp Infection (see also Chapter 52) Hp is a gram-negative microaerophilic bacterium that infects nearly half the world’s population and is recognized as the primary etiologic agent for gastric cancer. Indeed, H. plyori has been classified as a class I (or definite) carcinogen by the International Agency for Research on Cancer, a branch of the WHO. Infection with Hp has been found in every population studied, although the prevalence is higher in developing countries and most parts of East Asia.32,33 The natural history of chronic Hp infection includes 3 possible outcomes34: (1) simple gastritis, where patients often remain asymptomatic; (2) duodenal ulcer phenotype, which occurs in 10% to 15% of infected subjects; and (3) gastric ulcer/gastric cancer phenotype. The risk for gastric cancer development varies with the type of background gastritis, but in general, corpusdominant gastritis resulting in a low acid state is mainly associated with an increased risk. Hp-induced duodenal ulcer disease is associated with a high gastric acid output as well as a reduced risk for developing gastric cancer.35 Studies suggest that Hp-infected patients develop chronic atrophic gastritis at a rate of 1% to 3% per year of infection.18,36,37 Thus, those patients who are genetically predisposed to developing atrophic gastritis in response to

823

Hp infection are likely to be also predisposed to gastric cancer. Although Hp infection is associated with both diffuse-type and intestinal-type adenocarcinomas, we focus in this chapter mainly on the mechanisms responsible for the formation of intestinaltype adenocarcinoma because they have been better studied. The association of Hp with mucosa-associated lymphoid tissue lymphoma is discussed in Chapter 32. The increased risk of development of gastric adenocarcinoma due to Hp infection depends on multiple factors including host genetic factors, the strain of bacteria (including bacterial virulence factors), the duration of infection, and the presence or absence of other environmental risk factors (e.g., poor diet, smoking). In a Japanese cohort, only those infected with Hp developed gastric adenocarcinoma during follow-up (2.9% vs. 0%; P A 621+3A >G 711+3A >G

Abundance

Mild

Potentiators Yes Yes

VI

A455G 3849+10kbC >T 2789+5G >A 621+3A >G 711+3A >G

Stability

Mild

Stabilizers

VII

Del2,3(21kb) 1717-1G>A 1898+1G >A

No Protein

Severe

Unrescuable

Class

  

Examples to illustrate variants in each CFTR functional class and approved therapy in the USA New therapies and expanded indications are in a continuous development and approval pipeline so therapeutic decisions should be based on the most current updates.   

has 3 or more CFTR gene variants, then at least 2 of them must be on the same allele (known as complex alleles). Variants that are on the same allele are said to be in cis, whereas those on opposite alleles are in trans. If there are multiple pathogenic CFTR variants that are all in cis, then the person is a CFTR variant carrier and will be asymptomatic unless there are unidentified variants on the trans allele (e.g., Class VII) or if they have a complex disorder involving other genes and environmental factors. CFTR functional phenotypes. Many of the organs that are affected in patients with CF have alternative pathways and protective mechanisms that minimize the impact of complete loss of CFTR function. The pancreas and sweat gland are 2 exceptions, where there is good genotype-phenotype correlation. Because complete loss of one CFTR copy has no phenotype, the relative severity of bi-allelic pathogenic CFTR variants is defined by the least severe variant. Thus, a person with 2 severe CFTR genotypes will likely have classic, early-onset CF with pancreatic insufficiency (PI), whereas a person with one severe and one mild-variable CFTR genotype may have a milder form of CF, later age on onset, and pancreatic sufficiency (PS).146 However, the pancreas is not easily studied, and therefore testing CFTR function in an individual is typically done by sweat chloride testing.

873

Measures of variant CFTR function. Of the approximately 2000 CFTR variants, a clear majority are tentatively classified as severe, mild-variable, borderline, or benign based on the patient phenotype when the unclassified variant is in trans with a known, severe variant. The most accurate measure of CFTR protein function is to perform site-directed mutagenesis and test the permeability and conductance characteristics of the mutant CFTR in an optimized cell system under a variety of experimental conditions.147,148 This information provides direct functional insight into the effect of protein sequence-altering variants. The sum of the most damaging variants on each allele (in trans) should hypothetically predict the severity of disease in the patient. Although this approach is a useful approximation, many other factors contribute to function including other pathogenic variants in complex haplotypes, the mechanistic role of CFTR and other molecules within various organs, modifying factors, epigenetics, environmental factors, and so on. Thus, even within patients with similar or identical genotypes, such as identical twins,149 there may be a wide spectrum of phenotypic features or severity. Furthermore, because the clinical spectrum of symptoms in patients with CF overlaps other non-CF diseases, a diagnosis of CF or CFTR-RD requires not only the clinical setting, the family history, and/or the CFTR genotype, but also testing of CFTR function in the patient. Bicarbonate defective CFTR variants. Phenotyping diseases by focusing on one organ may lead to classifying variants as benign, whereas they are strongly associated with disease in other organs. Such is the case of a class of CFTR variants that are associated with pancreatitis but classified as benign by investigators seeing patients referred for lung disease. Epithelial cells have an internal chloride concentration monitoring receptor called WNK1 that regulates the activity of multiple ion channels, transporters, and pumps.150 WNK1 directly regulates CFTR, dynamically changing the permeability and conductance characteristics from a chloride-type channel to a bicarbonate-type channel.151 LaRusch and colleagues148 demonstrated the critical role of CFTR-dependent bicarbonate secretion in the human pancreas based on this paradigm and previous mathematical modeling.138 They screened 984 well-phenotyped pancreatitis cases from the NAPS2 study for candidate mutations in CFTR with bicarbonate-defective conductance (CFTR-BD) from among 81 previously described CFTR variants in pancreatitis patients. Nine variants (CFTR p.R74Q, p.R75Q, p.R117H, p.R170H, p.L967S, p.L997F, p.D1152H, p.S1235R, and p.D1270N) not associated with typical CF were associated with pancreatitis (OR 1.5, P  = 0.002). The variants were cloned and tested for chloride and bicarbonate conductance in EK 293T cells, and although chloride was normal, bicarbonate permeability and conductance were significantly diminished in the presence of WNK1. A 3-dimensional model suggests that defective bicarbonate conductance may be caused by at least 4 mechanisms (Fig. 57.7). Molecular dynamics simulations suggest physical restriction of the CFTR channel and altered dynamic channel regulation. Because several other organs use CFTR to secrete bicarbonate, the NAPS2 cohort was further evaluated for chronic sinusitis (because bicarbonate is needed for mucus hydration), and male infertility because bicarbonate is necessary for vas deference development (avoiding congenital bilateral absence of the vas deferens; CBAVD) and sperm survival. CFTR-BD variants significantly increased risk for rhinosinusitis (OR 2.3, P < 0.005) and male infertility (OR 395, P < 0.0001). Furthermore, heterozygous CFTR-BD variants plus SPINK1 p.N34S variant genotypes were strongly associated with pancreatitis without the sinus or infertility effects.104,148 Sweat chloride testing. Sweat chloride testing remains the most reliable, standardized, and widely available functional test of CFTR function, because normal sweat gland function is directly dependent on CFTR function and because most of the other glands and organs linked to the morbidity of CF disease are relatively inaccessible.152 The sweat gland is composed of a secretory coil (eccrine gland) that generates an isotonic salt solution and a sweat duct connecting the

57

874

PART VII  Pancreas

Fig. 57.7  CFTR structure—bicarbonate variants (CFTR-BD). Panels A and B display the CFTR molecule from the side and bottom with residues 1–859 in black, residues 860–1480 in blue, the CFTR-BD variants are in red, and the shaded region indicates the location of the plasma membrane. The various locations of the CFTR-BD variants suggest multiple mechanisms including obstruction of the channel, altered interactions of the NBDs, altered intracellular signaling, and/ or other mechanisms. Panel C is the predicted location of wild-type p.D1152 viewed by looking down the barrel of the channel. Panel D is the predicted location of the pathogenic variant p.H1152. Panels C and D illustrate the effect of CFTR p.D1152H on bicarbonate conductance through physical obstruction of the pore for the larger bicarbonate ion. The charge distribution around p.D1152H is highlighted with negatively charged residue in red and positively charged residues in green. The variant residue in Panel D, H1152 (cyan), can move toward the center of the channel, thus leading to a constriction in the channel diameter. Å, channel diameter at the location of wild type and variant residues measured in Ångströms; MSD, membrane-spanning domains; NBD, nucleotide-binding domains. (From LaRusch J, Jung J, General IJ, et al. Mechanisms of CFTR functional variants that impair regulated bicarbonate permeation and increase risk for pancreatitis but not for cystic fibrosis. PLOS Genetics 2014; 10[4]: e1004376.)

gland to the skin surface. CFTR and epithelial sodium channels (ENaC) are expressed in both the eccrine gland and especially the duct, where they absorb chloride and sodium resulting in a hypotonic (low sodium and chloride concentrations) solution (sweat) that evaporates to provide body cooling, without the loss of electrolytes. Normally, the concentration of chloride in sweat is less than 20 mmol/L, but levels increase with increasing rates of secretion and can reach nearly 60 mmol/L in some people.152 In CF, the concentrations of chloride are 3 to 5 times higher than normal, with resting concentrations above 60 mmol/L and stimulated chloride levels approaching 120 mmol/L. Subjects who are heterozygous for severe, CF-causing mutations typically have nearly normal sweat chloride testing.152 Of note, extensive genetic testing of some patients with clinical CF and with a very abnormal sweat chloride test have only one identifiable pathogenic CFTR variant (i.e., they appear to be heterozygous), suggesting that other important factors that strongly affect CFTR function are yet to be identified. Current clinical guidelines for the diagnosis of CF include a sweat chloride of ≥60 mmol/L as

well as clinical features consistent with CF (including positive newborn screening, NBS) and/or a positive family history.153 Patients with features of CF and an intermediate sweat chloride test results of 30 to 59 mmol/L may still have CF.153 Patients with CFTR variants that only affect bicarbonate conductance may be missed by sweat chloride testing. Sweat chloride testing may also be important in the evaluation of symptomatic patients who may have undiagnosed CF or CFTR-RD. CFTR-RD includes RAP and CP, CBAVD, disseminated bronchiectasis, and sclerosing cholangitis, alone or in combination with other features.154-156 When a patient with unexplained RAP and/or early CP are found to have likely pathogenic CFTR variants, the clinically validated functional test to determine if they have CF or CFTR-RD is the sweat chloride test. The importance of diagnosing CF or CFTR-RD is highlighted by the availably of new therapies that specifically target CFTR function (later). Although secretin-stimulated pancreatic function testing also measures CFTR function, the interpretation of the results is confounded by the diminished bicarbonate concentrations in pancreatic juice in progressive pancreatic disease and by environmental factors such as smoking.157-159 The Cystic Fibrosis Foundation Clinical Care Guidelines suggests further evaluation of intermediate sweat chloride levels as outlined in Fig. 57.8. The algorithm begins with “clinical presentation of CF,” which may include patients with elevated immunoreactive trypsinogen levels during NBS in the USA, but who have intermediate sweat chloride test results.160 This approach may also be useful with CFTR-RD affecting only the pancreas, but the utility of this approach in an adult RAP or CP population has not yet been reported. Newborn CF screening—CRMS/CFSPID. The vast majority of infants with NBS and an intermediate sweat chloride test result remained disease free for an indeterminate time. These infants have therefore been classified as CF transmembrane conductance regulator-related metabolic syndrome in the USA (the “metabolic syndrome” reflected a billing code issue rather than any metabolic feature) and CF screen positive, inconclusive diagnosis (CFSPID) in other countries.160 A new unified definition by a US/European consensus group defines CRMS/CFSPID as a feature in an infant who has a positive NBS test for CF and either (a) a sweat chloride less than 30 mmol/L and 2 CFTR mutations, at least 1 of which has unclear phenotypic consequences, or (b) an intermediate sweat chloride value (30 to 59 mmol/L) and 1 or 0 CF-causing mutations.160 The CF-causing mutations are generally defined in the CFTR2 database (www.cftr2.org) with others variants classified as mutations of varying clinical consequence (MVCC, e.g., Class IV or Class V), non CF-causing mutation when the mutation in trans with another CF-causing mutation will not result in CF (which does not exclude the possibility that the mutation may contribute to CF-like clinical characteristics resembling mild CF or CFTR-RD), variants of unknown significance, or benign.156 Genetic counseling and follow-up clinical evaluations by qualified physicians and further testing is recommended.160 CFTR disease mechanism. The medical approach to CF is presented later whereas the mechanism of CFTR in disease is discussed here. Severe mutations in both CFTR alleles leading to total or near-total loss of CFTR function results in CF. The molecular consequences of CF include inability to adequately hydrate mucus and other macromolecules, leading to accumulation of viscid material and inspissated glands. This condition results in progressive organ destruction of the pancreas and respiratory system, and dysfunction of the liver, intestine, sweat glands, and other sites where epithelial cell secretion plays an important physiologic role. As noted earlier, the pancreas incurs a double risk because most of its proteins are zymogens and trypsin activation will lead to recurrent injury and eventually destruction of the pancreas through progressive fibrosis. Trypsin-mediated

CHAPTER 57  Genetic Disorders of the Pancreas and Pancreatic Disorders in Childhood

875

Clinical Presentation of CF

57

Sweat Chloride Results: 30-59 mmol/L with Genetic Testing and Analysis 2 CF-causing CFTR mutations

< 2 CF-causing CFTR mutations

CFTR physiology = dysfunction

Undefined or Unknown MVCC

CFTR physiology = equivocal or unavailable*

No CFTR mutations

CFTR physiology = normal

NBS Pancreatitis, etc.

CF Diagnosis

Time & Testing

CRMS/CFSPID

CFTR-Related Disorder

CF Unlikely

Fig. 57.8  CF and CFTR-RD Diagnostic Guidelines. Diagnosis of cystic fibrosis, CRMS/CFSPID, and CFTRRD. Clinical manifestations of CF include positive newborn screening results (NBS), signs and symptoms of CF, and/or family history of CF. Evaluation begins with sweat chloride testing. A sweat chloride greater than 60 mmol/L is diagnostic of CF, and less than 29 mmol/L makes CF unlikely (not shown). Sweat chloride of 30 to 59 mmol/L (blue bar) represents an intermediate range and extended CFTR gene analysis and/or functional analysis should be considered. If the CFTR genetic testing identifies one pathogenic CFTR variant and/or MVCCs and/or undefined variants, then CFTR physiology testing (NPD or ICM) is needed to define a final classification of CF, CRMS/CFSPID (in infants), CFTR-related disorder (typically older children or adults), or another disorder that is not CF. Note that CRMS/CFSPID category (light yellow box) does not exclude an eventual CF diagnosis because clinical features may develop with time or further testing (dashed arrow). The dashed arrow is one-way because a diagnosis of CF is almost impossible to erase in the minds of patients and their families. Patients with complex genotypes that include one CFTR variant plus another pathogenic variant (e.g., in SPINK1, CTRC) may be at high risk of pancreatitis, but are at low risk of CF and may have close to normal CFTR physiology by NPD or ICM because this measures overall genotype rather than the function of each allele product (classified as CF Unlikely, light blue box). CRMS/CFSPID, cystic fibrosis related metabolic syndrome/cystic fibrosis screen positive inclusive diagnosis; ICM, intestinal current measurement; MVCC, mutations of varying clinical consequence; NPD, Nasal potential difference. *See text for clinical signs and symptoms of the CF syndrome. (Modified from Farrell PM, White TB, Ren CL, et al. Diagnosis of cystic fibrosis: consensus guidelines from the Cystic Fibrosis Foundation. J Peds 2017; S4-S15e.1. Illustration property of David C Whitcomb, used with permission.)

injury and destruction of the pancreas in children with CF is consistent with this model because the pancreatic pathology in CF is pseudocyst formation and fibrosis rather than atrophy alone (as expected with duct obstruction).161 It appears that pancreatic gland injury in CF children roughly parallels the expression of trypsinogen in the developing acinar cells, which begins at 16 weeks gestation and gradually increases in concentration until birth and through the first 6 months of life when levels markedly rise.162,163 The resulting histology has many of the features of end-stage CP that develops in children and adults, but also has striking expanded ducts that appear as multiple protein-filled cysts (Fig. 57.9). The overall clinical picture in an individual with pathogenic CFTR variants depends on the nature of the combined CFTR mutations, the genetic background in which the defective genes operates (e.g., modifier genes), and environmental factors.156,161,164 About 70 to 90% of non-Hispanic white patients with CF have p.F508del. Distinct mutations are common to other ethnic and ancestral groups, including 3120 + 1G greater than A which is the second most frequent CF allele in African Americans (9.5 to 12.3%),165 the p.R334W mutation which is common in Hispanics, and the p.W1282X in Ashkenazi Jews (∼45%).156,166,167

Patients with 2 CFTRsevere mutations in trans typically develop classic features of CF, with elevated chloride levels in sweat glands, PI, recurrent and chronic pulmonary infections, and CBAVD in males. Complicating manifestations of severe CF can also include meconium ileus, distal intestinal obstruction syndrome (DIOS), gallbladder dysfunction, liver cirrhosis, and other GI problems. Patients with one severe CFTR mutation (Class I-III, e.g., p.F508del) and one mild-variable CFTR mutation (Class IV or V, e.g., p.R117H or p.R334W) typically have CF with PS CF due to incomplete loss of CFTR function, partially reduced chloride and/or bicarbonate conductance, and subsequent residual duct cell function, resulting in acinar cell survival.138,146 This residual pancreatic parenchyma with abnormal CFTR function leaves a PS-CF patient at high risk for AP and RAP, with an incidence of 22%.146 These patients are more likely to have only a subset of organs expressing CFTR affected and presenting symptoms may occur later in life (teens or 20s). Environment and modifier gene variants. Many of the features of CF cannot be explained by variations in CFTR sequence. Instead, these features are caused by specific environmental factors or modifier genes.156,161 Environmental factors, such as bacterial colonization of the respiratory system, tobacco smoke,

876

PART VII  Pancreas

Fig. 57.9  Histopathology of the pancreas from an autopsy of a child with severe features of CF. There are no residual normal ducts or acini. Instead, dilated ducts and “cysts” with inspissated material are seen. Other cases of CF span the spectrum between this image and chronic pancreatitis seen with other forms of pancreatitis, with acinar atrophy, fibrosis, and chronic inflammation. Arrows demonstrate residual islets. (From Whitcomb DC. Cystic fibrosis–associated pancreatitis. In: Beger HG, Warshaw A, Buchler MW, et al, editors. The pancreas: an integrated textbook of basic science, medicine and surgery. Oxford: Blackwell; 2008.)

poor nutritional status,168 and environmental allergens169 contribute to the severity of lung disease. The other major factors are modifier genes that strongly contribute to the wide range of clinical features in patients with apparently identical CFTR genotypes.156,167,170 In 1998 2 groups171,172 demonstrated that pathogenic CFTR variants were also very common in idiopathic and alcoholic CP, suggesting that CFTR mutations may be part of a more complex trait.104,173 Because heterozygous pathogenic CFTR variants are common in populations with European ancestry, and because the parents of CF children (obligate CFTR mutation carriers without CF) do not appear to have an increased incidence of AP or CP compared with the normal population,174 it is likely that a second factor that specifically targets the pancreas is required.37,173 In early-onset idiopathic pancreatitis, this second factor may be a genetic variant in SPINK1, CTRC, or CASR, an anatomical factor like pancreatic divisum, an environmental factor, or other mechanism.99,103-105,148,175 Although high-quality treatment trials for these patients are still needed, the problem is one of “plumbing” and methods to restore lost CFTR function and/or reduce resistance to pancreatic juice flow should be considered. 

Calcium-Sensing Receptor Gene (CASR) Variants Calcium plays multiple roles in pancreatic physiology and pathophysiology. On one hand the regulation of intra-acinar cell calcium is critical for the prevention of pancreatic injury,176,177 whereas increasing concentrations of calcium in the pancreatic duct increases the risk of sustained trypsin activation and precipitation as calcium-containing stones. The calcium-sensing receptor gene (CASR) is a membrane-bound member of the G-protein–coupled receptor superfamily. CaSR plays an important role in calcium homeostasis, as is reflected in its expression by cells of the parathyroid gland and renal tubules that are involved in the calcium homeostasis. CaSR has been identified in human pancreatic acinar and ductal cells, as well as in various non-exocrine tissues,178 although its functional significance

in the pancreas has not yet been determined. A possible role of the CaSR in the pancreatic duct is plausible by extension of duodenal physiology, noting that CaSR is coexpressed with CFTR in bicarbonate-secreting epithelial cells.179 CaSR activation dose-dependently raises intracellular calcium levels which causes calcium-dependent CFTR bicarbonate secretion as well as modulating other molecules involved in the process.179 More than 170 functional mutations (activating and inactivating) have been described in the CASR related to familial hypocalcuric hypercalcemia, neonatal severe primary hyperparathyroidism, autosomal dominant hypocalcemia, and related hypercalcemic or hypocalcemic disorders.180 The common CASR variants p.R990G, p.A986S, and p.Q1011E are strongly associated with urolithiasis and hypercalcuria in various populations.181 In 2003 Felderbauer182 investigated a kindred with familial pancreatitis and the SPINK1 p.N34S variant. However, only 2 of these family members had CP, and both were found to have a novel CASR c.518T>C mutation that was linked to hypercalcemia. An association between additional CASR variants, with or without SPINK1 mutations, was subsequently identified in patients in India with TP,183 as well as in the USA in sporadic and alcoholic CP in which the CASR p.R990G (rs1042636) variant doubles and triples the relative risk, respectively184 (the rs number is given because the amino acid number may change based on the CASR transcript used). Multiple rare CASR variants were also identified in a French cohort185 and the p.A986S variant (rs1801725) in multiple Chinese pancreatitis patients.186 CASR p.Q1011E (rs1801726) is also widely studied, but a clear role in pancreatic disease has not been established. The finding of different CASR polymorphisms in different populations is intriguing, but it appears that the presumed mild hypercalcemia is a cofactor for pancreatitis rather than an independent risk factor, as seen in animal models of hypercalcemia,63,187 or as part of complex functional genotypes with SPINK1 or CFTR or other factors. CASR variants that reduce CaSR function may also contribute to pancreatic disease because CaSR also serves as an amino acid receptor in the duodenum, linking luminal nutrients with release of cholecystokinin that subsequently stimulates pancreatic enzyme secretion.188 

GENES THAT MODIFY INFLAMMATION, PROGRESSION TO CHRONIC PANCREATITIS AND MODIFIER PHENOTYPES A number of pathogenic genetic variants have been identified in genes that are associated with the response to injury and inflammation. The pathogenic effects of these variants do not appear to be through causing injury, but rather in altering the response to injury or inflammation caused by other etiologies.

CLDN2-MORC4 Claudin 2 is a tight junction molecule that is coded for by CLDN2. Claudins seal the space between epithelial cells, mark the transition between the apical and basolateral membrane, and control the paracellular flux of water and electrolytes. The human genome has up to 27 claudins, which are generally divided into “tight” sealing claudins (e.g., 1, 3, 5, 11, 14, 19) and “leaky” pore-forming claudins (e.g., 2, 10, 15, 17).189 Claudin 2, which is inserted into the tight junction in exchange for “sealing” claudins during active secretion/absorption or with inflammation, forms pores that are permeable to sodium and water.189-191 The first GWAS identified a strong association between a large complex haplotype at the CLDN2 locus that extended from the TBC1D8B—RIPPLY genes across CLDN2 and the MORC4 genes defined by rs7057398 and rs12688220.51 The risk allele is prevalent in the control population (about 26% in European, 36% in

CHAPTER 57  Genetic Disorders of the Pancreas and Pancreatic Disorders in Childhood

Asian, and 2% in African ancestries), suggesting that it may be a disease severity modifier. The association with this locus and risk of pancreatitis has been replicated in multiple studies in multiple non-African ancestral groups.84-86,192 Claudin-2 is expressed in the pancreatic duct and acinar cells and up-regulated in AP.51,193 No mutations in the coding region of CLDN2 link with disease risk.51,194 MORC4 is a CW-type zinc finger protein and possible transcription factor expressed at low levels in most cells, but in high levels in testis and placenta.195,196 MORC4 expression in the pancreas does not appear to change pancreatitis,51 and further research is needed to determine possible pathogenicity in pancreatic diseases. RIPPLY1 and TBC1D8B are not known to be expressed in the pancreas.51 The CLDN2 locus (also known as the CLND2-MORC4 locus) requires separate analysis of populations by sex because it is located on the X chromosome. Males possess one chromosome (hemizygous genotype) and females possess 2 (homozygous or heterozygous genotypes). Using the NAPS2 cohort Whitcomb and colleagues51 modeled male risk allele carriers as homozygous (male hemizygote frequency is 0.26) and females who are truly homozygous for the risk allele (female homozygote frequency is 0.07) and suggested that this may help explain a higher risk of CP for males then females. Giri et al. calculated an OR for homozygous and heterozygous rs12688220 risk alleles at 14.62 and 1.51, respectively.86 Comparing CP subsets by alcohol and non-alcohol etiology, the CLDN2 high-risk haplotype was shown to be strongly associated with alcohol (P = 4 × 10−7), with the high-risk allele haplotype seen in 26% of controls, 32% of nonalcohol related etiologies, and 43% of alcohol-related pancreatitis,51 and with a stronger effect in men (OR 2.66) compared to women (OR 1.71).84 The importance of CLDN2 in precision medicine stems from the high frequency of the allele in most populations, and the strong interaction of the risk allele with alcohol. Although further work needs to be done to better understand the underlying mechanisms, these data are useful for risk stratification and counseling of patients with pancreatitis and alcohol use.

Hypertriglyceridemia-Associated Gene Variants Hypertriglyceridemia is a risk factor for AP, for AP severity, and for CP. Pathogenic variants in the lipoprotein lipase gene (LPL) serve as a prototype for hypertriglyceridemic disorders associated with pancreatitis. Triglycerides (TGs) themselves are not directly toxic, but their hydrolysis by lipases (including pancreatic lipases) produce saturated and unsaturated fatty acids that are proinflammatory and toxic at high levels to the pancreas and other organs.197,198 Patients are classified by fasting serum TG levels.199 The normal levels are less than 150 mg/dL (1 mmol = 88.6 mg/dL) with hypertriglyceridemia either mild (150 to 199 mg/dL), moderate (200 to 999 mg/dL), severe (1000 to 1999 mg/dL), or very severe (≥2000 mg/dL).199 The lifetime risk of pancreatitis in patients with severe hypertriglyceridemia is about 5% and very severe about 10% to 20%, which is significantly higher than the general population lifetime risk of about 0.5% to 1%.200 While the risk of developing AP is primarily seen with severe or very severe hypertriglyceridemia (see Chapter 58), in practice the serum TG levels vary markedly with diet, and outpatient levels do not correlate well with levels seen in patients with TG levels seen early in AP.201 TG levels directly correlate with severity and complications of AP. In a single-site study of 400 AP patients from Pittsburgh, Pennsylvania, USA the rate of persistent organ failure increased proportionally to TG levels, with 17% at less than 150 mg/dL, 30% at 150 to 199  mg/dL, 39% at 200 to 999  mg/dL, and 48% at greater than 1000  mg/dL.202 On multivariate analysis risk of

877

persistent organ failure increased by OR 2.6 and 4.9 for TGs of 200 to 999 mg/dL and greater than 1000 mg/dL respectively.202 A similar trend was seen among 1539 AP patients in Nanchang, Jiangxi, People’s Republic of China.203 The risk of hypertriglyceridemia AP is associated with untreated/poorly controlled diabetes mellitus, alcohol abuse, pregnancy, many medications, and genetic factors.200 Thus, hypertriglyceridemic AP represents a complex gene-environment and variable risk complex with the potential of being managed thorough precision medicine evaluation and targeted treatment. The genetics of hypertriglyceridemia involves a few familial syndromes with TG levels in the thousands, and more complex situations requiring a combination of genetic and environmental conditions. Familial hyperlipidemias, previously classified as Fredrickson Type I, V, and IV, are often associated with RAP. Type 1 hyperlipoproteinemia is now known as familial chylomicronemia syndrome (FCS) and is an autosomal recessive disorder associated with pathogenic variants in LPL or other genes. LPL. Lipoprotein lipase deficiency204-206 from mutations in LPL207 cause about 80% of the cases of FCS. The diagnosis of LPL deficiency is supported by the presence of markedly elevated serum TG concentrations and chylomicrons, and can be confirmed with an intravenous heparin test206 performed when the patient is not having an attack of AP. Other dyslipidemia genes. FCS can also be seen with loss of function mutations in other genes such as apolipoprotein C-II (APOC2),205 APOA5, glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1), and lipase maturation factor 1 (LMF1), and in the presence of circulating inhibitors to the LPL enzyme.208,209 In addition, Johansen and colleagues210 conducted a GWAS of patients with dyslipidemia/hypertriglyceridemia and identified common variants with strong disease associations in several genes, including APOA5, GCKR, LPL, and APOB. It is now clear that many patients with familial or sporadic hypertriglyceridemia have a complex syndrome, termed multifactorial chylomicronemia syndrome (MCS). Patients with MCS may have a combination of a heterozygous loss of function mutation and/or likely pathogenic frequent variants in TG-raising genes, thus producing severe hypertriglyceridemia as a complex genetic disorder.211 A recent expert panel recommended defining a FCS Score to differentiate FCS from MCS, with the assumption that this would help determine who was at risk of AP.211 However, this hypothesis has not been adequately tested. The relationship between familial hyperlipidemias and CP is complex and represents a subset of patients with hypertriglyceridemic AP. In the NAPS2-CV cohort of 521 well phenotyped patients with CP, physicians identified hypertriglyceridemia to be the primary etiology in 4% of the cases, and a risk factor in another 13%, indicating an increased risk of CP with hypertriglyceridemia to be about 2- to 6-fold.49 In another study of 121 AP patients with serum TG levels ≥ 500 mg/dL from the University of Pittsburgh, CP was identified in 16.5% of patients after a mean follow-up of 64.7 ± 42.8 months.212 Taken together, it appears that CP can develop in the most severe, prolonged, and poorly controlled cases of familial hypertriglyceridemia who suffer recurrent attacks of AP (e.g., patients with genetic LPL deficiencies) as well as patients with complex hypertriglyceridemia and AP. 

SLC26A9: CF Disease Severity Modifier The role of genetic modifiers in pancreatic diseases is well defined in CF. Genetic association studies in patients with CF have identified a number of modifier genes associated with worse pancreatic disease during newborn screening for CF, and CF-related diabetes (CFDM), as discussed later.213,214 One of the strongest modifying genes in CF is the Solute Carrier Family 26 member 9

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gene (SLC26A9), a multifunctional ion transporter that functions as a Cl−/HCO3− exchange, chloride channel, and sodium chloride cotransport215 that was originally identified as the primary CFDM modifier in a GWAS study.213 SLC26A9 is expressed in high concentrations in the salivary glands, stomach, and lung, with lower levels in the kidney, duodenum, pancreas, and other organs. SLC26A9 is not critical to pancreatic function; the primary phenotype of knock-out mice is complete loss of gastric acid secretion rather than pancreas dysfunction, indicating an essential role of this channel/transporter in gastric acid secretion.215 However, SLC26A9 cooperates with CFTR in many fluid-secreting epithelial cells, and loss of both CFTR function and reduction in SLC26A9 function results in a much worse CF phenotype.213,214,216,217 Patients with CF and high-risk SLC26A9 genetic variants have worse pancreatic disease,214,216,218 as well as a much higher risk of meconium ileus,214 lung dysfunction,217 and other effects.216,219 Furthermore, patients carrying pathogenic SPC26A9 variants are at high risk of DM, as GWAS studies identified SLC26A9 SNPs with the highest association between CF and DM of all loci in the human genome.213 Although it is clear that other solute carrier family genes and other genes also modify CF, other syndromes, and diseases with defining pathologic features, SLC26A9 represents a prototype of genetic variants that are not associated with a specific human disease but make a variety of dysfunctional cell and organs systems worse. The opportunity to target these modifiers to improve patient disease severity is a goal of future research. 

CF-Related Diabetes Risk In non-CF pancreatic diseases, DM represents a common, variable, and potentially severe complication that likely has multiple genetic and environmental risks, as well as anatomical mechanisms. A non-type 1, non-type 2 DM due to severe, end-stage destruction of the pancreas in CP, or surgical removal of some or all of the pancreatic parenchyma with obligate reduction of the islet cell mass has been called type 3cDM. However, 20% to 30% of patients with RAP or earlier stage CP also have DM, possibly due to modifiers or other factors rather that loss of the entire islets. To investigate the non-genetic risk factors for DM, researchers used the NAPS2 cohort to compare demographic and disease characteristics from CP patients with or without DM.23 The risk profile was similar to population controls with type 2 DM, being more likely if the patient had a family history of DM, was of African ancestry, overweight (OR 1.62), or obese (OR 2.8). Severity of CP also affected risk as measured by calcifications, atrophy, and prior pancreas surgery, with EPI also a significant risk (OR 1.9).23 The fact that ancestry and family history significantly affected risk suggest that genetic modifiers contribute to DM in CP. 

INTEGRATION OF GENETICS AND PATIENT MANAGEMENT A precision medicine approach adds to the multidisciplinary training and care of the health care industry through the use of new technologies. The first technical advance is the organization and standardization of health care information for detailed tracking of all features, tests, and biomarkers of a patient’s disease journey, framed and compared with other patients with overlapping or distinct diseases and outcomes.220,221 To be fully useful this information must be readily available to the patient and various healthcare providers.30 The second is advancing imaging technology, providing structural and functional evidence of disease pathology and disease stage. Third is the “omics” revolution, where millions of analytes can be measured in a patient within a specific clinical context. Foremost among these “omics” is deciphering the patient’s entire genome, which does not change throughout their

life and contains powerful predictive implications on how specific genes, protein products, cell types, and biological systems are likely to work under different conditions. Fourth, the availability of research and population data sets linked to new computational and analysis tools are needed to provide context and comparisons for the rich data sets to advance biomedical discovery.220-222 Fifth, simple and sophisticated disease models are needed to organize the variables within a single patient, and determine the disease drivers, disease stage, disease activity, complication susceptibilities, and targets for treatment.1,2,7 Fortunately, simple models such as pancreatic duct secretory deficits linked to mutations in CFTR can be readily detected by genetic testing, and effective targeted treatment strategies have been demonstrated.223 Finally, the “smart phone” and other devices allow the patient to track and record their condition and response to therapies continually, and to more fully participate in their health care.30 Because unique combinations of risk and features of uncommon disorders are few, novel approaches are also required to parse the features of these complex disorders, such as N-of-one trials, to collect, organize, and evaluate the evidences as to whether specific interventions are effective under defined conditions.39,224 Consensus recommendations for managing pancreatic disease include early diagnosis and structured longitudinal care.2,225,226 No consensus exists for diagnosing early CP, although there is agreement that it exists and is important.2,38 Because the diagnosis of early, mild, non-calcific, or minimal change CP is challenging, some experts suggest that patients should be followed using a “place-holder” diagnosis of probable CP, or “insufficient evidence.”227 Clinical data collection and recording should be standardized during evaluation and follow up of patients with suspected or proven CP.225 Tracking the function of each component of pancreatic diseases is important because imaging, exocrine function, endocrine function, pain, and cancer risk do not correlate well with each other. The initial evaluation for suspected or documented pancreatitis patients should address the risk factors (family history and genetics, environmental exposures, and clinical setting such as prior episodes of AP), differential diagnosis, signs and symptoms, and baseline measures of nutrition and pancreatic structure and function. The family history (preferably using a standardized family tree) should include pancreatitis, pancreatic cancer (PC), diabetes mellitus and hypertriglyceridemia, and previous genetic testing results considered. If no genetic testing, or an inadequate panel of variants was performed, then an extended genetic panel should be ordered after appropriate genetic counseling. Alcohol and smoking history should be quantified. Anthropomorphic measures including height, weight, blood pressure, and heart rate should be documented. High-quality imaging of the pancreas with standardized techniques and reporting is required,228 and better methods of standardizing and reporting structure and physical features, such as fibrosis with elastography or functional with secretin-stimulated magnetic resonance cholangiopancreatography (sMRCP) are emerging.24,229-231 Laboratory tests should include serum levels of fat-soluble vitamins (A, D, E, K), vitamin B12, minerals, and trace elements, a baseline bone mineral density, and screening for diabetes mellitus (e.g., fasting glucose, hemoglobin A1c, referral if abnormal).225,232 Common measures of nutrition and inflammation include total protein, albumin, ionized calcium, prealbumin, osteocalcin, selenium, C-reactive protein, and a lipid panel.233 Pancreatic exocrine function testing should be included as well. Although there is no consensus on the best method, human fecal elastase-1 testing (in formed stool), secretin-stimulated pancreatic function test (in the absence of CFTR mutations), or serum trypsinogen levels (in patients without a painful flair) are often used. Pain assessment should use multidimensional scales measuring its intensity, nature and location, frequency, and pain’s impact on mood or activity level.226

CHAPTER 57  Genetic Disorders of the Pancreas and Pancreatic Disorders in Childhood

As part of a baseline evaluation, the patient should have counseling about genetic testing if this has not previously been provided. Genetic testing for Mendelian disease has utility for identifying the disease-causing variant in affected family members, clarifying etiology and prognosis, and providing information for at-risk family members and family planning. However, additional considerations are required for complex genetic disorders, and the role of a qualified genetic counselor in the evaluation process is different than with Mendelian disorders.234 Genetic testing for risk variants may also clarify disease etiology, outcomes, and management strategies. These are particularly important to interpret in the context of other risk factors. Patients should be specifically counseled prior to testing so that they understand the benefits, risks (e.g., life insurance), and limitations, and provide informed consent.234 Patients should also be counseled after testing so that they understand what was identified and what it means for them and their family (and provided their test results). Many genetic testing companies provide this service. Patients should be evaluated at least annually, with assessment and documentation of changes in pancreatitis-related symptoms or interval hospitalizations, development of new symptoms (particularly those that may suggest cancer), functional abnormalities (exocrine and/or endocrine insufficiency), morphological changes on imaging (if performed), and laboratory testing.225,235 Patients should be asked for symptoms suggestive of EPI, including abdominal bloating, distention, frequent bowel movements (particularly after eating), weight loss, and the presence of steatorrhea.225 Patients with CP should be screened for nutritional deficiencies in fat-soluble vitamins, minerals, and trace elements on at least an annual basis and be monitored for bone density and treated based on assessment of fracture risk.225 Although there is insufficient data to recommend routine PC screening for patients with CP, clinicians should track for new-onset diabetes mellitus, painless jaundice, weight loss, or new abdominal pain radiating to the back. The emergence of new and established drugs and therapies that can be repurposed and used in pancreatic diseases continues to be examined and applied to specific problems.39,223 The systematic collection of recommended measures of individual patients over time will allow the use of these therapies to be studied and optimized. 

PANCREATITIS IN CHILDREN Once considered uncommon, the incidence of pancreatic disease in children appears to be increasing. Increased physician awareness appears to account for the most of the increase.236 AP occurs in all pediatric age groups including infants.237,238 Common causes of AP in adults—excessive alcohol use and gallstones—are less often seen in children. The majority of cases of RAP and CP in children have a structural or genetic basis (Box 57.2).60,100,239 The genetic factors predisposing to AP appear to be similar to those associated with CP and are discussed in detail in the following sections.

Acute Pancreatitis Etiology. AP (defined earlier) is a sudden inflammatory disease of the pancreas with multiple etiologies (see Box 57.2). The most common known causes in children are biliary tract disease (10% to 30%), medications (25%), systemic disease (33%), trauma (10% to 40%), metabolic disease (2% to 7%), and HP (5% to 8%); 13% to 34% of cases are idiopathic.240 Much of the variation in incidence results from studies done at a time when AP was underdiagnosed in children. Some of these cases occur in children with high-risk genetic alterations, especially pancreatic-specific combinations of SPINK1 and CFTR mutations.241 Genetic testing, discussed later, is usually performed after recurrent episodes and when other common causes have been excluded.

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Trauma. Trauma is a cause of AP even though the pancreas is well protected from minor injury by its retroperitoneal location. The trauma is usually blunt, associated with injuries to other abdominal viscera, and becomes evident soon after the injury, although injury may apparently precede the manifestation or recognition of pancreatitis by several weeks. Injury to the pancreas is often not considered in a severely injured or battered child. Structural abnormalities. Structural abnormalities are being recognized earlier as imaging techniques such as MRI and MRCP improve. Pancreas divisum is the most common anatomic aberration, although a wide variety of other structural abnormalities of the bile and pancreatic duct also have been observed (see Chapter 55). Post-ERCP pancreatitis has been a significant cause of pancreatitis in several series,242,243 and this etiology is seen wherever ERCP is performed in children. The widespread availability of MRCP has drastically reduced the use of diagnostic ERCP, although ERCP remains invaluable for therapeutic intervention (see Chapter 61). Biliary tract disease. Gallstone pancreatitis is less common in children than in adults and is probably a reflection of the relative infrequency of cholelithiasis before puberty.60 However, this diagnosis must be considered, regardless of age. Medications. Medications remain a frequent cause of AP in children, although the disease underlying the prescription must also be considered in the differential diagnosis.244,245 Recent studies identified valproate as the most frequent drug associated with pancreatitis in children, followed by l-asparaginase, prednisone, or 6-mercaptopurine.242,243,246,247 The development of persistent abdominal pain in a child receiving any medication should suggest the possibility of drug-induced pancreatitis. This is confirmed only by documentation of pancreatic disease, improvement on drug withdrawal, and return of disease when the drug is reintroduced. Infections. Infections, particularly with viruses,248 are frequently associated with childhood pancreatitis. Enteroviruses, particularly coxsackievirus, are associated with idiopathic AP.249 Pancreatitis has been reported in children with EBV infections.250 Pancreatitis in children is often attributed to mumps virus on the basis of abdominal pain and an elevated serum amylase value with parotitis.251 Mycoplasma pneumoniae infection and AP, sometimes developing a week or 2 later has been documented in multiple cases reports.248 Although uncommon in the USA, ascariasis is among the most frequent causes of pancreatitis in children in regions such as South Africa and India; worms can be found within the pancreatic duct. Pancreatitis was common in patients with HIV/AIDS, possibly due to medications and associated with hyperlipidemia and/or mitochondrial toxicity (see Boxes 57.1 and 57.2, and Chapter 35). Systemic diseases. Hemolytic uremic syndrome was the most common systemic cause of AP in 2 studies.242,243 The mechanism is unknown and likely multifactorial although uremia from any cause is a risk factor for pancreatic injury. SLE252 and Kawasaki disease253 have been associated with pancreatitis. AP should be considered in the ICU when the child is not responding to other therapies or appears to have an unexplained acute inflammatory process. AP is also common after organ transplantation (see Chapter 36). Pancreatitis is occasionally observed in diabetic ketoacidosis242,243,254 and various inborn errors of metabolism.255 Acquired metabolic derangements. The most common metabolic derangement associated with development of pancreatic disease in children is protein-calorie malnutrition. In severely malnourished children, pancreatic enzyme secretion is often compromised, whereas volume and bicarbonate secretion are preserved. Recovery of pancreatic function is said to occur more promptly after kwashiorkor than after marasmus, but in either case the pancreatic disease may contribute to malabsorption during convalescence. Vigorous early refeeding of malnourished children has been associated with the development of clinically significant pancreatitis. Malnutrition

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BOX 57.2 Causes of Acquired Pancreatitis in Children TRAUMA

ERCP Medications α-methyldopa Antimony (pentavalent) Azathioprine Azodisalicylate Cimetidine Cytosine arabinoside Didanosine Erythromycin Estrogen Furosemide Glucocorticoids Isoniazid IV lipid emulsion Lamivudine l-Asparaginase 6-Mercaptopurine Mesalamine Metronidazole Pentamidine Procainamide Rifampin Sulfasalazine Sulfonamides Sulindac Tetracycline Valproic acid Zalcitabine  INFECTIONS AIDS/HIV-associated Ascariasis

was considered a major contributing factor to TP, but this has now been questioned because TP is observed primarily in well-nourished patients, often with genetic mutations.42,44,256 Clinical features. The diagnosis of AP is based on the syndrome of sudden onset of typical abdominal pain with elevation of serum amylase or lipase to at least 3 times the upper limit of normal levels (see Chapter 58).31,257,258 The pain is usually supraumbilical, worsens with eating, and may be accompanied by nausea, vomiting, and occasionally jaundice. A transient fever is often present. In infants and toddlers, vomiting, fever, irritability, and abdominal distention can be presenting symptoms.237 Normal serum amylase values increase with age, which is explained perhaps by the delayed appearance of pancreatic isoamylase, which is usually not present before the age of 3 months and often not detected until the age of 11 months; even then it is not present at adult levels until the age of 10 years. Salivary isoamylase appears and matures much sooner. After the initial episode of AP, recurrent AP is seen in about 10% of children.243 The most common diagnoses in patients with recurrent AP are structural abnormalities, or familial pancreatitis or complex genetic risk.60,100,243 A careful evaluation aimed at identifying or ruling out reversible causes should be undertaken to prevent further attacks and to reduce the risk for developing CP and its complications.235 

Recurrent Acute Pancreatitis and Chronic Pancreatitis Once thought to be rare, numerous children with RAP and CP are being reported. Improvement in abdominal imaging,

Coxsackie B virus Echovirus Enterovirus EBV HAV Herpesviruses Influenza A Leptospirosis Malaria Measles Mumps Mycoplasmosis Rabies Rubella Typhoid fever  BILIARY TRACT DISEASE

Pancreas Divisum Metabolic Disorders CF Hypercalcemia Hypertriglyceridemia Protein-calorie malnutrition Reye syndrome  FAMILIAL DISORDERS Miscellaneous Causes Congenital partial lipodystrophy Diabetic ketoacidosis Henoch-Schönlein purpura Tropical pancreatitis Kawasaki disease Perforated duodenal ulcer SLE

physician awareness, and possible change in prevalence demonstrated that CP is a major medical problem in children with very high costs.259 A recent multinational cross-sectional study of RAP and CP in children (International Study Group of Pediatric Pancreatitis: In Search for a CuRE; INSPPIRE) provides new insights into this complex of pediatric pancreatic disorders beyond CF.100 Among 301 cases in the initial cohort the mean and standard deviation of the children’s ages was 11.9 ± 4.5 years, with 57% female. CP was documented in 146 patients and 84% of them reported prior recurrent episodes of AP. Hispanic children were more likely to have RAP than CP. At least 1 gene mutation in pancreatitisrelated genes was found in 48% of patients with RAP versus 73% of patients with CP (P < 0.001). Children were more likely to present with CP than with RAP if they had pathogenic variants in PRSS1 (OR 4.2) or SPINK1 (OR  2.30).100 Pancreatitis-related abdominal pain was a major symptom in 81% of children with RAP or CP within the previous year, with emergency department visits, hospitalizations, and medical, endoscopic, and surgical interventions being more common in the CP group.100 Children have less exposure to environmental risk factors for AP and CP than adults, especially long-standing alcohol use and smoking. Demographic and clinical information on children with RAP or CP in the INSPPIRE cohort was evaluated for risk factors according to age.60 Among 342 cases, 38% of the children were less than 6 years of age at first diagnosis, 32% were 6 to 11 years of age, and 30% were ≥ 12 years of age. Early-onset disease was significantly associated with pathogenic genetic variants in PRSS1 and CTRC, a family history of AP or CP, biliary cysts, or

CHAPTER 57  Genetic Disorders of the Pancreas and Pancreatic Disorders in Childhood

TABLE 57.2  Hereditary and Congenital Disorders of the Exocrine Pancreas and the Associated Gene Disorder

Defective Gene or Protein (Inheritance)

TABLE 57.3  Frequency of Selected GI Manifestations in CF* Organ

Manifestation

Pancreas

Total achylia Abnormal glucose tolerance Partial or normal function Pancreatitis

Exocrine Pancreatic Insufficiency Pancreatic agenesis (see Chapter PDX1 or PTF1A (recessive) 55) CF

CFTRsev/CFTRsev (recessive)

Shwachman-Diamond syndrome

SBDS (recessive)

Johanson-Blizzard syndrome

UBR1 (recessive)

Pearson marrow-pancreas syndrome

Mitochondrial DNA (mitochondrial)

Isolated enzyme deficiency

See text

Pancreatitis Hereditary Familial

PRSS1 (autosomal dominant) CEL SPINK1/SPINK1 (autosomal recessive) CFTRsev or CFTRbl/SPINK1 (complex)

CFTR-RD

CFTRsev/CFTRm-v (recessive)

Sporadic

CTRC (complex) CASR (complex)

Modifiers

CLDN2 SLC26A9 (CFTR-associated)

Hypertriglyceridemia

Lipoprotein lipase (dominant)

881

Diabetes mellitus Intestine

Frequency in all Frequency in Patients (%) Adults (%) 85-90 20-30

85-90* 20-30

10-15

10-15

1-2 (all CF) 22% (PS-CF) 4-7

2-3 4-7

Meconium ileus Rectal prolapse Distal intestinal obstruction syndrome Intussusception

10-25 1-2 3

18

1

1-2

Liver

Fatty liver Focal biliary cirrhosis Portal hypertension

7 2-3 2-3

20-60 11-70 28

Biliary tract

Gallbladder abnormal, 25 nonfunctional, or small Gallstones 8 Bile duct strictures 1-20

5-20

GERD

80

Esophagus

Unknown

10-25 1-20

  

*Frequency may depend on the genotype. PS-CF, CF with pancreatic sufficiency.   

Apolipoprotein C-II   

Add footnote from prior Table 57.2 and add to it CEL, PRSS1, CLDN2, SLC26A9, which are defined in the chapter.   

chronic renal failure.60 Later-onset RAP and CP were associated with hypertriglyceridemia, ulcerative colitis, autoimmune diseases, or medication use.60 Children with later-onset disease also were more likely to visit the emergency department (P < 0.05) or have diabetes mellitus (P < 0.01).60 Recommendations for the evaluation of patients with newonset AP, RAP, and CP continue to evolve. The INSPPIRE consortium recently made a series of recommendations for the causal evaluation of RAP and CP.235 Systematic evaluation of anatomical, metabolic, and genetic causes is recommended, including a sweat chloride test or CFTR genetic testing (even if newborn screening for CF was negative), PRSS1, CTRC, and SPINK1 genetic testing and for screening for celiac disease.235 Testing for EPI and related vitamin and nutritional deficiencies, diabetes, and complications should also be evaluated annually.235 

CLINICAL MANAGEMENT OF MENDELIAN DISORDERS OF THE PANCREAS Several genes that are critical to pancreatic function manifest genetic variations and polymorphisms that lead to Mendelian pancreatic disorders, usually with multisystem involvement (Table 57.2).

Cystic Fibrosis CF is the most common lethal genetic defect of white populations, seen in 1/2500 to 1/3200 live births. Compared to children of European ancestry, the incidence of CF is lower in children of African, Native American, Asian, East Indian, or

Middle Eastern backgrounds.260 Prognosis has dramatically improved, with the predicted median survival of CF patients extending beyond age 47 years.261 Still, the median age at death is about 30 years. Here we focus on manifestations of CFTR gene mutations on the pancreas, with briefer discussions of intestinal, hepatobiliary, and nutritional problems also seen by gastroenterologists (Table 57.3). Clinical features. Over 60% of CF patients are diagnosed by newborn screening in the USA. 261 In 2016, the median age at diagnosis for all patients was 4 months and 67% were diagnosed in the first year of life. Around 10% of all patients were diagnosed after age 10 and a few were diagnosed after age 40. Most infants identified by newborn screening are minimally symptomatic or asymptomatic when screened. Of the infants who screen positive for CF, most are easily confirmed after demonstration of elevated sweat chloride concentrations (Table 57.4) or demonstration of an abnormal nasal bioelectrical response in specific testing protocols that also reflects abnormal CFTR function. When performed appropriately, these tests are reliable. However, false-positive as well as falsenegative results may be observed in newborns, in patients with malnutrition, with some medications, or if inadequate sweat is obtained (see Table 57.4). Thus, most experts insist on using the standardized methods performed at CF centers that use these testing methods frequently. Because of the explosion of new phenotypic and genotypic information in patients with CF, the CF Foundation selected an international consensus committee to provide recommendations on the diagnosis of CF,153 in large part by recognition that many patients have CFTR-associated abnormalities but do not have CF.262 The panel concluded that a presumptive diagnosis of CF can be made in a patient with a positive newborn screen and 2 CF mutations from the CFTR2 mutation list (http://cftr2.org/) or signs and symptoms of CF or meconium

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ileus, but the diagnosis must be confirmed with a positive sweat chloride test (>60 mmol/L). The guidelines classified patients who did not have CF into 2 groups: CFTR-related metabolic syndrome (CRMS) and CFTR-related disease (CFTR-RD), as described earlier. The clinical features of CF are listed in Box 57.3, and frequencies of the various GI manifestations of CF are listed in Table 57.3. The early clinical features are those of maldigestion or TABLE 57.4  Sweat Test (Quantitative Pilocarpine lontophoresis): Indications and Conditions with High Sweat Electrolyte Levels Indications Siblings with CF Chronic pulmonary symptoms Persistent cough Recurrent respiratory infection Bronchitis Bronchiectasis Lobar atelectasis Failure to thrive (stunting of growth) Rectal prolapse Nasal polyposis Intestinal obstruction of newborn Meconium ileus Jaundice in early infancy Cirrhosis in childhood or adolescence Portal hypertension Adult males with aspermia or azoospermia Heat stroke Hypoproteinemia Hypoprothrombinemia

Conditions With High Sweat Electrolyte Levels CF Ectodermal dysplasia Glycogen storage disease, type 1 Adrenal insufficiency Familial hypoparathyroidism Fucosidosis Pitressin-resistant diabetes insipidus Mucopolysaccharidosis Familial cholestasis syndrome Environmental deprivation syndrome Acute respiratory disorders (croup, epiglottitis, viral pneumonia) Chronic respiratory disorders (bronchopulmonary dysplasia) α1-Antitrypsin deficiency

other pancreatic and intestinal manifestations of CFTR mutations (discussed later). The phenotype-genotype relationship between some childhood disorders and CFTR mutations is often striking, with severe CFTR mutations detected in more than 85% of all children presenting with PI and in the majority of infants presenting with meconium ileus.164 Pulmonary function is normal in patients with CF at birth but accounts for much of the morbidity and almost all of the mortality associated with CF beyond the neonatal period. The severity of lung disease depends on known and unknown factors. Genetic and environmental factors contribute proportionally to pulmonary function variation in CF,263 demonstrated by a wide variation in severity of lung disease among patients with identical CFTR genotypes. Environmental factors may include chronic infection with Pseudomonas aeruginosa, nutritional status, tobacco smoke, and environmental allergens,169 whereas genetic factors include variants in inflammatory response genes264,265 and modifier genes.266-268. Pancreatic pathology. Most (85% to 90%) patients with CF present with evidence of exocrine pancreatic dysfunction.146,269 Although pancreatic dysfunction in an infant with CF may initially appear minimal, it usually progresses to pancreatic exocrine failure. When severely affected, the pancreas is shrunken, cystic, fibrotic, and fatty. Histologically, hyperplasia and eventual necrosis of ductular and centroacinar cells, together with inspissated secretions, lead to blockage of pancreatic ductules and subsequently encroach on acini, causing flattening and atrophy of the epithelium (see Fig. 57.9). Cystic spaces are filled with calcium-rich eosinophilic concretions. A mild inflammatory reaction may be present around obstructed acini, and progressive fibrosis gradually separates and replaces the pancreatic lobules. The islets of Langerhans are spared in most cases until late in the process and become concentrated in the shrinking pancreas. Calcification, although rare, may be apparent on radiographs. US, MRI, and CT can document progression of pancreatic disease.

BOX 57.3 Clinical Manifestations of CF UPPER RESPIRATORY Sinusitis Mucous membrane hypertrophy, nasal polyposis  LOWER RESPIRATORY Atelectasis Emphysema Infections Bronchitis, bronchopneumonia, bronchiectasis, lung abscess Respiratory failure, right-sided heart failure  GI Bile salt deficiency Pancreatic insufficiency GERD PUD Meconium ileus Volvulus Peritonitis Ileal atresia Distal intestinal obstruction syndrome Fecal masses Intussusception Rectal prolapse  PANCREATIC Pancreatitis Nutritional failure

Diabetes mellitus Calcification Maldigestion with steatorrhea and azotorrhea Vitamin deficiencies  HEPATOBILIARY Mucus hypersecretion Gallstones, atrophic gallbladder Focal biliary cirrhosis Portal hypertension ± esophageal varices Hypersplenism  REPRODUCTIVE Females: increased viscosity of vaginal mucus, decreased fertility Males: sterility; absent ductus deferens, epididymis, and seminal vesicles  SKELETAL Retardation of bone age Demineralization Hypertrophic pulmonary osteoarthropathy  OPHTHALMOLOGIC Venous engorgement Retinal hemorrhage  OTHER Salt depletion through excessive loss of salt through skin Heat stroke Hypertrophy of apocrine glands

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The pancreas can appear normal, have incomplete or complete lipomatosis (most common), be cystic or macrocystic, or appear as an atrophic pancreas.270 Correlation of abnormalities with the degree of exocrine dysfunction is poor.2 Exocrine pancreas dysfunction and pancreatitis. Patients with CF are usually PI, a problem compounded by intestinal pathology, high caloric demands, and poor appetite. Fat and protein maldigestion with fecal losses are the primary pancreatic manifestations of CF, although there may be considerable variation in severity from one patient to another. Steatorrhea and azotorrhea are generally greater with PI than with mucosal malabsorption. EPI may be recognized only when the secretion of lipase and trypsin falls to below 10% of normal.271 Most patients with CF exhibit this pattern of PI. RAP may complicate the course of CF in patients who do not experience complete loss of pancreatic function in infancy. Pancreatitis tends to be more problematic in older patients.146 Endocrine pancreas dysfunction and diabetes mellitus. Glucose intolerance has been reported in 30% to 75% of patients with CF, and clinically significant diabetes mellitus occurs in up to 10% of young patients. CF-related diabetes mellitus (CFRD) develops with increasing age. At 20 years of age, 30% of CF patients will require insulin and 40% require insulin by age 30.272 The development of CFRD differs in etiology and presentation from typical type 1 or type 2 diabetes mellitus and may reflect destruction of the islets of Langerhans similar to what is observed in other forms of CP. However, the severity of the endocrine deficiency lags behind the exocrine deficiency because the islets are relatively spared until later in the course of pancreatic destruction (see Fig. 57.9). CFRD is associated with deterioration in both respiratory and nutritional status, the development of late microvascular complications, and increased mortality.273 Experts emphasize the need for a multidisciplinary team approach, use of a high-energy diet (>100% of the recommended daily intake), and appropriate adjustment of insulin doses.273 Overnight enteral feedings may be necessary to maintain adequate nutrition. The choice of therapies should also be carefully considered for maximizing endogenous incretins, optimizing metabolism, preserving beta cell function, and reducing risk of PC.232

Treatment of Pancreatic Dysfunction Pancreatic enzyme supplements. Nutrition is a major challenge in CF (see Nutrition Management). Treatment of maldigestion from pancreatic exocrine failure in CF requires delivery of active digestive enzymes to the proximal small intestine with meals (see Chapter 59). Numerous pancreatic preparations are available, but enzyme activities vary considerably from one product to another, and reduced activity of lipase remains a problem for some CF patients. Enteric-coated mini-microspheres are the preferred form of replacement because they protect the digestive enzymes from destruction by gastric acid (pH < 4) and are effective. The size of the microspheres must be considered. If the majority of the spheres are too large (>1 mm), emptying of the spheres/enzymes can be delayed until after food is well into the small intestine. H2RAs or PPIs, together with uncoated or enteric-coated pancreatic enzyme supplements, also should be considered, especially because the pancreatic and duodenal bicarbonate transport systems that help neutralize gastric acid are disrupted. In contrast with other forms of PI, bicarbonate secretion within the duodenum and biliary tree is also impaired in CF, resulting in a significantly lower-than-normal duodenal pH.274,275 Thus, without acid suppression, the uncoated enzymes are susceptible to inactivation by gastric acid, and enteric-coated products may not release their contents.274 The use of antacids containing calcium carbonate or magnesium hydroxide should be avoided because they may interfere with the pancreatic enzyme supplements.

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Initial therapy for pancreatic exocrine insufficiency in CF includes pancreatic enzyme replacement at doses ranging from 500 to 2000 units of lipase activity per kilogram of body weight per meal, given just before a meal and with snacks.276 The amount is usually advanced to 1000 to 2500 units of lipase activity per kilogram, with final dosage depending on the age, the degree of PI, the amount of fat ingested, and the commercial preparation chosen. Adequacy of treatment is typically determined on clinical grounds. Frequent, bulky, and fatty stools; excessive bloating and flatus; and excessive appetite or inadequate growth velocity are signs of inadequate treatment. Even with optimized treatment, fat absorption may not return to normal. In large part, inability to normalize fat absorption may reflect decreased uptake of fatty acids by the abnormal intestinal mucosa.277 Pancreatic enzyme replacement commonly causes perioral and perianal irritation in infants, although less commonly with microsphere preparations. Because of the high purine content of pancreatic extracts, hyperuricosuria may develop in some patients taking large doses of enzyme preparations. Colonic strictures and fibrosing colonopathy were reported with very high-dose administration of pancreatic enzymes and led to a withdrawal of all the high-dose formulations of enzymes. Fibrosing colonopathy, first recognized in 1994,278 had nearly disappeared by 1996.279 Vitamin supplements. Fat-soluble vitamin deficiencies (A, D, E, and K) may develop in CF as a consequence of fat maldigestion and malabsorption.233,280 Vitamin A deficiency in CF rarely manifests with clinical abnormalities or causes eye and skin problems, whereas excessive levels of vitamin A can harm the respiratory and skeletal systems in children and interfere with the metabolism of other fat-soluble vitamins.281 However, because there are no randomized, controlled studies on retinoid supplementation, no conclusion on the supplementation of vitamin A in people with CF can be made.281 Vitamin D deficiency may occur, affecting calcium homeostasis, bone mineralization, inflammation, mood, and other extraskeletal effects. Vitamin D levels are affected by dietary intake, sunlight exposure, and genetics, and deficiencies are more complex than intake alone.233,282,283 Supplementation can be effective and replacement has been recommended for individual patients based on serum measurements.284,285 Vitamin E deficiency is common in CF children and can cause a host of conditions such as hemolytic anemia, cerebellar ataxia, and cognitive difficulties.286 Although treatment such as water-soluble vitamin E can significantly improve serum vitamin E levels compared with control, studies have not yet demonstrated clinical benefit to therapy.286 Vitamin K deficiency with coagulopathy may occur at any age. Its manifestations vary from mildly increased bruising or purpura to catastrophic hemorrhage and affects bone formation. Supplementation of 1 mg vitamin K per day appears to improve osteocalcin levels, a marker of bone metabolism, and no harm was identified with vitamin K supplementation in a systematic review.287 All CF patients should receive a multivitamin preparation daily, and many require vitamin A, D, E, and K supplements, plus pancreatic enzyme replacement therapy (PERT) for patients with EPI.233,239 Annual monitoring of the serum concentrations of fat-soluble vitamins is important in children with CF and is recommended.239

Intestinal manifestations Because CFTR is expressed at the apical membrane of enterocytes, CF significantly affects the GI tract.288 Distal ileal obstruction syndrome, intussusception, appendicitis, chronic constipation, colonic wall thickening, fibrosing colonopathy, pneumatosis intestinalis, GERD, and PUD have been described.270 Pathology. The mucosal glands of the small intestine of patients with CF may contain variable quantities of inspissated secretions within the lumen but rarely have increased numbers of goblet cells. The appendix is often involved and may rarely cause

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appendicitis or intussusception.289 Brunner glands may show dilation, flattening of epithelial lining cells, and stringy secretions within their lumens. The small intestinal mucosa in older CF patients often shows widely dilated crypts packed with mucus; the mucus frequently appears laminated or may extrude from a gaping crypt. Bulging goblet cells seem to crowd out the intervening columnar epithelium. Variable cellular infiltration may be present in the lamina propria. Mucus in CF is more abundant, stains more intensely, and contains more weak acid groups and protein. Radiologic features. Radiographic features of the GI tract vary widely in CF.270 Radiographic examination is typically done in response to specific symptoms, and both CF-related and non-CF related pathologies can be detected. Meconium ileus in infants and DIOS in children and adults (described later) are exceptions and have clear radiographic appearances.270,290,291 Intestinal pathophysiology. The changes in small bowel mucosa cause physiological dysfunction of the intestine. Various studies have demonstrated absorption defects that are apparently unexplained by EPI or that persist after adequate pancreatic replacement therapy. Basal and stimulated duodenal bicarbonate secretion is largely dependent on functional CFTR. The same abnormalities in duodenal bicarbonate secretion are also present in CF patients, which partially explains the decrease in postprandial pH in the proximal duodenum of CF patients, even after pancreas stimulation.275 Unlike the small bowel and respiratory tract, the CFTR defect in the colon cannot be compensated by any other chloride channel.292 Therefore, the defect in colonic function closely relates to the CFTR genotype. Lactase deficiency with lactose malabsorption in patients with CF merely reflects a normal ethnic- and age-related phenomenon. However, patients with adult-type hypolactasia and lactose malabsorption may have decreased bone mineral density.293 Meconium ileus. Meconium ileus can be uncomplicated or complicated. Complicated meconium ileus includes intestinal obstruction with segmental volvulus, atresia, necrosis, perforation, meconium peritonitis (generalized), and giant meconium pseudocyst formation.294,295 Uncomplicated meconium ileus characteristically demonstrates a narrow distal ileum with a beaded appearance caused by waxy, gray pellets of inspissated meconium, beyond which the colon is unused. As many as half of the cases of meconium ileus are complicated by volvulus, atresia, or meconium peritonitis from extravasation of meconium into the peritoneal cavity after intestinal perforation; this may manifest clinically merely as intra-abdominal calcifications, a meconium pseudocyst, generalized adhesive meconium peritonitis, or meconium ascites. Fetal volvulus and vascular compromise may cause atresia. Characteristic radiologic findings are unevenly distended loops of bowel with absent or scarce air-fluid levels.270,290,291,296 Small bubbles of gas trapped in the sticky meconium may be scattered throughout the distal small bowel.297 Barium enema demonstrates a microcolon and may outline the obstructing meconium mass in the distal ileum (Fig. 57.10). Abdominal calcification reflects meconium peritonitis, and a meconium pseudocyst may displace loops of bowel. Meconium ileus classically manifests with signs of intestinal obstruction within 48 hours of birth in an infant who is otherwise well; complicated meconium ileus manifests even earlier, and infants appear much sicker. Hydramnios is a common prenatal finding. When feedings are initiated, bilious emesis occurs with or without abdominal distention. The infant with meconium peritonitis often presents with additional signs of abdominal tenderness, fever, and shock.297 A family history of CF is helpful in establishing the diagnosis. Dilated, firm, rubbery loops of bowel may be visible and palpable through the abdominal wall, particularly in the right lower quadrant. Genetic screening for CFTR variants should be performed in patients with abnormal prenatal ultrasonographic evidence of

Fig. 57.10  Film from a barium enema examination in an infant with meconium ileus demonstrating a microcolon as well as meconium in the distal ileum (arrows). Distended small bowel loops are also noted.

meconium ileus such as hyperechoic bowel or peritoneal calcifications.297 If the results indicate normal CFTR genotypes, genetic counseling should focus on limits of testing and an expanded differential diagnosis, whereas detection of pathogenic CFTR alleles in one or more parents or the child should lead to more focused counseling on CF.297 Meconium ileus was considered invariably fatal until 1948, when the first patients were successfully treated by surgery. More recent reports indicate a very low operative mortality, and long-term survival approaches 90% for uncomplicated meconium ileus.297 Complicated meconium ileus requires surgical therapy.298 Various irrigating solutions have been used during the operation and postoperatively to dissolve and dislodge the abnormal meconium. N-acetylcysteine (Mucomyst), which reduces the viscosity of mucoprotein solutions by cleaving disulfide bonds in the mucoprotein molecule, and polysorbate 80 (Tween 80), a mild industrial detergent and preservative, are now generally recognized as safe and effective. For most infants with uncomplicated meconium ileus, nonoperative relief of bowel obstruction by enema administration using diluted diatrizoate (Gastrografin, Hypaque) or full-strength Omnipaque or Cysto-Conray II reduces the length of hospitalization and early respiratory complications.294,297 These enemas are hyperosmolar (1900 mOsm/L) and work by hydrating the contents of the colon by drawing water out of the infant’s body.294 Reflux of the enema into the terminal ileum is critical for the bowel obstruction to be relieved.294 However, water-soluble hypertonic enemas may cause dangerous fluid and electrolyte shifts, especially in small, sick infants, and they can cause colonic perforation. In addition, more recent case series suggest that use of Gastrografin enemas only have success rates of 36% to 39%.294 A diagnostic barium enema should precede a therapeutic Gastrografin enema. Infants with CF and meconium ileus who survive beyond 6 months of age have the same prognosis as any patient with CF and do not tend to have more severe disease. DIOS. The DIOS is complete or incomplete intestinal obstruction by viscid fecal material in the terminal ileum and proximal

CHAPTER 57  Genetic Disorders of the Pancreas and Pancreatic Disorders in Childhood

colon in patients with CF.299,300 The incidence and prevalence of DIOS among CF patients is less than 3%. Recent incidence estimates in Europe are 5 to 12 episodes/1000 patient-years.300,301 The European Society for Pediatric Gastroenterology and Nutrition CF Working Group defined DIOS as “a short history (days) of abdominal pain and/or distension and a fecal mass in ileocecum, but without signs of complete obstruction.”301 In contrast to DIOS, constipation in CF was defined as “abdominal pain and/ or distension or a decline in the frequency of bowel movements in the last few weeks to months and/or increased consistency of stools in the last few weeks or months, while the symptoms are relieved by the use of laxatives.”301 Reduced fluid secretion and hydration of the intestinal contents and delayed or inadequate fat and nutrient digestion contributes to DIOS, possibly through slow intestinal transit induced by nutrient-mediated release of ileal break hormones such as peptide YY.302 Other risk factors for DIOS include a severe genotype, dehydration, history of meconium ileus or DIOS, organ transplantation, and CF-related diabetes mellitus.299,300 The possible role of modifier genes causing meconium ileus has not been fully addressed in DIOS. Intussusception and, less frequently, volvulus may complicate DIOS. DIOS may be the presenting symptom of CF. A clinical spectrum from partial or complete obstruction of the bowel by abnormal intestinal contents occurs in DIOS: (1) recurrent and cramping abdominal pain caused by constipation or fecal impaction; (2) soft, palpable cecal masses that may eventually pass spontaneously; and (3) complete obstruction of the bowel by firm, putty-like fecal material in the terminal ileum, right colon, or both. Acute onset of vomiting of bilious material with progressive, colicky abdominal pain and/or fluid levels in the small intestine on abdominal radiography are signs of DIOS with complete intestinal obstruction.299 The fecal bolus can be identified on barium enema but may have to be differentiated from a cecal neoplasm or appendiceal abscess. Abdominal-pelvic CT typically shows significant proximal small bowel dilation with inspissated fecal material in the distal ileum.299 The differential diagnosis of DIOS includes constipation, appendicitis, appendicular abscess or mucocele, intussusception, Crohn disease, adhesions, volvulus, fibrosing colonopathy, and malignancy.299 Treatment of DIOS is largely empirical.299,301,303 Once a surgical issue, uncomplicated DIOS now usually responds to medical management, with less than 5% of patients now requiring surgery.300,304 A stepwise approach with therapeutic trials of more than one modality should be attempted in each patient before a consideration of surgery.303 Vigorous medical therapy includes regular oral doses of pancreatic enzymes and stool softeners, including polyethylene glycol,304 oral or rectal administration of 10% N-acetylcysteine, and Gastrografin enemas if necessary, although high-quality evidence from randomized trials for prevention or treatment is lacking.305 Maintenance treatment with oral doses of N-acetylcysteine, increased doses of pancreatic enzymes, and lactulose has been used successfully to prevent recurrent episodes of the syndrome. Treatment of this disorder with balanced intestinal lavage solutions may also be beneficial. Maintenance therapy with polyethylene glycol continues to grow in popularity because it is effective and there are few side effects.

Liver and Biliary Manifestations CF liver disease (CFLD) covers a number of liver abnormalities seen in patients with CF including hepatic steatosis, elevated serum transaminase levels, cholangiopathy, neonatal cholestasis, multilobular cirrhosis, and focal biliary cirrhosis.306,307 Liver disease accounted for 2.7% of deaths in CF in 2016.261 In a large French cohort the incidence of CFLD increased by approximately 1% every year, reaching 32.2% by age 25 years.308 In addition, the incidence of severe CFLD increased only after the age of 5, reaching

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10% by age 30.308 Risk factors for CFLD and severe CFLD are male sex, neonatal liver disease, severe CFTR genotypes, pancreatic exocrine insufficiency, a history of meconium ileus, and modifier genes.216,308-310 Additional risk factors may predispose CF patients to development of hepatobiliary problems and some features overlap with non-CF patients who have non-alcoholic steatosis.310 One study of children with CFLD suggested these patients had a more severe CF phenotype than age- and gender-matched controls without liver disease.311 In 2016, gallstones (0.6%), cirrhosis (2.8%), non-cirrhotic liver disease (3.9%), acute hepatitis (0.1%), hepatic steatosis (0.4%), and other liver disease (2.0%) were reported.261 Another study found cirrhosis in 28% of adults with CF, two thirds of whom had associated portal hypertension.312 The prevalence of liver abnormalities in CF patients with PS is markedly lower. Liver injury tests may be moderately elevated and fluctuate over the course of the illness. Up to 20% of CF patients with PI have elevated serum ALT values, and 40% to 50% of patients have intermittently increased serum aminotransferase levels. Fasting bile acid levels are elevated in many CF patients, and this may be among the more sensitive measures of liver function in this disease. Bile acid metabolism is disturbed in patients with CF and EPI. Fecal bile salt losses are high, often approaching those of patients with ileal resection (see Chapter 64). Pancreatic enzyme replacement improves fat absorption, thereby reducing fecal bile acid excretion and steatorrhea. The fractional turnover rate of the bile acid pool is increased and the total bile acid pool size diminished in the absence of pancreatic enzymes,313 whereas the biliary lipid composition and saturation index approach those of patients with cholelithiasis.314 Treatment with pancreatic supplements returns abnormal biliary lipid values toward normal. Gallbladder and biliary tract. The gallbladder and biliary tract are abnormal in approximately 25% of patients with CF, independent of age, clinical course, or hepatic pathology. Micro-gallbladders are found in 23% and stones or sludge in 8% of patients. Data from the Cystic Fibrosis Registry suggest that only about 0.3% of individuals with CF eventually require gallbladder surgery.261 Small gallbladders are commonly found, characteristically containing thick, colorless “white bile.” Mucus is present within the epithelial lining cells, and numerous mucus-filled cysts may exist immediately beneath the mucosa. The cystic duct may be atrophic or occluded with mucus. Obstruction of the hepatic or bile ducts by mucous plugs does not occur, but intraductal stones sometimes cause obstructive symptoms and predispose to cholangitis.

Other Manifestations Genital abnormalities in male patients. Although male reproduction is not a digestive system complication, infertility is among the most sensitive phenotypes associated with severe or mild CFTR variants and overlaps with CFTR-associated pancreatitis, including bicarbonate defective conductance variants (described earlier). The most striking changes in the male genital tract occur in the epididymis, the vas deferens, and the seminal vesicles. The rete testes are intact. Multiple histologic sections of the spermatic cord rarely show patency at more than 1 level. In addition to these defects, there is a striking increase in abnormalities associated with testicular descent, such as inguinal hernia, hydrocele, and undescended testes. Approximately 97% of males with CF are sterile as a result of these changes. These defects may be found in male infants shortly after birth and may be useful in supporting the diagnosis of CF in atypical cases. Evaluation of patients with congenital absence of the vas deferens who are not clinically suspected of having CF reveals a high frequency of CFTR mutations.315 Up to 70% of men with the sole finding of congenital absence of the vas deferens have a detectable mutation in at least 1 allele of CFTR. Alterations in RNA transcription also may be associated with this defect, inasmuch as

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a mutation, 5T, which reduced functional messenger RNA transcripts of wild-type CFTR, is found in high frequency in men with congenital absence of the vas deferens.315 Secretion of bicarbonate through CFTR is critical to sperm and infertility can occur in men with CFTR-BD variants.148 This group of men, without other manifestations of CF, are classified as CFTR-RD.154 Cancer risk. With CF patients reaching older ages, a higher risk of cancer is being recognized. Cancer tended to occur in the third decade of life and involved the esophagus, small and large intestines, stomach, liver, biliary tract, pancreas, or rectum.316,317 A recent 20-year study in the USA of almost 42,000 patients demonstrated an increased risk of digestive tract cancer, especially after transplantation.318 This same study also found an increased risk of lymphoid leukemia and testicular cancer but a decreased risk of melanoma. The pathogenesis is uncertain, but an increased risk of PC317,319 has also been seen in CF patients as well as patients with CP from other causes.320,321 This heightened cancer risk should be kept in mind as the survival of persons with CF continues to increase. Adolescents and adults with unexplained complaints, especially relating to the abdominal organs, should be evaluated for occult malignancy. A recent consensus panel on colorectal cancer screening in CF patients recommended colonoscopy at age 40 years with follow-up screening as indicated by individual findings.322 Organ transplant recipients should be screened for colorectal cancer starting at 30 years of age. 

Nutritional Management Nutrition goals. In the routine clinical setting, the nutritional management of patients with CF is based on an assessment of nutritional requirements (see Chapter 5), considering age, height, weight, and anthropometrics for age in children and BMI in adults, the severity of lung disease, as well as anorexia, PI, and mucosal dysfunction.239,323 Ideally, an age-appropriate diet that is 1.1 to 2 times the reference calorie intake for healthy populations should be encouraged, with adequate PERT provided (and with gastric acid suppression, if indicated) to achieve as normal a fat balance as possible.239 High-calorie, high-fat, and liberal salt diets are also encouraged by many CF centers. The role of nutrition is important in lung function, as patients with a BMI ≥ the 50th percentile tend to have pulmonary function (FEV1) within 80% of normal.239,323 In 2005, the Cystic Fibrosis Foundation revised the nutrition classification guidelines to eliminate the use of percentage of ideal body weight to define nutritional failure. The guidelines were reviewed and updated in 2008.323 For children younger than age 2, weight-for-length percentile should be maintained at or above the 50th percentile. Up to age 20, BMI ≥ the 50th percentile was recommended. It was also recommended that women should have a BMI of 22 kg/m2 or greater, and men 23 kg/m2 or greater. Similar recommendations were given in the ESPENESPGHAN-ECFS guidelines on nutrition care for infants, children, and adults with CF in 2016.239 Malnutrition in CF can result from a variety of factors that increase nutrient loss, reduce energy intake, and increase energy expenditure. Increased losses are primarily related to underlying PI but are also influenced by conditions such as poorly controlled diabetes mellitus, vomiting and/or regurgitation, excess intestinal mucus, and inadequate bile salt secretion. Energy intake can be affected both by disease complications and by psychosomatic issues, psychosocial issues, stress, and treatment noncompliance, especially in children and adolescents.239 Severe respiratory symptoms can be accompanied by anorexia, nausea, and vomiting. GI symptoms or complications such as abdominal pain, GERD with chest pain, anorexia, and vomiting can lead to reduced caloric intake. In some patients, clinical depression, physical fatigue, a disordered sense of smell (food is unappetizing), and altered body image can lead to reduced food intake. Increased energy

expenditure also frequently accompanies the severe respiratory disease of CF and is likely related to variables including chronic infections, fever, increased work of breathing, and bronchodilator medications.239 The optimal dietary intake for a CF patient is greater than the RDA of healthy children and adults. To prevent or delay onset of nutritional deficits, the ESPEN-ESPGHAN-ECFS guidelines on nutrition recommends advising patients on macronutrient balance in the diet, with attention to protein and fat intake that is sufficient to prevent or delay loss of muscle mass and function. In general, intake of energy should be age-appropriate and supporting normal weight, noting a wide interindividual range from about 1.1 to 2 times the reference intake for healthy populations. Advice on dietary intake of electrolytes, with supplementation as needed; supplementation of fat-soluble vitamins; and prescription of PERT for individuals with PI is also recommended.239 The use of PERT in CF is lifesaving, but the dosing is more empiric and may not translate well to recommendations for adult patients with CP and EPI. A recent consensus recommendation for CF patients who are infants (up to 12 months) was: 2000 to 4000 U lipase/120 mL formula or estimated breast milk intake and approximately 2000 U lipase/g dietary fat in food.239 For children 1 to 4 years, use 2000 to 4000 U lipase/g dietary fat, increasing the dose upward as needed (maximum dose 10,000 U lipase/ kg/day).239 For children more than 4 years and adults, start at 500 U lipase/kg/meal, titrating upward to a maximal dose of 1000 to 2500 U lipase/kg/meal, or 10,000 U lipase/kg/day, or 2000 to 4000 U lipase/g dietary fat taken with all fat-containing meals, snacks, and drinks.239 This would equate to 70,000 to 175,000 U lipase/meal for a 70 kg patient with CF, which is similar to a dose of 72,000 U lipase units per meal shown to be effective in improving the coefficient of fat absorption in a double-blind, randomized, placebo-controlled, parallel-group trial of pancreatin capsules (3 Creon 24,000).324 Enteral tube feeding. Even without supporting evidence from randomized trials, enteral tube feeding remains a frequent therapy for malnutrition in CF. About 10% of CF patients require supplemental tube feeding.261 A recent retrospective Belgian CF registry study of enteral tube feeding demonstrated that enteral tube feeding improved BMI z-score and stabilized the FEV1.325 The finding is in line with prior studies showing an association between nutritional status and pulmonary function.323 Importantly, the registry study found that tube feedings were not started until patients already had significantly worse nutritional and pulmonary status than the CF cohort as a whole. This observation implies that better anticipatory planning and early markers of pending nutritional failure are needed. The presence and severity of GERD symptoms may influence the decision on the preferred route for tube feeding. Some adolescents learn to pass soft Silastic feeding tubes nightly in order to administer nasogastric feedings. Gastrostomy feedings may be preferred by some families and patients, especially in younger children. Gastrostomy or jejunostomy feedings are instituted at the first sign of nutritional failure. Standard formulas are usually well tolerated. Nocturnal infusion is encouraged to promote normal eating patterns during the day. Initially, 30% to 50% of the estimated caloric needs should be provided overnight. Very lowfat, elemental formulas may be used without enzyme supplements for patients with an enteral feeding tube, and should be given by continuous infusion.326 For standard formulas, the approach to providing PERT during the feeds is variable. A novel in-line cartridge containing immobilized lipase offers another attractive option.327,328 Patients receiving enteral feedings should be monitored for carbohydrate intolerance on at least 2 separate nights by measuring blood glucose levels 2 to 3 hours into the feeding and at the end of the feeding. Insulin may be required to prevent hyperglycemia, with adjustment of the insulin dosage during acute illness, glucocorticoid therapy, or other changes in health

CHAPTER 57  Genetic Disorders of the Pancreas and Pancreatic Disorders in Childhood

status. In some cases, parenteral nutrition may be necessary, but it should be reserved for acute support with a return to some form of enteral nutrition as soon as possible. Treatment of CFTR functional variants with targeted drug therapy. After considerable effort to treat CF by increasing functional CFTR in the lung through delivery of DNA or protein failed to provide long-lasting improvement in humans, efforts turned toward recovering function of endogenous CFTR.329 Using highthroughput screens with thousands of small molecules, investigators identified compounds that improved endogenous, mutant CFTR function.330 The first targeted therapy with one of these compounds, VX-770 or ivacaftor (Kalydeco), was directed at the third most common CF-causing mutation, p.G551D. VX-770 improves function of p.G551D CFTR by altering the gating function of mutant CFTR to increase the probability of channel opening, thereby increasing Cl− secretion.331 In phase II and III clinical trials VX-770 improved predicted FEV1, decreased sweat chloride concentration, and decreased the frequency of pulmonary exacerbations.332,333 Follow-up of a subset of subjects who did not have an early response to treatment showed they had longterm clinical benefits.334 VX-770 was FDA-approved for use in patients with a variety of mutations that cause gating dysfunction in CFTR.335-337 This population does not include patients carrying the most common disease-causing variant, CFTR p.F508del. That variant causes multiple defects in CFTR folding, trafficking, membrane stability, and chloride channel activity. The issue was approached by combining VX-770 with VX-809 (lumacaftor), a small molecule that facilitates CFTR folding. The combination results in a partial rescue of p.F508del CFTR function.338 Clinical trials of the combination therapy showed improved clinical outcomes in patients homozygous for p.F508del CFTR and the therapy was approved by the FDA.339 However, it appears that, in general, the effects of CFTR enhancers and correctors are not mutation specific. Instead, the magnitude of drug response is highly correlated with residual CFTR function for the potentiator ivacaftor, the corrector lumacaftor, and ivacaftor-lumacaftor combination therapy, and the effects are additive.340 About half of eligible CF patients take the combination of ivacaftor and lumacaftor.261 Other small molecule combinations are in development or trials and improvements in efficacy will likely result.341 Prognosis. Survival statistics estimated from data in national CF registries are often confusing because different groups use different methods and terminology when reporting survival data.342 The latest estimate of median predicted survival for patients born between 2012 and 2016 in the USA is 42.7 years of age.261 For patients who attain 40 years of age, the median predicted survival is almost 60 years of age. Still, for the 373 people who died from CF in 2016, their median age was only 29.6 years. Most of the morbidity and mortality is related to chronic pulmonary disease; respiratory or cardiorespiratory disease contributes to 67% of deaths.261 The relative roles of nutritional support, pancreatic enzyme replacement, and aggressive treatment of pulmonary disease in improving the quality and duration of life remain under study. CF patients with PS have better pulmonary status than those with PI, suggesting that the disease is heterogeneous and that survival is improved with better nutrition and treatment. As survival improves, the problems facing CF patients will likely change and begin to spill over into the domain of caretakers predominantly focused on the issues of CF adults. These medical problems will include such entities as pancreatitis, malnutrition, cirrhosis with portal hypertension, diabetes mellitus with its long-term complications, osteopenia, and reproductive issues, as well as all of the more common problems seen in childhood. In the 2016 report from the Cystic Fibrosis Registry, the prevalence of bone disease, GERD, sinus disease, asthma, anxiety, and depression is higher in older patients. CF-related diabetes is more common in adults than in children (35.1% vs. 6.4%). Pulmonary disease is more severe in adults than in children,

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and malnutrition continues to be a problem in adults with CF although nutritional outcomes are improving overall.261 Increasingly these patients will require evaluation for potential malignancies of the digestive tract, and evaluation for liver disease or other complications that will necessitate the specialized attention of a gastroenterologist. 

Hereditary Pancreatitis HP is a syndrome of RAP, often leading to CP, that develops in an individual from a family in which the pancreatitis phenotype appears to be inherited through a disease-causing gene mutation expressed in an autosomal dominant pattern.9,343 The most common cause is a gain-of-function mutation in the cationic trypsinogen gene (PRSS1) that alters the regulatory domains usually controlled by calcium (see Fig. 57.4). Most kindreds with PRSS1 mutations are from the USA and Europe, with a few from Japan and South America but none from southern Asia. Most (65% to 81%) but not all kindreds with an autosomal dominant-appearing inheritance pattern of pancreatitis have PRSS1 mutations.344,345 Clinical features. The phenotypic features of HP caused by PRSS1 mutations are confined to the pancreas because the pancreas is the primary site of trypsinogen expression. The primary phenotype is RAP, with a subset of patients progressing to CP with all of the complications shared with other forms of CP. Acute pancreatitis. An attack of AP typically signals the onset of disease in patients with HP. The median age for the first diagnosis of pancreatitis in a family/cohort of 181 symptomatic PRSS1 mutation carriers in the USA was 7 years of age (interquartile range, 3 to 16; range 30 kg/m2)313 Altered mental status223,224 Comorbid disease11 Systemic inflammatory response syndrome (SIRS)11,20,217,223,224 Two or more of the following (SIRS criteria) Pulse >90/min Respirations >20/min or PaCO2 38°C or 12,000 or 10% band forms  LABORATORY FINDINGS BUN >20 mg/dL or rising BUN level225 Elevated serum creatinine level314 Hematocrit >44% or rising hematocrit231  IMAGING FINDINGS Pleural effusion(s)195 Pulmonary infiltrate(s)11 Multiple or extensive extrapancreatic fluid collections203 BUN, Blood urea nitrogen level.

cytokine-mediated SIRS; if organ failure is persistent, then AP is considered severe. The first phase of AP usually lasts 1 week. During this phase, the disease severity is directly related to extrapancreatic organ failure from the patient’s SIRS elicited by acinar cell injury. Multiple cytokines are involved, including platelet activating factor (PAF), TNF-α, nuclear factor κB (NF-κB), and numerous interleukins (ILs; see Chapter 2). During this first week, the initial state of inflammation evolves dynamically, with variable degrees of pancreatic and peripancreatic ischemia or edema toward either resolution, irreversible necrosis and liquefaction, or the development of fluid collections in and around the pancreas. The extent of the pancreatic and peripancreatic changes is usually proportional to the severity of extrapancreatic organ failure. However, organ failure may develop independent of pancreatic necrosis.16 Conversely, patients with pancreatic necrosis may have no evidence of organ failure. The development of organ failure appears to correlate with the persistence of the systemic inflammatory response cascade (discussed later). Approximately 75% to 80%, of patients with AP have a resolution of the disease process (interstitial pancreatitis) and do not enter a second phase. However, in ∼20% of patients, a more protracted course develops, typically related to the necrotizing process (necrotizing pancreatitis) lasting weeks to months. Mortality in this second phase is related to a combination of factors, including organ failure secondary to sterile necrosis, infected necrosis, local complications from the severe necrotic process, or complications from surgical/minimally invasive intervention.18-20 There are 2 time peaks for mortality in AP. Most studies in the USA and Europe reveal that about half the deaths occur within the first week or 2, usually from multiorgan failure.18-20 Death can be very rapid. For example, in Scotland about one quarter of all deaths occurred within 24 hours of admission, and one third within 48 hours.20 After the second week of illness, patients succumb to pancreatic infection associated with multiorgan failure. Some studies in Europe report a very high late mortality rate from infection.21 It is unclear if this is related to endogenous infection of the pancreatic necrosis or to surgical interventions

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for infectious complications. Patients who are older and have comorbid illnesses have a substantially higher mortality rate than younger healthier patients. In those who survive their illness, severe pancreatic necrosis can result in chronic pancreatitis, with all of its complications (see Chapter 59).21 

PATHOGENESIS AND PATHOPHYSIOLOGY Most of the published data on the pathogenesis of AP comes from work in animal models. Although gallstones and alcohol may contribute to 60% of more of AP in humans, there is no animal model of for these 2 predisposing causes. Cerulein and taurocholate used to induce pancreatitis in animal models does not cause human pancreatitis. Despite these limitations, the anatomic and biochemical abnormalities in AP in animal models are similar to humans. Once the process of AP is initiated, the subsequent progression of events resulting in local and systemic complications are similar regardless of the inciting event. This is important because if any drug therapy becomes available to treat this disease, it should be administered very early on and be able to block the progression of events at that early stage. The initial step in the pathogenesis of AP is conversion of trypsinogen to trypsin within acinar cells in sufficient quantities to overwhelm normal mechanisms to remove active trypsin (see Fig. 57.3). Trypsin, in turn, catalyzes conversion of proenzymes, including trypsinogen and inactive precursors of elastase, phospholipase A2 (PLA2), and carboxypeptidase, to active enzymes (see Chapter 56). Trypsin also may activate the complement and kinin systems. Active enzymes autodigest the pancreas and initiate a vicious cycle of releasing more active enzymes. Normally, small amounts of trypsinogen are spontaneously activated within the pancreas, but protective intrapancreatic mechanisms quickly remove the trypsin. Pancreatic secretory trypsin inhibitor (now called SPINK1) binds and inactivates about 20% of the trypsin activity. Other mechanisms for removing trypsin involve mesotrypsin, enzyme Y, and trypsin itself, which splits and inactivates other trypsin molecules. The pancreas also contains nonspecific antiproteases such as α1-antitrypsin and α2-macroglobulin. Additional protective mechanisms are the sequestration of pancreatic enzymes within intracellular compartments of the acinar cell during synthesis and transport and the separation of digestive enzymes from lysosomal hydrolases as they pass through the Golgi apparatus, which is important because cathepsin B can activate trypsin from trypsinogen. Low intra-acinar cell calcium concentrations also prevent further autoactivation of trypsin. In experimental pancreatitis, activation of trypsin occurs within 10 minutes, and large amounts of trypsin22 and increased concentrations of trypsinogen activation peptide (TAP) accumulate within the pancreas.23,24 TAP is produced when trypsinogen is activated to trypsin, and concentrations of TAP in plasma, urine, and ascites correlate with the severity of the pancreatic inflammatory response, with the highest levels associated with acinar cell necrosis and intrapancreatic hemorrhage.25,26 Co-localization of pancreatic enzymes in lysosomes, followed by acinar cell injury, is an attractive hypothesis for the pathogenesis of AP, but the relevance of such co-localization to the pathogenesis of AP is unclear. Activation of trypsinogen occurs before biochemical or morphologic injury to acinar cells, in association with co-localization of lysosomal enzymes, such as cathepsin B, and digestive enzymes, including trypsinogen within unstable vacuoles.26,27 Complete inhibition of pancreatic cathepsin B activity in vitro prevents trypsinogen activation induced by the CCK analog cerulein,28 supporting the co-localization hypothesis. Thus, complete inhibition of cathepsin B may prevent or become a treatment for AP. However, enzyme co-localization may occur without inducing significant acinar cell injury.29 Two other features of experimental AP are (a) early blockade of the secretion of pancreatic enzymes while enzyme synthesis

continues and (b) disruption of the paracellular barrier of acinar cells and intralobular pancreatic duct (PD) cells. This barrier disruption facilitates the extravasation of pancreatic enzymes from acinar cells and from the duct lumen into interstitial spaces. This phenomenon may explain the rapid development of interstitial edema and the increase in the concentration of pancreatic enzymes in the serum.30 As discussed in Chapter 57, genetic mutations associated with hereditary pancreatitis also lend support to the hypothesis that intrapancreatic activation of pancreatic zymogens is central to the pathogenesis of AP.30-32 The mutant trypsins in patients with hereditary pancreatitis (usually a R122H or a N29I mutation) cause trypsin to be resistant to degradation or causes premature trypsinogen activation (gain-of-function mutation), leading to autodigestion of the pancreas and episodes of AP. Mutations in the CFTR gene have also been implicated in pancreatitis (see Chapter 57). The CFTR anion channel allows for chloride and bicarbonate secretion into the PDs and thus allows flushing of the liberated enzymes and proenzymes into the duodenum (see Chapter 56). There are more than 1200 mutations that have been described for the CFTR gene. Some of these are considered severe and some mild. Homozygous severe mutations produce a viscid, concentrated, acidic pancreatic juice, leading to ductal obstruction and pancreatic insufficiency in childhood. Heterozygotes carrying minor or major mutations may have acute recurrent or chronic pancreatitis by altering acinar or ductal cell function (e.g., alteration of bicarbonate conductance). More recently, CFTR mutations associated with pancreas divisum have suggested a synergistic effect in the pathogenesis of AP. Although most patients with pancreas divisum (7% to 10% of the general population; see Chapter 55) never develop pancreatic disease, it may be that those persons who also harbor a dysfunction of the CFTR transporter are at risk of developing pancreatitis when both are present.33 A third genetic abnormality associated with pancreatitis is a mutation of the SPINK1 gene.34 As already noted, SPINK1 protects the pancreatic acinar cell by inhibiting prematurely activated trypsin. Mutations of this gene presumably limit the activity of this protein, but the exact mechanism is unclear. The pathogenesis of gallstone-related pancreatitis is unknown (see Chapter 65). Factors that may initiate gallstone pancreatitis include reflux of bile into the PD35,36 or obstruction of the PD at the ampulla from stone(s) or from edema resulting from the passage of a stone.37 Reflux of bile into the PD could occur when the distal bile and PDs form a common channel and a gallstone becomes impacted in the duodenal papilla. Alternatively, bile could reflux into the PD from the duodenum through an incompetent sphincter of Oddi injured by recent passage of a gallstone. Experimentally, reflux of bile into the PD, particularly if the bile is infected or mixed with pancreatic enzymes, causes pancreatic injury. Mixtures of bile and pancreatic enzymes increase the permeability of the main PD, which is associated with local parenchymal inflammation.38 The common channel theory is somewhat problematic because PD pressure is invariably higher than bile duct pressure, making bile reflux into the PD unlikely. Reflux of bile from the duodenum also is unlikely because pancreatitis does not occur in conditions with easily demonstrable reflux, such as after surgical sphincteroplasty or endoscopic sphincterotomy. A popular theory for the mechanism of gallstone pancreatitis is that an impacted gallstone in the distal bile duct obstructs the PD, increasing pancreatic pressure, thereby damaging ductal and acinar cells. Experiments in the opossum supporting this theory are the observations that ligation of the PD causes severe necrotizing pancreatitis,36 and that decompression of the ductal system within 3 days prevents progression to acinar cell necrosis and severe inflammation.37

CHAPTER 58  Acute Pancreatitis

The pathophysiology of AP starts with acinar injury that, if unchecked, leads to local inflammatory complications, a systemic inflammatory response, and even sepsis. Pathophysiologic mechanisms include microcirculatory injury, leukocyte chemoattraction, release of pro- and anti-inflammatory cytokines, oxidative stress, leakage of pancreatic fluid into the region of the pancreas, and bacterial translocation to the pancreas and systemic circulation. The release of pancreatic enzymes damages the vascular endothelium, the interstitium, and acinar cells.39-41 Acinar injury leads to expression of endothelial adhesion molecules (e.g., VCAM-1), which further propagates the inflammatory response.42 Microcirculatory changes, including vasoconstriction, capillary stasis, decreased local oxygen saturation, and progressive ischemia, occur early in experimental AP. These abnormalities increase vascular permeability and lead to edema of the gland (edematous or interstitial pancreatitis). Vascular injury could lead to local microcirculatory failure and amplification of the pancreatic injury. It is uncertain whether ischemia-reperfusion injury occurs in the pancreas.41 Reperfusion of damaged pancreatic tissue could lead to the release of free radicals and inflammatory cytokines into the circulation, which could cause further injury. In early stages of animal and human pancreatitis, activation of complement and the subsequent release of C5a play significant roles in the recruitment of macrophages and polymorphonuclear leukocytes.43,44 Active granulocytes and macrophages release proinflammatory cytokines in response to transcription factors such as NF-κB. Proinflammatory cytokines include TNF, IL-1, IL-6, and IL-8, and PAF. Proinflammatory cytokines frequently are followed by production of anti-inflammatory cytokines (IL-2, IL-10, IL-11) that attempt to downregulate inflammation.45 Other mediators of inflammation include arachidonic acid metabolites (prostaglandins, PAF, and leukotrienes), nitric oxide, proteolytic and lipolytic enzymes, and reactive oxygen species that overwhelm scavenging by endogenous antioxidant systems. These substances also interact with the pancreatic microcirculation to increase vascular permeability, which induces thrombosis and hemorrhage and subsequently pancreatic necrosis. A recent study suggests that gene polymorphisms that reduce acinar cell glutathione concentrations may lead to increased oxidant stress and more severe pancreatitis.42 Meanwhile, ischemia and severe inflammation of the gland can lead to disruption of the main and secondary PDs, leading to local fluid accumulations within and surrounding the pancreas that can eventuate into pseudocysts.46,47 Some patients with severe pancreatic damage develop systemic complications, including fever, acute respiratory distress syndrome (ARDS), pleural effusions, renal failure, shock, myocardial depression, and metabolic complications. SIRS is common in patients with AP and is probably mediated by activated pancreatic enzymes (phospholipase, elastase, trypsin) and cytokines (TNF, PAF) released into the portal circulation from the inflamed pancreas.48 Cytokines reaching the liver activate hepatic Kupffer cells, which, in turn, induces hepatic expression and secretion of cytokines into the systemic circulation. These cause acute phase protein synthesis (e.g., C-reactive protein [CRP], IL-6) and may cause SIRS and damage to the kidneys, lungs, and other organs leading to multiorgan dysfunction and failure.49 ARDS may be induced by active phospholipase A (lecithinase), which digests lecithin, a major component of lung surfactant. Acute renal failure has been explained on the basis of hypovolemia and hypotension. Myocardial depression and shock are likely secondary to vasoactive peptides and release of a myocardial depressant factor. Metabolic complications include hypocalcemia, hyperlipidemia, hyperglycemia with or without ketoacidosis, and hypoglycemia. The pathogenesis of hypocalcemia is multifactorial and includes hypoalbuminemia (the most important cause), hypomagnesemia, calcium-soap formation, hormonal imbalances (e.g., involving parathyroid hormone, calcitonin, and

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glucagon), binding of calcium by free fatty acid–albumin complexes, intracellular translocation of calcium, and systemic exposure to endotoxin.50 Pancreatic infection (infected necrosis and infected pseudocyst) can occur from the hematogenous route or from translocation of bacteria from the colon into the lymphatics. Under normal circumstances bacterial translocation does not occur, because there are complex immunologic and morphologic barriers to it. However, during AP, these barriers break down, which can result in local and systemic infection.51 Penetration of the gut barrier by enteric bacteria is likely due to gut ischemia secondary to hypovolemia and pancreatitis-induced arteriovenous shunting in the gut.52 In canine experimental pancreatitis, luminal Escherichia coli translocate to mesenteric lymph nodes and to distant sites.53 In feline experimental pancreatitis, enclosing the colon in impermeable bags prevents translocation of bacteria from the colon to the pancreas.54 More recent studies present strong evidence that, although trypsinogen activation to trypsin is likely a necessary first step in the inflammatory cascade underlying pancreatitis, sustained pancreatic inflammation is dependent on damage-associated molecular pattern-mediated cytokine activation causing the translocation of commensal (gut) organisms into the circulation and their induction of innate immune responses in acinar cells. Quite unexpectedly, these studies reveal that the innate responses involve activation of responses by nucleotide-binding oligomerization domain 1 (NOD1), and that such NOD1 responses have a critical role in the activation/production of NF-κB and type I interferon. Recent advances thus challenge the long-believed trypsin-centered understanding of pancreatitis. It is becoming increasingly clear that activation of intense inflammatory signaling mechanisms in acinar cells is crucial to the pathogenesis of pancreatitis, which may explain the strong systemic inflammatory response in pancreatitis.58 Evidence has emerged indicating that smoking is an independent risk factor for AP. Using a stepwise approach, Barreto reviewed the effects of the various metabolites of cigarette smoke on the constituents of the pancreas (exocrine, endocrine, sneurohormonal, stellate cells, ductal system) and highlights their proven, and potential, mechanisms in triggering AP.55 In different animal models of AP, there is a central role for mitochondrial dysfunction, and for impaired autophagy as its principal downstream effector, in development of AP. In particular, the pathway involving enhanced interaction of cyclophilin D with ATP synthase mediates L-arginine-induced pancreatitis, a model of severe AP the pathogenesis of which has remained unknown. Strategies to restore mitochondrial and/or autophagic function might be developed for the treatment of AP.56 

PREDISPOSING CONDITIONS A wide variety of causes of AP have been reported; however, it is always difficult to be certain about the cause in a given patient. For example, in a patient with alcohol history and gallstones, either of the 2 factors or even a combination of both might be responsible for the etiology of AP. If the serum ALT level is elevated in such a patient, then gallstones as the cause may be even a stronger consideration. However, an attempt must be made in every patient to ascertain a cause by a thorough history and physical examination, laboratory tests, and imaging. Before one labels an episode as “idiopathic AP,” more specialized tests and procedures like secretin-MRCP, EUS, and genetic testing should be performed. Although the goal is to eventually reduce the proportion of cases labeled as idiopathic, it may not be appropriate to list conditions as the cause for AP if those conditions are not convincingly proved to cause AP (sphincter of Oddi dysfunction, pancreas divisum, and others).

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BOX 58.3 Conditions That Predispose to Acute Pancreatitis Obstruction Gallstones Tumors Parasites Duodenal diverticula Annular pancreas Choledochocele Alcohol/other toxins/drugs Ethyl alcohol Methyl alcohol Scorpion venom Organophosphorus insecticides Drugs (see Box 58.4) Metabolic abnormalities Hypertriglyceridemia Diabetes mellitus Hypercalcemia Infection Vascular disorders Vasculitis Emboli to pancreatic blood vessels Hypotension/ischemia Trauma Postoperative state Post-ERCP (see Box 58.5) Hereditary/familial/genetic Controversial Pancreas divisum SOD Miscellaneous Idiopathic

Whereas gallstones and alcohol appear to be the cause of AP in the majority of cases, many other conditions predispose to AP to varying degrees (Box 58.3). Although the following sections describe individual causes of AP, it is possible that some of the uncommon causes are related to a combination of factors. For example, there have been conflicting studies regarding whether pancreas divisum is a cause of AP. However, studies have shown that a combination of genetic mutations in CFTR in the PD may predispose patients with pancreas divisum to the development of AP.33,58 This list of causes will undoubtedly expand, and the number of cases diagnosed as “idiopathic” will, hopefully, decrease as our understanding of the disease improves.

Obstruction Gallstones The most common obstructive process leading to pancreatitis is gallstones (see Chapter 65), which cause approximately ∼40% to 60% of cases of AP.57,59 However, only 3% to 7% of patients with gallstones develop pancreatitis. Gallstone pancreatitis is more common in women than men because gallstones are more frequent in women. AP occurs more frequently when stones are less than 5 mm in diameter (odds ratio, 4 to 5),60 because small stones are more likely than large stones to pass through the cystic duct and cause ampullary obstruction. Cholecystectomy and clearing the bile duct of stones prevents recurrence, confirming the cause-and-effect relationship.61 The triad of serum GGT ≥40 U/L, ALT ≥150 U/L, and lipase ≥15× ULN within 48 hours of presentation have been used as simple clinical predictors of acute biliary pancreatitis in children. Children with values falling below 2 or 3 of these thresholds are very unlikely to have AP due to

a biliary cause.62 AP is rare in pregnancy, occurring most commonly in the third trimester, and gallstones are the most common cause.63 Gallstones are the dominant etiology of AP in southern Europe and alcohol in Eastern Europe with intermediate ratios in northern and Western Europe.2,64 

Biliary Sludge and Microlithiasis Biliary sludge is a viscous suspension in gallbladder bile that may contain small (6 months) before the onset of AP. Drug-induced pancreatitis tends to occur within 4 to 8 weeks of beginning a drug. In the absence of well-designed clinical trials,

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clinicians largely rely on these published case reports for the determination that a drug may have caused AP. Drug-induced pancreatitis rarely is accompanied by clinical or laboratory evidence of a drug reaction, such as rash, lymphadenopathy, or eosinophilia. Although a positive rechallenge with a drug is the best evidence available for cause and effect, it is not proof because many patients with idiopathic pancreatitis or biliary microlithiasis have recurrent attacks of AP. Therefore, stopping and restarting a drug with recurrence of pancreatitis may be a coincidence and not cause and effect. Despite the lack of a rechallenge, a drug may be strongly suspected if there is a consistent latency among the case reports between initiating the drug and the onset of AP. Box 58.4 shows the drugs whose published case reports demonstrate the greatest evidence for causing AP, those with rechallenge evidence or with a relatively predictable latency.104 Some drugs have been implicated as causing AP through reporting to the FDA Adverse Event Reporting System. However, because the Adverse Event Reporting System largely depends on clinicians submitting Medwatch reports, the system is plagued by reporting bias. In a population-based study from Sweden, increasing the use of AP-associated drugs, however, did not have any major impact on the observed epidemiological changes in occurrence, severity, or recurrence of AP.105 There are several potential pathogenic mechanisms for drug-induced pancreatitis. The most common is a hypersensitivity reaction. This tends to occur 4 to 8 weeks after starting the drug and is not dose related. On rechallenge with the drug, pancreatitis recurs within hours to days. Examples of drugs that may operate through this mechanism are 5-aminosalicylates, metronidazole, and tetracycline. The second mechanism is the presumed accumulation of a toxic metabolite that may cause pancreatitis, typically after several months of use. Examples of drugs in this category are valproic acid and didanosine (DDI). Drugs that induce hypertriglyceridemia (e.g., thiazides, isotretinoin, tamoxifen) are also in this category. Finally, a few drugs may have intrinsic toxicity wherein an overdose of them can cause pancreatitis (erythromycin, acetaminophen). There has been significant literature in recent years about the risk of AP due to dipeptidyl peptidase-4 inhibitors, which are used with increasing frequency to treat type 2 diabetes. The published reports were conflicting about the risk. A recent meta-analysis of thirteen studies revealed a marginally higher risk of AP with DPP-4 inhibitors. However, this risk was not observed in cohort studies.106 Thus further clinical trials are required to confirm this finding. In a population with type 2 diabetes at high cardiovascular risk, there were numerically fewer events of AP among patients treated with liraglutide (a GLP-1 receptor agonist) regardless of previous history of pancreatitis than in the placebo group. Liraglutide was associated, however, with increases in serum lipase and amylase, which were not predictive of an event of subsequent AP.107 A meta-analysis of a large number of patients with type 2 diabetes revealed a nearly 2-fold increased risk of AP.108 In general, drug-induced pancreatitis tends to be mild and self-limited. The diagnosis should only be entertained after alcohol, gallstones, hypertriglyceridemia, hypercalcemia, and tumors (in appropriate-aged patients) have been ruled out. Some medications have been shown to cause AP in randomized trials at relatively high frequencies (e.g., 6-mercaptopurine in 3% to 5% and didanosine in 5% to 10%),111 but many drugs are falsely assigned causation and therefore discontinued merely because no other cause of the AP is identified by the frustrated clinician. For some drugs (e.g., statins), such discontinuation could prove harmful. Clinicians should be careful to make a diagnosis of drug-induced AP largely based on the absence of an obvious etiology and the mere presence of 1 or a few previously published case reports. Finally, there is no evidence that any medication causes chronic pancreatitis. 

BOX 58.4 Drugs Associated With Acute Pancreatitis* Acetaminophen 5-Aminosalicylic acid compounds (sulfasalazine, azodisalicylate, mesalamine) l-Asparaginase Azathioprine Benazepril Bezafibrate Cannabis Captopril Carbimazole Cimetidine Clozapine Codeine Cytosine arabinoside Dapsone Didanosine Dexamethasone Enalapril Erythromycin Estrogen Fluvastatin Furosemide Hydrochlorothiazide Hydrocortisone Ifosfamide Interferon-α Isoniazid Lamivudine Lisinopril Losartan Meglumine Methimazole Methyldopa Metronidazole 6-Mercaptopurine Nelfinavir Norethindrone/mestrol Pentamidine Pravastatin Procainamide Pyritinol Simvastatin Sulfamethazine Sulfamethoxazole Stibogluconate Sulindac Tetracycline Trimethoprim/sulfamethoxazole Valproic acid   

*Class 1 and class 2 drugs only are listed. Class 1 drugs: 2 or more case reports published, absence of other causes of acute pancreatitis, rechallenge documented in at least 1 report. Class 2 drugs: 4 or more case reports published, absence of other causes of acute pancreatitis, consistent latency in at least 75% of cases published. From Badalov N, Baradarian R, Iswara K, et al. Drug induced acute pancreatitis: an evidence based approach. Clin Gastroenterol Hepatol 2007; 101:454-76.

Metabolic Disorders Hypertriglyceridemia Hypertriglyceridemia is perhaps the third most common identifiable cause of pancreatitis, after gallstones and alcoholism, accounting for anywhere from 2% to 5%1 to 20% of cases. A

CHAPTER 58  Acute Pancreatitis

systematic review of 31 studies comprising 1340 patients with hypertriglyceridemic AP reported that this condition accounts for 9% of all cases of AP, and that 14% of patients with significant hypertriglyceridemia will develop AP. Hypertriglyceridemia is also implicated in more than half of cases of gestational pancreatitis. Serum TG concentrations above 1000 mg/dL (11 mmol/L) may precipitate attacks of AP. However, more recent studies suggest that the serum TGs may have to be even higher to precipitate AP, perhaps above 2000 mg/dL, and with obvious lactescent (milky) serum due to increased concentrations of chylomicrons.110 The pathogenesis of hypertriglyceridemic pancreatitis is unclear, but the local release of free fatty acids by pancreatic lipase may damage pancreatic acinar cells or endothelial cells.91 Release of free fatty acids that induce free radical damage can directly injure cell membranes.92 Most adults with hyperchylomicronemia have a mild form of genetically inherited type I or type V hyperlipoproteinemia and an additional acquired condition known to raise serum lipids (e.g., alcohol abuse, obesity, diabetes mellitus, hypothyroidism, Cushing syndrome, pregnancy, nephrotic syndrome, and drug therapy [estrogen111 or tamoxifen, glucocorticoids, thiazides, or beta adrenergic blockers]). Typically, 3 types of patients develop hypertriglyceridemia-induced pancreatitis. The first is a poorly controlled diabetic patient with a history of hypertriglyceridemia. The second is an alcoholic patient with hypertriglyceridemia detected on hospital admission. The third (15% to 20%) is a nondiabetic, nonalcoholic, nonobese person who has drug- or diet-induced hypertriglyceridemia. Drug-induced disease is more likely to occur if there is a background of hypertriglyceridemia prior to drug exposure. Most persons who abuse alcohol have moderate but transient elevations of the serum TG level. This condition is likely an epiphenomenon and not the cause of their pancreatitis,112 because alcohol itself not only damages the pancreas (see earlier) but also increases serum TG concentrations in a dose-dependent manner. Alcoholic patients with severe hypertriglyceridemia often have a coexisting primary genetic disorder of lipoprotein metabolism. Whether hyperlipidemic AP results in more severe disease compared with the other causes of AP is not clear.113 On the other hand, a meta-analysis of 15 studies (1564 patients) found a worse prognosis compared with non-hypertriglyceridemia causes.114 The serum amylase and/or lipase level may not be substantially elevated at presentation in patients with hypertriglyceridemic pancreatitis (see later). 

Diabetes Mellitus Diabetics are at an increased risk for developing AP (see Chapter 37).108 The risk may be due to the increased prevalence of gallstones and hypertriglyceridemia in this population. In a large study of type 2 diabetic patients (LEADER, Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results), nearly 25% had elevated serum lipase or amylase levels without symptoms of AP. The clinician must take these data into account when evaluating abdominal symptoms in type 2 diabetic patients.115 Patients with diabetes tend to develop gallstones due to a combination of concurrent dyslipidemia, leading to cholesterol-supersaturated bile resulting in precipitation of cholesterol crystals (see Chapter 65). Also, patients with long-standing diabetes often develop bile stasis in the gallbladder, leading to the precipitation of cholesterol crystals and to gallstones. Epidemiologic studies have confirmed the increased risk of AP in the diabetic population.116-118 The diabetic population is also at greater risk for developing severe AP because they often have many of the known risk factors

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for developing severe disease, such as obesity and underlying comorbidities.12 

Hypercalcemia Hypercalcemia of any cause is rarely associated with AP. Proposed mechanisms include deposition of calcium salts in the PD lumen and calcium activation of trypsinogen to trypsin within the pancreatic parenchyma.119 The low incidence of AP in chronic hypercalcemia suggests that mechanisms other than the serum calcium level per se responsible for pancreatitis (e.g., acute elevations of serum calcium). Acute calcium infusion into rats leads to conversion of trypsinogen to trypsin, hyperamylasemia, and dose-dependent morphologic changes of AP. Primary hyperparathyroidism causes less than 0.5% of all cases of AP, and the incidence of AP in patients with hyperparathyroidism varies from 0.4% to 1.5% (Chapter 37).120 Interestingly, in a community-based study there was no increased occurrence of AP in patients with hyperparathyroidism and there was no cause and effect association.121 Rarely, pancreatitis occurs with other causes of hypercalcemia, including metastatic bone disease, TPN, sarcoidosis, vitamin D toxicity, and infusion of calcium in high doses during cardiopulmonary bypass. 

Infections Although many infectious agents have been proposed as causing AP,83 these published reports often do not clearly establish a causal relationship. The diagnosis of AP caused by an infection requires evidence of AP, evidence of an active infection, and the absence of a more likely cause of AP. AP has been associated with viruses (mumps, coxsackievirus, hepatitis A, B, and C, and several herpesviruses, including cytomegalovirus, varicella-zoster, herpes simplex, and EBV); the vaccine that contains attenuated measles, mumps, and rubella viruses; bacteria (Mycoplasma, Legionella, Leptospira, Salmonella, TB, and brucellosis); fungi (Aspergillus, Candida); and parasites (Toxoplasma, Cryptosporidia, Ascaris lumbricoides, Clonorchis sinensis). C. sinensis and A. lumbricoides cause pancreatitis by blocking the main PD. In patients with AIDS (see Chapter 35), infectious agents causing AP include cytomegalovirus, Candida species, Cryptococcus neoformans, Toxoplasma gondii, and possibly Mycobacterium avium complex.83 

Vascular Disease Rarely, pancreatic ischemia causes AP. In most cases it is mild, but fatal necrotizing pancreatitis may occur. Ischemia may result from vasculitis (e.g., SLE,122 polyarteritis nodosa),123 atheromatous embolization of cholesterol plaques after transabdominal aortography,124 intraoperative hypotension,125 hemorrhagic shock,127 ergotamine overdose, and transcatheter arterial catheter embolization for hepatocellular carcinoma. Also, ischemia is 1 possible explanation for pancreatitis after cardiopulmonary bypass. In pigs, cardiogenic shock induced by pericardial tamponade causes vasospasm and selective pancreatic ischemia due to activation of the renin-angiotensin system.127 AP has occurred in long-distance runners, which may be on an ischemic basis.128 

Trauma Either penetrating trauma (gunshot or stab wounds) or blunt trauma can damage the pancreas.129 Blunt trauma results from compression of the pancreas by the spine, such as in an automobile accident with compression by the steering wheel. In blunt trauma, it is important to determine preoperatively whether there is injury to the pancreas because, depending on the severity of pancreatic injury, it will be necessary to include the pancreas in the surgical plan. Secondly, even in the absence of serious injury

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to adjacent organs, surgery or endoscopic therapy may be necessary to treat a pancreatic ductal injury. The diagnosis of traumatic pancreatitis is difficult and requires a high degree of suspicion. Trauma can range from a mild contusion to a severe crush injury or transection of the gland; the latter usually occurs at the point where the gland crosses over the spine. Transection injury can cause acute duct rupture and pancreatic ascites. It is impossible to determine on the basis of the characteristics of the abdominal pain and tenderness whether the pancreas has been injured as opposed to adjacent intra-abdominal structures. Serum amylase or lipase activity may be increased in patients with abdominal trauma whether or not the pancreas has been injured. Diagnosis of pancreatic trauma is highly dependent on CT, MRI, or MRCP, which may show enlargement of a portion of the gland caused by a contusion or subcapsular hematoma, pancreatic inflammatory changes, or fluid within the anterior pararenal space if there is ductal disruption. CT may be normal during the first 2 days despite significant pancreatic trauma. If there is a strong clinical suspicion of pancreatic injury, or if the CT or MRCP scan shows an abnormality, ERCP is required to define whether there is PD injury. If the PD is intact and there are no other significant intra-abdominal injuries, surgery is not required. However, if ERCP reveals duct transection with extravasation of pancreatic fluid and there are no other intra-abdominal injuries, stenting of the PD across the leak if possible may be curative.130 Serious injuries to the pancreas can be treated with appropriate debridement. Associated injuries to the duodenum or bile duct can be treated by biliary diversion, gastrojejunostomy, and feeding jejunostomy. External pancreatic fistulas occur in approximately one third of patients after surgery for pancreatic trauma. Octreotide may be beneficial after pancreatic injury to decrease pancreatic secretion.131 The prognosis in patients with pancreatic trauma is favorable if there is no serious injury to other structures (regional blood vessels, liver, spleen, kidney, duodenum, and colon). However, duct injuries can scar and cause a stricture of the main PD, resulting in obstructive chronic pancreatitis. 

Post-ERCP AP is the most common and feared complication of ERCP, associated with substantial morbidity and occasional mortality (see Chapter 42). Asymptomatic hyperamylasemia occurs after 35% to 70% of ERCPs.133 Clinical AP occurs in 5% of diagnostic ERCPs, 7% of therapeutic ERCPs, and up to 25% in those with suspected SOD or in those with a history of post-ERCP pancreatitis (PEP).133 A recent systematic review of 108 randomized controlled trials (RCTs) with 13,296 patients in the placebo or no-stent arms reported an overall incidence of PEP of 9.7%, and the mortality rate was 0.7%. Severity of PEP was reported for 8857 patients: 5.7%, 2.6%, and 0.5% of patients had mild, moderate, and severe AP, respectively. The incidence of PEP in 2345 high-risk patients was 14.7% (mild, moderate, and severe in 8.6%, 3.9%, and 0.8%, respectively, with a 0.2% mortality rate). The incidence of PEP was 13% in North American RCTs, compared with 8.4% in European and 9.9% in Asian RCTs. ERCPs conducted before and after 2000 had a PEP incidence of 7.7% and 10%, respectively.134 The mechanisms that lead to PEP are complex and not fully understood. Rather than a single pathogenesis, PEP is believed to be multifactorial, involving a combination of chemical, hydrostatic, enzymatic, mechanical, and thermal factors. Although there is some uncertainty in predicting which patients will develop PEP, a number of risk factors acting independently or in concert have been proposed as predictors of PEP (Box 58.5).135,136 Identification of these risk factors for PEP is essential to recognize

BOX 58.5 Factors That Increase the Risk of Post-ERCP Pancreatitis PATIENT-RELATED Young age, female gender, suspected SOD, history of recurrent pancreatitis, history of post-ERCP pancreatitis, normal serum bilirubin level  PROCEDURE-RELATED Pancreatic duct injection, difficult cannulation, pancreatic sphincterotomy, precut access, balloon dilation  OPERATOR OR TECHNIQUE-RELATED Trainee (fellow) participation, nonuse of a guidewire for cannulation, failure to use a pancreatic duct stent in a high-risk procedure

cases in which ERCP should be avoided if possible, or in which protective endoscopic or pharmacologic interventions should be considered. In general, the more likely a patient is to have an abnormal bile duct or PD, the less likely the patient will develop PEP.138 Cheng created a 160-variable database that prospectively evaluated more than 1000 patients from 15 centers in the midwestern USA.134 Their study emphasized the role of patient factors including age, SOD, prior history of PEP pancreatitis, and technical factors, including number of PD injections, performance of a sphincterotomy of the minor papilla, and operator experience. The patient most at risk of developing PEP was a woman with suspected choledocholithiasis and normal serum bilirubin, who underwent a sphincterotomy and no stone was found. In this patient population, 27% developed PEP. MRCP and EUS, which do not cause pancreatitis, can provide useful information (perhaps as accurate as ERCP) in many of these cases and are preferred modalities in the initial evaluation of such patients. In a study of 2715 therapeutic ERCPs, it was found that the endoscopist’s experience reduces patient- and procedure-related risk factors for post-ERCP complications.138 Early recognition of PEP may be possible by evaluating serum amylase or lipase after the procedure.139,140 In a study that involved 231 patients, the 2-hour serum amylase and lipase were more accurate than a clinical assessment in distinguishing nonpancreatitis abdominal pain from post-ERCP AP. Serum amylase values above 276 IU/L (reference range, 30 to 70 IU/L) and lipase above 1000 IU/L (reference range, 45 to 110 IU/L) 2 hours after completing the procedure had almost a 100% positive predictive value (PPV) for PEP.141 More recently, Ito and colleagues found that if the serum amylase was normal after 3 hours, only 1% of patients developed PEP, compared with 39% if the amylase was greater than 5 times the upper limit of normal.142 A serum amylase or lipase alone should not guide a decision of whether a patient has PEP, because the disease may unfold over the next 24 hours. However, in the presence of abdominal pain, a normal serum amylase and or lipase rules out AP at that moment. Although there has been an interest in developing medications that can prevent PEP, few studies have identified a medication worthy of widespread use. A number of drugs have not shown any benefit including nitroglycerin, nifedipine, sprayed lidocaine, and injected botulinum toxin. The protease inhibitor gabexate showed some benefit in small trials but is very expensive.144 Inhibiting exocrine pancreatic secretion by somatostatin was not beneficial in many studies, and its analog octreotide reduces only hyperamylasemia. The 3 major modalities shown to reduce the risk are postERCP pancreatitis include prophylactic pancreatic stents, preprocedural intravenous fluids, and rectal administration of NSAIDs. Pancreatic stent placement clearly decreases the risk of PEP in high-risk patients.144 Placement of PD stents has become

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a standard practice for patients who are thought to be at high risk for pancreatitis after the procedure (see Box 58.5). PD stent placement is effective, presumably by preventing cannulationinduced edema that can cause PD obstruction. The rationale behind this is the spasm and edema of the ampulla after ERCP because of cannulation and cautery results in obstruction and AP. Several studies and meta-analysis confirmed the benefit of prophylactic pancreatic ductal stents in patients at high risk of postERCP pancreatitis. Prophylactic PD stents are either a 3 French or 5 French and can be less than 5 cm or greater than 5 cm in length and placed temporarily to cover the 2- to 3-day period of ampullary edema. More than 70% of the stents spontaneously fell out within 3 to 4 days after providing an access for the bile and pancreatic juice during the period of ampullary edema and swelling. If a radiograph after a week suggests the stent has not migrated, it needs to be removed endoscopically, usually before 14 days. Stents left longer than that interval can cause chronic ductal injury and hence the need for removal. A Swedish national registry data from 43,595 ERCP procedures showed that pancreatic stents with a diameter of >5 Fr and a length of >5 cm seems to have a better protective effect against post-ERCP pancreatitis, compared with shorter and thinner stents.145 However, it is not possible to determine the exact type of pancreatic stent (apart from material, length, and diameter) that has been introduced, so their conclusion must be interpreted with caution. If post-ERCP pancreatitis is developing in patients who did not get a prophylactic pancreatic stent or if the stent has migrated and the patient is getting severe symptoms, urgent salvage ERCP with de novo pancreatic stent placement or replacement of a migrated stent is a novel approach in the setting of early PEP, and was associated with rapid resolution of clinical pancreatitis and reduction in serum levels of amylase and lipase.146 Guidewire cannulation, whereby the biliary or PD is initially cannulated by a guidewire inserted through the catheter or sphincterotome, has been shown to decrease the risk of pancreatitis with comparable high levels (∼98%) of cannulation success (see Box 58.5).147 A meta-analysis of patients with difficult cannulation, sole use of the double guide wire technique appears to increase the risk of PEP without any superiority in achieving biliary cannulation compared with other techniques. PD stenting may reduce the risk of PEP when the DGT is used.55 The influence of co-intervention in the form of peri-procedural NSAID administration is unclear. In terms of attenuating the local inflammatory response, the most promising results have been seen with NSAIDs. A multicenter, double-blind, placebo-controlled, RCT of 602 patients undergoing a high-risk ERCP demonstrated a significant reduction of PEP when patients were given rectal indomethacin after the procedure.148 There have been many studies published on the type of NSAID (e.g., diclofenac vs. indomethacin) to administer to high-risk patients as well as all patients undergoing ERCP and the timing of such rectal administration (i.e., prior to the procedure or after the procedure if the endoscopist feels there is a higher risk of PEP because of the nature of the procedure. Two meta analyses concluded that rectal indomethacin is useful only for high-risk patients, even when given before the procedure.148,149 Another meta-analysis suggested pre-ERCP rectal indomethacin administration for all patients undergoing ERCP without risk of procedural bleeding,150 and another showed benefit with rectal indomethacin for all patients undergoing a ERCP with unclear timing with regards to the procedure.151 The most recent meta-analysis suggested a benefit of rectal NSAIDs for all patients undergoing ERCP given before or after the procedure.152 Thus, it appears that rectal administration of NSAIDs mostly indomethacin is definitely useful and probably can be given to all patients undergoing ERCP before the procedure unless there are specific contraindications. Extending the observation that intravenous volume administration with normal saline or lactated Ringer solution has become

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an important to in the early management of AP (discussed later), several studies reported the beneficial effects of both types of fluid in preventing PEP. The timing of such administration differed in studies, starting before the procedure or during the procedure and continuing for variable period postprocedure, depending on the PEP risk factors of the patient and the procedure per se. A systematic review of peri-procedural IV volume administration concluded that there is some evidence to suggest that volume administration affords protection against PEP, but study heterogeneity precludes firm conclusions.153 Adequately powered randomized trials are needed to evaluate the preventive effect of periprocedural volume administration. Another systematic review reported that aggressive periprocedural volume administration with lactated Ringer solution can reduce the overall incidence of PEP, moderate to severe pancreatitis, and hyperamylasemia; shorten the length of hospitalization; and reduce pain.154 This meta-analyses demonstrated many drawbacks in the studies using intravenous volume administration in the perioperative period and particularly whether it has an added value in patients receiving rectal NSAIDs. Furthermore, the cost-effectiveness of the combined approach has not been investigated. To address these drawbacks, a randomized controlled adequately-powered trial is being planned to assess whether fluid administration schedule and fluid type further reduce PEP in patients receiving prophylactic rectal NSAIDs.155 It is hoped that with the ongoing trials the role of prophylactic PD stents, rectal NSAID administration, periprocedural fluid therapy, and combinations of these 3 modalities will better define their role in preventing PEP. 

Postoperative State Postoperative pancreatitis can occur after thoracic or abdominal surgery.156 Pancreatitis occurs after 0.4% to 7.6% of cardiopulmonary bypass operations.125,157 Twenty-seven percent of patients undergoing cardiac surgery develop hyperamylasemia, and 1% develop necrotizing pancreatitis.115 Significant risks for pancreatitis after cardiopulmonary bypass are preoperative renal insufficiency, postoperative hypotension, and administration of calcium chloride perioperatively. Pancreatitis occurs after 6% of liver transplantations.158 Mortality from postoperative pancreatitis is said to be higher (up to 35%) than for other forms of pancreatitis. Contributors to morbidity and mortality from postoperative pancreatitis are delay in diagnosis, hypotension, medications (e.g., azathioprine/perioperative calcium chloride administration), infections, and comorbidities. Postoperative pancreatitis should also be recognized as a pancreas specific complication after pancreatic surgery.159 

Hereditary and Genetic Disorders Hereditary pancreatitis, an autosomal dominant disorder with variable penetrance, is discussed in Chapter 57. 

Miscellaneous Causes AP has been rarely associated with Crohn disease.160 A recent case-control study from Denmark found a 4-fold increase in AP in patients with Crohn’s and a 1.5-fold increase in patients with UC. This increase has been attributed by some to the use of drugs such as 5-aminosalicylates/sulfasalazine and thiopurines (azathioprine/6-mercaptopurine; see Box 58.4). Theories to support a putative relationship between idiopathic IBD and pancreatitis include that pancreatitis is an extraintestinal manifestation of IBD, that duodenal Crohn disease can cause obstruction to the flow of pancreatic juice, that granulomatous inflammation in Crohn’s can involve the pancreas, or that there is an associated autoimmune pancreatitis. A data base of patients with Crohn disease from Alberta reported that 6.2% of patients who do were

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taking thiopurines developed AP.161 Celiac disease162 has also been described in association with pancreatitis, but the relationship remains uncertain. It has been suggested that abnormalities in the normal barrier of the small bowel seen in patients with celiac disease may allow excessive absorption of amylase from the intestinal lumen, leading to hyperamylasemia. In the setting of abdominal pain in a patient with celiac disease, it is not uncommon to find elevations in the serum amylase in the absence of AP.163 Pancreatitis has been seen in patients after severe burns.164 Autoimmune pancreatitis (discussed in the next chapter in more detail). AP or recurrent AP resulting from autoimmune pancreatitis is rare, seen in type II disease, and is associated with granulocyte epithelial lesions.165 Investigators have also described patients with autoimmune recurrent pancreatitis, especially in younger women, often without the classic elevation of serum IgG4.166 As discussed in Chapter 53, PUD (penetrating duodenal or gastric ulcers) can involve the pancreas and cause pancreatitis that may be fatal. Though uncommon nowadays, penetrating ulcer as a cause of pancreatitis should be considered in the appropriate clinical setting.167 

Controversial Causes Pancreas Divisum Pancreas divisum is the most common congenital malformation of the pancreas, occurring in 5% to 10% of the general healthy population, the vast majority of whom never develop pancreatitis (see Chapter 55). Controversy continues to surround the issue as to whether pancreas divisum with otherwise normal ductular anatomy is a cause of acute recurrent pancreatitis.168 The presumed mechanism of action in those who develop pancreatitis is that there is relative obstruction to the flow of pancreatic juice through the minor papilla. Arguments in favor of attributing pancreatitis to pancreas divisum include: (1) various series from ERCP referral centers show that patients referred with recurrent AP have a higher frequency of pancreas divisum than would be expected from the general population; (2) multiple observational series report that performing endoscopic sphincterotomy or placing a stent across the minor papilla reduces the rate of recurrent pancreatitis169; and (3) there is a small randomized controlled study suggesting that patients with pancreas divisum who undergo duct stenting for 1 year have a lower frequency of attacks of pancreatitis than those not stented.170 Arguments against the association include: (1) there are other studies showing that the incidence of pancreatitis in pancreas divisum patients is the same as the general population171; (2) the observational reports are flawed in that follow-up was not long enough (usually only 1 to 2 years) and that recurrent AP is a disease of great variability151; (3) the single randomized study170 was flawed in that it was not blinded, had only 19 patients, and its patients probably had chronic pancreatitis in that they had multiple pain attacks in between attacks of AP. In addition, when considering the lack of evidence, it is worth considering the high risk of endoscopic therapy in causing PEP in patients with pancreas divisum, therefore making the risk-benefit ratio of treating pancreas divisum endoscopically questionable. The prevalence of genetic abnormalities in patients with pancreas divisum and acute recurrent pancreatitis are either the same171 or higher172 than expected in the general population or population of patients with AP of other etiologies, suggesting a possible genetic contribution. For example, there appears to be a higher incidence of CFTR mutations in patients with pancreas divisum who develop AP.173 Because several authors reported associations of SPINK-1 and CFTR mutations in patients with AP and pancreas divisum, expert review suggested that idiopathic pancreatitis (either acute or acute recurrent) in a patient with

pancreas divisum is associated with genetic abnormalities and not solely due to pancreas divisum. This observation along with the finding that minor papilla endoscopic therapy is associated with significant amount of complications like stricture should make one think carefully before subjecting patients with pancreas divisum and AP to invasive therapy. Every effort should be made to seek other causes of such attacks of AP. Therefore, it may not be the presence of pancreas divisum alone that predisposes to AP, but other factors may be necessary to precipitate an attack. (See the earlier discussion in the section on genetic factors.)174 

SOD (See Chapter 63) SOD is also a controversial cause of AP. Investigators who study patients with recurrent AP report that SOD (usually defined as a basal pancreatic sphincter pressure >40 mm Hg) is the most common abnormality discovered, occurring in approximately 35% to 40% of patients. The main argument in favor of this entity as a cause of AP is the many observational series that report that endoscopic pancreatic sphincterotomy or surgical sphincteroplasty reduces recurrent attacks of pancreatitis.174 The arguments against SOD as a cause of AP include: (1) the lack of any prospective controlled blinded trials in the treatment of this disorder; (2) the short duration of follow-up in the observational reports; (3) the high risk of pancreatitis (25% to 35%) associated with ERCP, sphincter of Oddi manometry, and pancreatic sphincterotomy in patients with suspected SOD; (4) the extremely variable natural history of idiopathic recurrent pancreatitis, which may mask the minimal effects of therapy175; and (5) the relative dearth of data determining the normal range of pancreatic sphincter pressure that is the basis for the pathogenesis of SOD.175 Although one could debate if idiopathic recurrent AP can be labeled as type 2 SOD, a large number of patients with abdominal pain after cholecystectomy, but no objective evidence of biliary or pancreatic disease is subjected to ERCP, sphincter of Oddi manometry, and biliary and or pancreatic sphincterotomy with a diagnosis of type 3 SOD. For patients with type 3 SOD, the results of a large rigorously conducted multicenter RCT, the EPISOD trial, has been published.176 The trial concluded that in patients with abdominal pain after cholecystectomy undergoing ERCP with manometry, sphincterotomy versus sham sphincterotomy did not reduce disability due to pain. These findings do not support ERCP and sphincterotomy for these patients. 

CLINICAL FEATURES It is difficult to diagnose AP by history and physical examination, because clinical features are similar to those of many acute abdominal illnesses (Box 58.6).

History Abdominal pain is present at the onset of most attacks of AP. Biliary pain may herald or progress to AP. Pain in pancreatitis usually involves the entire upper abdomen. However, it may be

BOX 58.6 Differential Diagnosis of Acute Pancreatitis Biliary pain Acute cholecystitis Perforated hollow viscus (e.g., perforated peptic ulcer) Mesenteric ischemia or infarction Intestinal obstruction Myocardial infarction Dissecting aortic aneurysm Ectopic pregnancy

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epigastric, in the right upper quadrant, or, infrequently, confined to the left side. Pain in the lower abdomen may arise from the rapid spread of pancreatic exudation to the left colon. Onset of pain is rapid but not as abrupt as that of a perforated viscus. Usually it is at maximal intensity in 10 to 20 minutes. Occasionally, pain gradually increases and takes several hours to reach maximum intensity. Pain is steady and moderate to very severe. There is little pain relief with changing position. Frequently, pain is unbearable, steady, and boring. Band-like radiation of the pain to the back occurs in half of patients. Pain that lasts only a few hours and then disappears suggests a disease other than pancreatitis, such as biliary pain or peptic ulcer. Pain is absent in 5% to 10% of attacks, and a painless presentation may be a feature of serious fatal disease.6 Ninety percent of affected patients have nausea and vomiting. Vomiting may be severe, may last for hours, may be accompanied by retching, and may not alleviate pain. Vomiting may be related to severe pain or to inflammation involving the posterior gastric wall. 

mass may appear during the disease from a pseudocyst or a large inflammatory mass. The general physical examination, particularly in severe pancreatitis, may uncover markedly abnormal vital signs if there are third-space fluid losses and systemic toxicity. Commonly, the pulse is 100 to 150 beats/minute (sinus tachycardia). Blood pressure can be initially higher than normal (perhaps due to pain) and then lower than normal with third-space losses and hypovolemia. Initially the temperature may be normal, but within 1 to 3 days it may increase to 101°F to 103°F, owing to the severe retroperitoneal inflammatory process and the release of inflammatory mediators from the pancreas.177 Tachypnea with shallow respirations may be present if the subdiaphragmatic inflammatory exudate causes painful breathing. Dyspnea may accompany pleural effusions, atelectasis, ARDS, or heart failure. Chest examination may reveal limited diaphragmatic excursion if abdominal pain causes splinting of the diaphragm, or dullness to percussion and decreased breath sounds at the lung bases if there is a pleural effusion. There may be disorientation, hallucinations, agitation, or coma,178 which may be due to alcohol withdrawal, hypotension, electrolyte imbalance such as hyponatremia, hypoxemia, fever, or toxic effects of pancreatic enzymes on the central nervous system. Conjunctival icterus, if present, may be due to choledocholithiasis (gallstone pancreatitis) or bile duct obstruction from edema of the head of the pancreas, or from coexistent liver disease. Uncommon findings in AP include panniculitis with subcutaneous nodular fat necrosis that may be accompanied by polyarthritis (PPP syndrome; see Chapter 25).179 Subcutaneous fat necroses are 0.5- to 2-cm tender red nodules that usually appear over the distal extremities but may occur over the scalp, trunk, or buttocks. They occasionally precede abdominal pain or occur without abdominal pain, but usually they appear during a clinical episode and disappear with clinical improvement. Some physical findings point to a specific cause of AP. Hepatomegaly, spider angiomas, and thickening of palmar sheaths favor alcoholic pancreatitis. Eruptive xanthomas and lipemia retinalis suggest hyperlipidemic pancreatitis. Parotid pain and swelling are features of mumps. Band keratopathy (an infiltration on the lateral margin of the cornea) occurs with hypercalcemia. Microembolization in the retina can lead to typical fundus findings associated with visual disturbances including blindness. This

Physical Examination Physical findings vary with the severity of an attack. Patients with mild pancreatitis may not appear acutely ill. Abdominal tenderness may be mild, and abdominal guarding absent. In severe pancreatitis, patients look severely ill and often have abdominal distention, especially epigastric, which is due to gastric, small bowel, or colonic ileus. Almost all patients are tender in the upper abdomen, which may be elicited by gently shaking the abdomen or by gentle percussion. Guarding is more marked in the upper abdomen. Tenderness and guarding can be less than expected, considering the intensity of discomfort. Abdominal rigidity, as occurs in diffuse peritonitis, is unusual but can be present, and differentiation from a perforated viscus may be impossible in these instances. Bowel sounds are reduced and may be absent. Additional abdominal findings may include ecchymosis in 1 of both flanks (Gray Turner sign [Fig. 58.3A]) or about the periumbilical area (Cullen sign [Fig 58.3B]), owing to extravasation of hemorrhagic exudate to these areas. These signs occur in less than 1% of cases and are associated with a poor prognosis. Rarely there is a brawny erythema of the flanks caused by extravasation of pancreatic exudate to the abdominal wall. A palpable epigastric

A

B Fig. 58.3 A, Grey Turner sign. Ecchymosis in the left flank of a 57-year-old man with a 1-week history of epigastric pain secondary to acute biliary necrotizing pancreatitis. B, Cullen sign: Ecchymosis and subcutaneous edema in the periumbilical area of a 40-year-old man with alcoholic pancreatitis. (Courtesy of Dr. Shilpa Sannapaneni, Dallas, TX.)  

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is known as Purtscher retinopathy and can be seen in a variety of conditions besides AP.180 

DIFFERENTIAL DIAGNOSIS The abdominal pain of biliary pain may simulate AP. It is frequently severe and epigastric, but it typically lasts for several hours rather than several days (see Chapter 65). The pain of a perforated peptic ulcer is sudden, becomes diffuse, and precipitates a rigid abdomen; movement aggravates pain. Nausea and vomiting occur but disappear soon after onset of pain (see Chapter 53). In mesenteric ischemia or infarction, the clinical setting often is an older person with atrial fibrillation or atherosclerotic disease who develops sudden pain out of proportion to physical findings, bloody diarrhea, nausea, and vomiting. Abdominal tenderness may be mild to moderate, and muscular rigidity may not be severe despite severe pain (see Chapter 118). In intestinal obstruction, pain is cyclical, abdominal distention is prominent, vomiting persists and may become feculent, and peristalsis is hyperactive and often audible (see Chapter 123). Other conditions that enter into the differential diagnosis of AP are listed in Box 58.6. 

LABORATORY DIAGNOSIS Pancreatic Enzymes In general, the diagnosis of AP relies on at least a 3-fold elevation of serum amylase or lipase in the blood.181

Serum Amylase Level In healthy persons, the pancreas accounts for 40% to 45% of serum amylase activity, the salivary glands accounting for the rest. Simple analytic techniques can separate pancreatic and salivary amylases. Because pancreatic diseases increase serum pancreatic (P) isoamylase, measurement of P-isoamylase can improve diagnostic accuracy. However, this test is rarely used. The total serum amylase test is most frequently ordered to diagnose AP, because it can be measured quickly and cheaply. It rises within 6 to 12 hours of onset and is cleared fairly rapidly from the blood (half-life, 10 hours). Probably less than 25% of serum amylase is removed by the kidneys. It is uncertain what other processes clear amylase from the circulation. The serum amylase is usually increased on the first day of symptoms, and it remains elevated for 3 to 5 days in uncomplicated attacks. Sensitivity is at least 85%. The serum amylase may be normal or only minimally elevated in fatal pancreatitis,6 during a mild attack or an attack superimposed on chronic pancreatitis (because the pancreas has little remaining acinar tissue), or during recovery from AP as amylase is cleared from the circulation. The level may return to normal quickly, in just a few days. Serum amylase also may be falsely normal in hypertriglyceridemia-associated pancreatitis,182 because an amylase inhibitor may be associated with TG elevations. In this case, serial dilution of serum often reveals an elevated serum amylase. Hyperamylasemia is also not specific for pancreatitis; it occurs in many conditions. In fact, one half of all patients with an elevated serum amylase level may not have pancreatic disease.181 In AP, the serum amylase concentration is usually more than 2 to 3 times the upper limit of normal; it is usually less than this with other causes of hyperamylasemia.183 However, this level is not an absolute discriminator. Thus an increased serum amylase level supports rather than confirms the diagnosis of AP. In addition, there are some individuals who have persistent hyperamylasemia without clinical symptoms. This has been reported to be due to macroamylasemia (discussed later) or pancreatic hyperamylasemia on a familial basis.184 Nonpancreatic diseases that lead to hyperamylasemia include pathologic processes in other organs that normally produce amylase (e.g.,

salivary glands, fallopian tubes). Furthermore, mass lesions such as papillary cystadenocarcinoma of the ovary, benign ovarian cyst, and carcinoma of the lung can cause hyperamylasemia because they produce and secrete salivary (S-type) isoamylase. Leakage of P-type isoamylase across the intestine with peritoneal amylase absorption probably explains hyperamylasemia in patients with intestinal infarction or GI tract perforation. Renal failure can increase serum amylase up to 4 to 5 times the upper limit of normal because of decreased renal clearance of this enzyme.185 Patients on hemodialysis tend to have higher serum amylase levels than those on peritoneal dialysis. In patients with chronic kidney disease, there is not a clear inverse correlation between the creatinine clearance rate and serum levels of amylase, and about one third of patients with marked renal insufficiency (low creatinine clearance) have normal pancreatic enzyme levels. Chronic elevations of serum amylase (without amylasuria) occur in macroamylasemia. In this condition, normal serum amylase is bound to an immunoglobulin or abnormal serum protein to form a complex that is too large to be filtered by renal glomeruli and thus has a prolonged serum half-life.185 Macroamylasemia may lead to a false diagnosis of pancreatic disease, but it has no other clinical consequence. The urinary amylase-to-creatinine clearance ratio (ACCR) increases from approximately 3% to approximately 10% in AP.186 However, even moderate renal insufficiency interferes with the accuracy and specificity of the ACCR. Other than to diagnose macroamylasemia, which has a low ACCR, urinary amylase measurements and the ACCR are not used clinically. Macroamylasemia can also be measured directly in serum samples. Deliberate contamination of urine with saliva, as in Munchausen syndrome, can increase the urine amylase, with the serum amylase being normal. This situation can be excluded by measuring S-type amylase in the urine. In the emergency room, computer order set de-selection of amylase but using lipase was an effective tool to reduce non-valueadded testing and reduce cost while maintaining quality patient care and physician choice in patients presenting with abdominal pain.187 The rapid and easy-to-operate amylase assay may have potential application in the fields of point-of-care clinical diagnosis, particularly in rural and remote areas where lab equipment may be limited.188 

Serum Lipase Level The sensitivity of serum lipase for the diagnosis of AP is similar to that of serum amylase and is at least 85%.181 Lipase may have greater specificity for pancreatitis than amylase, however. Serum lipase is normal when serum amylase is elevated in nonpancreatic conditions such as salivary gland disease, amylase-producing tumors, gynecologic conditions such as salpingitis, and macroamylasemia. Serum lipase always is elevated on the first day of illness and remains elevated longer than does the serum amylase, providing a slightly higher sensitivity.189 Combining amylase and lipase does not improve diagnostic accuracy and increases cost. Specificity of lipase can suffer from some of the same problems as those of amylase, however. In the absence of pancreatitis, serum lipase may increase less than 2-fold above normal in renal insufficiency.190 With acute GI conditions that resemble AP,191 serum lipase increases to levels less than 3-fold above normal, presumably by absorption through an ischemic, inflamed, or perforated intestine. Rarely, a nonpancreatic abdominal condition such as small bowel obstruction can raise the serum lipase (and amylase) above 3 times normal. Some believe that serum lipase measurement is preferable to that of serum amylase because it is as least as sensitive as amylase measurement and more specific, whereas others find no clear advantage of one over the other.9 Many normal persons have elevations of serum amylase and/ or lipase of little clinical significance.192 Diabetics appear to have higher median lipase compared with nondiabetic patients for

CHAPTER 58  Acute Pancreatitis

unclear reasons.193 In this prospective study, it was shown that 20% of type 2 diabetics had an elevated serum lipase, and 2% had a serum lipase of more than 3-fold elevation despite the absence of symptoms. However, when evaluating serum amylase, only 5% of type 2 diabetics were found to have an elevated level and no patient had more than 3-fold elevation. Although the ramifications of these findings are unclear, there is a recent study that suggested that these low-level elevations in pancreatic enzymes may be associated with ductal changes in the pancreas consistent with chronic pancreatitis.194 Although further study is needed, extensive evaluation of patients with asymptomatic elevations of amylase and lipase in the absence of other clinical findings of AP should not be performed. It is also possible to analyze serum lipase subtypes such as the pancreatic fraction of the lipase. However, in the small study it was found that such subtype estimation is not superior to a regular lipase assay but can be used as an add-on test if required.195 A report from Australia and New Zealand showed that elevation of lipase on day 1 in children with AP predicted a severe disease with a sensitivity of 82% but a modest specificity of only 53%.196 Another study also reported that an early 7-fold elevation of lipase in pediatric AP had a sensitivity, specificity, positive and negative predictive values, and positive and negative likelihood ratios for severe disease of 85%, 56%, 46%, 89%, 1.939, and 0.27, respectively.197 The overall PPV of hyperlipasemia was 38%. Physicians should maintain caution when interpreting 3-fold hyperlipasemia in critically ill patients due its relatively low PPV. However, the greater lipase cutoff improves its diagnostic value in AP and helps to reduce unnecessary imaging in these patients. The most common primary diagnoses in non-AP patients with elevated lipase included shock, cardiac arrest and malignancy.198 Elevated serum lipase level can have non-pancreatic origins, with liver and renal failure being the most frequent.199 According to a recent study with proven AP, lipase was a more sensitive (91%) than amylase (62%), with specificity of >91%. Lipase should replace amylase as the first-line laboratory investigation for suspected AP.200 A Cochrane systematic review looked at the diagnostic accuracy of serum amylase, serum lipase, urinary trypsinogen-2, and urinary amylase, either alone or in combination, in the diagnosis of AP in people with the acute onset of a persistent, severe epigastric pain or diffuse abdominal pain, and found a false negative rate of 25% and a false-positive rate of 10%.201 Serum lipase levels of more than 2.5 times the upper limit of normal prior to refeeding is a potentially useful threshold to identify patients at high risk of developing oral feeding intolerance.202 

Other Pancreatic Enzyme Levels During acute pancreatic inflammation, pancreatic digestive enzymes other than amylase and lipase leak into the systemic circulation and have been used to diagnose AP. They include PLA2, trypsin/trypsinogen, carboxylester lipase, carboxypeptidase A, colipase, elastase, TAP, urinary and serum trypsinogen-2, and ribonuclease. None—alone or in combination—are diagnostically superior to serum amylase or lipase, and most are not available on a routine basis. 

Standard Blood Tests The WBC count frequently is elevated, often markedly so in severe pancreatitis, and does not generally indicate infection. The blood glucose also may be high and associated with high levels of serum glucagon. Serum AST, ALT, alkaline phosphatase, and bilirubin also may increase, particularly in gallstone pancreatitis. Presumably, calculi in the bile duct account for these abnormalities. However, pancreatic inflammation per se may partially obstruct the distal bile duct in AP. Serum aminotransferases may help distinguish biliary from alcoholic pancreatitis (see later).203

907

The decrease in serum calcium often seen in patients with AP is mainly related to the decreased serum albumin. As will be discussed later, the decrease in calcium is a marker of severity because it is carried bound to albumin-rich intravascular fluid that extravasates to the peritoneum. Decreased serum calcium is not from saponification. The erythrocyte mean corpuscular volume has been shown to help differentiate alcoholic from nonalcoholic AP.204 Alcoholic patients tend to have a higher mean corpuscular volume due to the toxic effects of alcohol on erythrocyte formation in the bone marrow. Serum TG levels increase in AP but also with alcohol use, uncontrolled diabetes mellitus, or defective TG metabolism. 

DIAGNOSTIC IMAGING Abdominal Plain Film Findings on a plain radiograph range from no abnormalities in mild disease to localized ileus of a segment of small intestine (“sentinel loop”) or the colon cutoff sign in more severe disease. In addition, an abdominal plain film helps exclude other causes of abdominal pain, such as bowel obstruction and perforation. Images of the hollow GI tract on an abdominal plain radiograph depend on the spread and location of pancreatic exudate. Gastric abnormalities are caused by exudate in the lesser sac producing anterior displacement of the stomach, with separation of the contour of the stomach from the transverse colon. Small intestinal abnormalities are due to inflammation in proximity to small bowel mesentery and include ileus of 1 or more loops of jejunum (the sentinel loop), of the distal ileum or cecum, or of the duodenum. Generalized ileus may occur in severe disease. Other abnormalities of the hollow GI tract may be present. The descending duodenum may be displaced and stretched by an enlarged head of the pancreas. In addition, spread of exudate to specific areas of the colon may produce spasm of that part of the colon and either no air distal to the spasm (the colon cutoff sign) or dilated colon proximal to the spasm. Head-predominant pancreatitis predisposes to spread of exudate to the proximal transverse colon, producing colonic spasm and a dilated ascending colon. Uniform pancreatic inflammation predisposes spread of exudate to the inferior border of the transverse colon and an irregular haustral pattern. Exudate from the pancreatic tail to the phrenicocolic ligament adjacent to the descending colon may cause spasm of the descending colon and a dilated transverse colon. Other findings on plain radiography of the abdomen may give clues to etiology or severity, including calcified gallstones (gallstone pancreatitis), pancreatic stones or calcification (acute exacerbation of chronic pancreatitis), and ascites (severe pancreatitis). Gas in the retroperitoneum may suggest a pancreatic abscess. 

Chest Radiography Abnormalities visible on the chest roentgenogram occur in 30% of patients with AP, including elevation of a hemidiaphragm, pleural effusion(s), basal or plate-like atelectasis secondary to limited respiratory excursion, and pulmonary infiltrates. Pleural effusions may be bilateral or confined to the left side; rarely they are only on the right side.205 Patients with AP found to have a pleural effusion and/or pulmonary infiltrate on admission are more likely to have severe disease.206 During the first 7 to 10 days, there also may be signs of ARDS or heart failure. Pericardial effusion is rare. 

Abdominal US Abdominal US is used during the first 24 hours of hospitalization to search for gallstones, dilation of the bile duct due to choledocholithiasis, and ascites. Ascites is common in patients with

58

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moderate to severe AP as protein-rich fluid extravasates from the intravascular compartment to the peritoneal cavity. If the pancreas is visualized by US (bowel gas obscures the pancreas 25% to 35% of the time), it is usually diffusely enlarged and hypoechoic. Less frequently, there are focal hypoechoic areas. There also may be US evidence of chronic pancreatitis, such as intraductal or parenchymal calcification(s) and dilation of the PD. US is not a good imaging test to evaluate extrapancreatic spread of pancreatic inflammation or pancreatic necrosis and consequently is not useful to ascertain severity of pancreatitis. During the course of AP, US can be used to evaluate progression of a pseudocyst (discussed later). Owing to overlying gas, the diagnosis of cholelithiasis may be obscured during the acute attack but may be found after bowel gas has receded. Contrast-enhanced US of the pancreas may be useful in the future to assess the severity of AP.207 

G P

EUS and ERCP Imaging of the pancreas by EUS during an attack of AP, and for weeks following an episode, reveals abnormal signals that are typically hypoechoic and indistinguishable from chronic pancreatitis and malignancy. EUS is useful at an early stage in AP to detect common bile duct stones and allow proceeding to ERCP at the same time, thus avoiding ERCP if the bile duct is clear of stones. EUS can also predict severity of AP by alterations in the echo texture of the pancreas.79 An RCT in patients at moderate or indeterminate risk for choledocholithiasis observed that EUS, done for confirmation of choledocholithiasis, avoids unnecessary ERCP in almost half of the cases.208 EUS done at admission can reliably detect pancreatic necrosis and co-existent disorders like CBD stones209 and predict mortality.210 In idiopathic AP, recent guidelines and reviews recommend obtaining EUS after a period of 8 to 12 weeks to look for causes like microlithiasis in the common bile duct, small tumors near the PD causing obstruction, chronic pancreatitis presenting as an AP attack, and some anatomical abnormalities missed on CT scan.211 In a recent meta-analysis comparing MRCP and EUS in the evaluation of idiopathic AP, EUS had a higher diagnostic accuracy than MRCP (64% vs. 34%) in establishing an etiology of pancreatitis.212 

Fig. 58.4  CT showing acute necrotizing pancreatitis. The pancreas (P) is surrounded by peripancreatic inflammation that contains bubbles of air (arrows) due to sterile necrosis. The patient was not clinically ill, and therefore an abscess was not considered likely. G, gallbladder.

CT

MRI provides similar information regarding the severity of pancreatitis, as does CT. However, MRI is superior to CT in assessing fluid collections by showing the necrotic debris better.220 MRI is better than CT, but equal to EUS and ERCP in detecting choledocholithiasis.221 MRI also has the advantage over CT in better delineating the PD and showing lesions like PD disruption or disconnection and stones in the PD. The MRCP contrast agent gadolinium222 can cause nephrogenic systemic fibrosis.223 However, the risk of nephrogenic systemic fibrosis is very low in patients with renal impairment, and newer agents are not associated with this disorder. MRI is less accessible and more expensive than CT. MRI also requires the patient to remain still during capture of images, which typically is much longer than with spiral CT. MRCP use prior to ERCP in patients at high risk for choledocholithiasis is common and associated with greater length of hospital stay, higher radiology charges, and a trend toward higher hospital charges.224 The use of IV secretin prior to MRCP allows a better visualization of the PDs.225 This has been shown to be particularly useful in the evaluation of patients with idiopathic pancreatitis and recurrent pancreatitis.225,226 Thus, whereas MRI and MRCP have a definite role in the management of AP, the limitations of this modality need to be recognized. 

CT is the most important imaging test for the diagnosis of AP and its intra-abdominal complications.213 The 3 main indications for a CT in AP are to (1) exclude other serious intra-abdominal conditions (e.g., mesenteric infarction or a perforated peptic ulcer), (2) stage the severity of AP, and (3) determine whether complications of pancreatitis are present (e.g., involvement of the GI tract or nearby blood vessels and organs, including liver, spleen, and kidney).214 Helical CT is the most common technique. If possible, scanning should occur after the patient receives oral contrast, followed by IV contrast to identify any areas of pancreatic necrosis. If there is normal perfusion of the pancreas, interstitial pancreatitis is said to be present (see Fig. 58.1). Pancreatic necrosis manifested as perfusion defects after IV contrast may not appear until 48 to 72 hours after onset of AP (see Fig. 58.2). It has been suggested that IV contrast media early in the course of AP might increase pancreatic necrosis because iodinated contrast medium given at the onset of pancreatitis increases necrosis in experimental AP in rats.215 However, it did not do so in other animal models. Data in humans are conflicting. Two retrospective studies suggested that early contrast-enhanced CT worsened pancreatitis,215 but this was not corroborated by a third retrospective study.216 The severity of AP has been classified into 5 grades (A to E) based on findings on unenhanced CT (discussed later).203 Although the presence of gas in the pancreas suggests pancreatic infection with a gas-forming organism, this finding can also

accompany sterile necrosis (Fig. 58.4) with microperforation of the gut or an adjacent pseudocyst into the pancreas.217 Moreover, the great majority of pancreatic infections occur in the absence of gas on CT scan. Perfusion CT scan is a recent development where IV perfusion of radiocontrast helps detect necrosis at an earlier stage compared with conventional CT scan.86 A multicenter study from Japan also showed that perfusion CT predicted persistent organ failure, along with early detection of pancreatic necrosis.218 Another development is subtraction CT, where a subtraction color map is generated from noncontrast and contrast CTs. This technique also allows early detection of necrosis compared with conventional CT scan.219 

MRI

DISTINGUISHING ALCOHOLIC FROM GALLSTONE PANCREATITIS Differentiation between alcoholic and gallstone pancreatitis is important because eliminating these etiologies may prevent

CHAPTER 58  Acute Pancreatitis

further attacks of pancreatitis. Alcoholic pancreatitis occurs more frequently in men approximately 40 years old. The first clinical episode usually occurs after 5 to 10 years of heavy alcohol consumption. By contrast, biliary pancreatitis is more frequent in women, and the first clinical episode is often after the age of 40 years. Recurrent attacks of AP suggest an alcohol etiology, but unrecognized gallstones may cause recurrent pancreatitis. Among patients with acute biliary pancreatitis discharged from the hospital without cholecystectomy, 30% to 50% develop recurrent AP relatively soon after discharge (average time to recurrent pancreatitis, 108 days).227 Thus removing the gallbladder in biliary pancreatitis is imperative. Laboratory tests may help distinguish between these 2 disorders. The specificity for gallstone pancreatitis of a serum ALT concentration greater than 150 IU/L (≈3-fold elevation) is 96%; the PPV is 95%, but the sensitivity is only 48%.205 The serum AST concentration is nearly as useful as the ALT, but the total bilirubin and alkaline phosphatase concentrations are not as helpful to distinguish gallstone pancreatitis from alcoholic and other etiologies. There are differing reports as to whether a high serum lipase-to-amylase ratio can differentiate alcoholic from other causes of pancreatitis.228,229 Conventional abdominal US should be performed in every patient with a first attack of AP to search for gallstones in the gallbladder, common duct stones, or signs of extrahepatic biliary tract obstruction. However, bile duct stones are frequently missed by abdominal US, and most stones pass during the acute attack. ERCP is limited to patients with severe AP due to gallstones with persistent bile duct obstruction and to those patients in whom the stone could not be removed during surgery. In most patients with biliary pancreatitis, common duct stones pass and no further evaluation is needed. Although the bile duct can be imaged with an operative cholangiogram at the time of laparoscopic cholecystectomy performed during the same admission, this is not necessary in most patients. Many clinicians prefer to evaluate the bile duct prior to surgery. Because most stones that cause biliary pancreatitis pass, it is not clear who should undergo evaluation. ERCP would be inappropriate in a patient with a moderate to low risk of choledocholithiasis, when the risk of PEP is greater than the benefit of ERCP (normal-sized bile duct and normal liver chemistry tests). However, if the bile duct is dilated and/or liver chemistry tests are elevated, further evaluation prior to surgery may be reasonable. Although EUS is an accurate method of detecting bile duct stones and has been recommended for evaluating the bile duct prior to cholecystectomy, it is rarely needed or used in this setting.230 It should be reserved for the patient who has findings suspicious for a retained stone and cannot undergo MRCP. MRCP is as accurate, but because of its noninvasive approach, it is preferred if a clinician has a lower suspicion that a common duct stone may be present. If a common duct stone is found at surgery, it is either removed during the operation or endoscopically after surgery.231 Laparoscopic exploration of the bile duct is as safe and effective as postoperative ERCP in clearing stones from the common duct.232 

PREDICTORS OF DISEASE SEVERITY According to the revised Atlanta classification there are 3 grades of severity of AP: mild, moderate, and severe. Nearly 80% of the patients have mild AP. Predicting the severity is very important during the first 24 to 72 hours, mostly at admission and during the first 24 hours. If such prediction suggests moderate or severe type of the disease, it may help communicate with the patient about the course of the disease; triage them to intensive care or step-up unit; and when specific interventions become available, administer them early on. A variety of clinical features, laboratory markers, and scoring systems have been described over the years to predict severe AP. There has been an extremely limited

909

number of reports predicting moderately severe AP, which has been included in the revised Atlanta classification.233 However, despite a large body of literature, no perfect predictor is available at the present time. Most predictors have a very high negative predictive value but not a useful PPV, and this is because a significant proportion of the patients with AP do not develop moderately severe or severe disease. From 2 prospectively collected cohorts, it was reported that the existing scoring systems seem to have reached their maximal efficacy in predicting persistent organ failure in AP. Sophisticated combinations of predictive rules are more accurate but cumbersome to use, and therefore of limited clinical use. Our ability to predict the severity of AP cannot be expected to improve unless we develop new approaches.234 A recent systematic review looking at predictors of persistent organ failure (severe AP) and infected pancreatic necrosis observed that it is justifiable to use the blood urea nitrogen (BUN) level for prediction of persistent organ failure after 48 hours of admission and procalcitonin for prediction of infected pancreatic necrosis in patients with confirmed pancreatic necrosis.234 There was no predictor of persistent organ failure found that can be justifiably used in clinical practice within 48 hours of admission.235 What is really required is a system or a marker that has high PPV for moderately severe or severe AP. Along the same lines, the most recent AGA technical review on early management of AP found no studies using a predictive tool that improved clinical outcomes.236 Hence it recommended using clinical judgment and a variety of predictive tools in clinical practice. It is for the same reason that this particular approach of predicting severity was not included in the meta-analysis in the same technical review. Thus many of the predictors will be listed below briefly, with added information on some predictors that were widely studied. At the present time, most of these systems are more useful for research purposes and to compare different cohorts, rather than being useful in directing clinical care. Recent guidelines and reviews recommended the following predictors at admission to be useful while considered together with clinical judgement: advanced age (>60 years), BMI, Charlson’s comorbidity index, pleural effusions or infiltrates on the admission chest radiograph, elevated hematocrit, elevated BUN level, elevated serum creatinine level, and CRP >15 mg/dL at 48 hours.1,211,237 The height of elevation of the serum amylase and lipase does not correlate with severity. However, in pediatric AP, it was reported that a 7-fold elevation of lipase predicted severe disease with a sensitivity, specificity, positive and negative predictive values, and positive and negative likelihood ratios of 85%, 56%, 46%, 89%, 1.939, and 0.27, respectively.197 When AP is superimposed on chronic pancreatitis, it is usually less severe than AP without chronic pancreatitis. When superimposed on chronic pancreatitis, weight loss, advanced age, and comorbidities predict severity in a population-based study.237 Radial EUS in acute biliary pancreatitis showed a significant relationship between the severity of AP with diffuse parenchymal edema, periparenchymal plastering, and/or diffuse retroperitoneal free fluid accumulation, and peri-pancreatic edema, and also predicted mortality.238 In a large administrative database, transferred patients with AP have more severe disease and higher overall mortality. Mortality is similar after adjusting for disease severity. Disease severity, insurance status, race, and age all influence the decision to transfer patients with AP.239 A large number of clinical and laboratory predictors of severity have been described in recent years. They include procalcitonin,240 TNF-α,241 thrombopoetin,242 carboxypeptidase-B activation peptide,243 polymorphonuclear elastase, PLA2, D-dimer in pediatric AP,244,245 higher urinary beta 2 microglobulin to saposin B ratio,246 hepcidin,247 elevated levels of soluble B7-H2 (sB7-H2),248 copeptin,249 IL-6,250 IL-17, IL-23,251 melatonin,252 resistin,253 lower serum lipid concentrations,254 mean platelet volume,255

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presepsin,256 soluble urokinase-type plasminogen activator receptor,257 urinary neutrophil gelatinase-associated lipocalin,258 the LP-PLA2 gene polymorphisms V279F and R92H,259 genetic polymorphisms in TLR3 and TLR6,260 increased visceral adipose tissue,261 matrix metalloprotease-8,262 IL13/IFN gamma ratio,263 antithrombin-III,264 high visceral fat with low skeletal muscle volume,265 admission heart rate variability,266 and others. The presence of SIRS at admission and persistence of SIRS at 48 hours increases the morbidity and mortality rate. In one study, death occurred in 25% of patients with persistent SIRS, in 8% with transient SIRS, and in less than 1% without SIRS.267 Although severity is now defined by the presence of organ failure or anatomic complications of AP, such as pancreatic necrosis, prospective systems using clinical criteria have been developed to determine disease severity. These systems include the Ranson’s and APACHE scores.13,14 Unfortunately, these scoring systems (discussed below) are cumbersome, requiring multiple measurements. In addition, the systems are not accurate until 48 hours after presentation.

TABLE 58.1  CT Grading System of Balthazar and the CT Severity Index (CTSI) Balthazar Grades Definition

Points

A

Normal pancreas consistent with mild pancreatitis

0

B

Focal or diffuse enlargement of the gland, including contour irregularities and inhomogeneous attenuation but without peripancreatic inflammation

1

C

Grade B plus peripancreatic inflammation

2

D

Grade C plus associated single fluid collection

3

E

Grade C plus 2 or more peripancreatic fluid 4 collections or gas in the pancreas or retroperitoneum CTSI=Balthazar Grade Points Plus Necrosis Score* Necrosis Score

Points

Absence of necrosis

0

Scoring Systems

Necrosis of up to 33% of the pancreas

2

APACHE II has been the most validated system for many years and none of the later scoring systems later reported proved to be superior in any consistent manner. However, APACHE II is cumbersome (like most of the systems) and is very rarely used in clinical practice. Most studies used a score of 8 or more as severe AP. Ranson and colleagues identified 11 signs that had prognostic significance during the first 48 hours. The original list13 was analyzed in patients who primarily suffered from alcoholic pancreatitis and was then modified 8 years later for those with gallstone pancreatitis.268 A score of 3 or more is considered to indicate severe AP. The Imrie or Glasgow score269 is a slightly simplified list (8 criteria) that is used commonly in the United Kingdom. The Pancreas Center at Brigham and Women’s Hospital performed a series of studies retrospectively and prospectively.270-272 The studies were performed on a large database including almost 37,000 patients from more than 200 hospitals. After careful analysis, including a validation study, they determined that a simpler system that included only 5 variables could accurately predict severity early in the course of the disease. The scoring system, referred to as BISAP (Bedside Index for Severity in AP), assigns each parameter 1 point: BUN greater than 25 mg/dL, Impaired mental status, SIRS, Age older than 60 years, and Pleural effusion, for a possible total of 5 points. A BISAP score of 4 or 5 is associated with a 7- to 12-fold increased risk of developing organ failure. BISAP is not superior to APACHE II. Other scoring systems include the harmless AP score,273 the Japanese AP severity score,274 and the PANC 3 score.275 APACHE II has stood the test of time and no score is convincingly superior to it, but it has the drawback of being cumbersome. The simple SIRS score is as good as any of the complex scoring systems that are available and is easy, cheap, and readily available at the time of admission.125 SIRS is defined by 2 or more of the following 4 criteria: pulse >90 beats/minute, rectal temperature 38°C, WBC count 12,000/mm3, and a respiratory rate greater than 20/minute or an arterial PCO2 50%

6

CT The finding of extensive fluid collections and/or extensive pancreatic necrosis on CT has been correlated with severe disease. Balthazar reported that 5 of 37 (13.5%) patients who had grade D or E findings on CT died, as opposed to none of 51 who had grades B or C findings (Table 58.1).213 Using the CT severity index (CTSI score; see Table 58.1), among those with a score of 0 to 6, 3 of 77 (3.8%) died, as compared with 2 of 11 (18%)

  

*Highest attainable CTSI score: 4 (Balthazar grade E) + 6 (necrosis of >50%) = 10 points.

with scores of 7 to 10. The CT grading scores correlate better with local complications (pseudocysts and abscesses) than with mortality. Among the 37 patients with a grade D or E score, 54% developed a local complication, whereas only 2 of 51 (3.9%) with grades A through C developed this problem.213 Thus the data do not confirm that the CTSI is any more predictive than the grades A through E score. There is controversy in the literature as to whether the extent of necrosis on CT predicts organ failure.11,12,16,245-247 A modified CTSI has been found to be more useful where a simplified assessment of inflammation and necrosis, as well as assessment of extrapancreatic complications, were included.276 

Chest Radiography A pleural effusion documented within 72 hours of admission by chest radiography (or CT) correlates with severe disease.205,206 

TREATMENT (FIG. 58.5) Initial Management During the First Week There is no specific drug therapy to treat AP and, thus, treatment guidelines are mainly for supportive care and for the treatment of complications once they develop. However, because of such good supportive care, including ICU care and more effective therapy of the ensuing complications, the mortality in AP has dropped from around 10% to 5% or less from different regions of the world. The patient is usually kept NPO until any nausea and vomiting have subsided. However, there has been a major change in this concept and currently gut rousing and not gut resting is the key management.277 By providing earlier oral intake, the gut mucosal barrier is preserved and prevents the undesirable translocation of bacteria from the lumen into circulation. Pain relief is an important area in the early management. Opiate analgesics like fentanyl and hydromorphone often by a patient-controlled anesthesia pump are the most widely used agents.278 Opiate dosing is monitored carefully and adjusted on a daily basis according to ongoing needs. Although morphine has been reported to

CHAPTER 58  Acute Pancreatitis

911

Early course: 0-72 hr Is there organ failure? No

58 Yes

Admission to medical/surgical floor NPO, IV hydration (250-400 cc/hr) Nasal oxygen Frequent evaluation of oxygen saturation Hematocrit daily/BUN twice daily for 48 hours Serum electrolytes daily Pain control

Admission to an ICU Same orders as for floor admission Central line placement Evaluate need for assisted ventilation Assess for bile duct obstruction If bilirubin rising, consider urgent ERCP

Later course: >72 hours Evidence of severe disease or organ failure? No

Yes

Early refeeding Evaluate for etiology If gallstones, early cholecystectomy If alcohol, address psychosocial issues If high serum TG, medical therapy

Interstitial pancreatitis on CT without peripancreatic necrosis: Continue supportive care Observation

To ICU if patient not already there Observe for biliary sepsis; if present, consider emergency ERCP Enteral feedings (NJ or NG) CT to evaluate for necrosis

Pancreatic/peripancreatic necrosis on CT: Continue supportive care Enteral feedings If infection suspected, consider antibiotics

Late course: 7-28 days Patient improving? Yes

No

Consider oral refeeding

If on antibiotics, consider FNA of pancreas for culture and change of antibiotics If not on antibiotics and FNA negative, keep off antibiotics Beyond 28 days Patient improving?

Yes Fig. 58.5  Algorithm for the management of acute pancreatitis at various stages in its course. BUN, blood urea nitrogen; NJ, nasojejunal.

No

Consider refeeding If patient cannot tolerate feedings, consider necrosectomy

increase sphincter of Oddi tone and to increase serum amylase,279 its use to treat the pain of pancreatitis has not been shown to adversely affect outcome. NG intubation is not used routinely because it is not beneficial in mild pancreatitis. It is used only to treat gastric or intestinal ileus or intractable nausea and vomiting. Similarly, routine use of PPIs or H2RAs have not been shown to be beneficial. The patient should be carefully monitored for any signs of early organ failure such as hypotension (systolic blood pressure less than 110 mm Hg despite IV volume administration), pulmonary failure (oxygen saturations less than 90% despite maximally possible oxygen replacement therapy by nasal cannula or

Consider necrosectomy by endoscopic, radiologic, or surgical means

face mask), or renal insufficiency (serum creatinine greater than 2 mg/dL despite maximal intravenous volume administration) by closely following vital signs and urine output. Tachypnea should not be assumed to be due to abdominal pain. Monitoring oxyhemoglobin saturation and, if needed, arterial blood gas measurement is advised, and oxygen supplementation is mandatory if there is hypoxemia. Any patient who exhibits signs of early organ dysfunction should be considered for a transfer to an ICU. Admission to an ICU is a practice that differs in different centers. Although many patients are managed on the floor in the USA (unless need for respiratory or blood pressure support is required), outside the USA early signs of organ failure (like

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PART VII   Pancreas

increasing oxygen requirements, intravenous fluids for maintaining the blood pressure, or renal replacement therapy) are indications for ICU or step-up unit care. 

Intravenous Fluid and Electrolyte Resuscitation As the inflammatory process progresses early in the course of the disease, there is an extravasation of protein-rich intravascular fluid into the peritoneal cavity and retroperitoneum, resulting in hemoconcentration and decreased renal perfusion with the associated elevation in the BUN level and, later, the serum creatinine level. Subsequently, the decreased perfusion pressure into the pancreas leads to microcirculatory changes that result in pancreatic necrosis. Thus an admission hematocrit of more than 44% and a failure of the admission hematocrit to decrease at 24 hours have been shown to be predictors of necrotizing pancreatitis,280 and an elevation and/or rising BUN is associated with increased mortality.272 The relationship of hematocrit and BUN, markers of intravascular volume, to severity of AP implies that the opposite is also true. Early vigorous IV volume repletion for the purpose of intravascular resuscitation is of foremost importance. The goal is to provide enough intravascular volume to decrease the hematocrit and the BUN, thereby increasing pancreatic perfusion. This is one of the extensively studied management strategies in AP over the years. Intravenous volume administration has been widely recommended by experts and in various guidelines, although there is significant variation in the various aspects of such intravenous volume administration in these guidelines and reviews.9,211,280-282 Haydock et al. in a systematic review observed that the level of evidence of such an important area in the management is at best very poor.283 The various aspects of such intravenous volume administration include the type of fluid, total amount given, rate, timing, duration, and the weight to monitor the therapy. It not surprising that a national survey in New Zealand found that there is significant variation in intravenous volume administration in AP, that aggressive volume administration is prescribed mostly for organ failure and there is no adherence to the published guidelines.284 Lactated Ringer solution is supposed to reduce intracellular acidosis in the pancreas and thus the tryptic activity. A small RCT showed a benefit with lactated Ringer solution over normal saline with regards to a decrease in SIRS score as well as CRP levels, but not in any of the important clinical outcomes.285 An AGA technical review237 reported the meta-analysis of many eligible studies on the role of intravenous volume administration therapy in the early management of AP as follows: “In conclusion, there is insufficient evidence to state that goaldirected therapy, using various parameters to guide fluid administration, reduces the risk of persistent single or multiple organ system failure, infected (peri-) pancreatic necrosis or mortality from AP. There is also no RCT evidence that any particular type of fluid therapy (e.g., lactated Ringer’s) reduces the risk of mortality or persistent single or multiple organ failure. The addition of hydroxyethyl starch to usual intravenous fluids does not reduce the risk of mortality, and may increase the risk of persistent multiple organ system failure in AP.” Based on this meta-analysis, the accompanying AGA guidelines suggested goal directed therapy for fluid management but cautioned the quality of evidence is very low and future trials have to address the various aspects of such therapy in the early management of AP.286 Despite these limitations for practical purposes, one could suggest a fluid rate of 5 to 10 mL per kilogram body weight per hour or 250 to 500 mL per hour of probably lactated Ringer solution, preferably during the first 24 hours after admission. Besides clinical monitoring for volume overload, hourly urine output, decreases in hematocrit and BUN/serum creatinine levels may be used for directing such therapy with very minimal need for invasive monitoring. Agents like hydroxyethyl starch should not be used. 

Respiratory Care Because of the common and indolent nature of hypoxemia affecting patients with AP, current guidelines recommend the initial routine use of nasal cannula oxygen in all patients with AP.287 Supplemental oxygen, ideally by nasal prongs or by face mask if needed, is given to maintain oxygen saturations well over 90%. If nasal or face mask oxygen fails to correct hypoxemia or if there is fatigue and borderline respiratory reserve, noninvasive positive pressure ventilation or endotracheal intubation and assisted mechanical ventilation are required early. US of the nondependent lung can reliably detect evolving respiratory dysfunction in AP. This simple bedside technique shows promise as an adjunct to severity stratification.288 ARDS is associated with severe dyspnea, progressive hypoxemia, and increased mortality. It generally occurs between the second and seventh day of illness (but can be present on admission) and consists of increased alveolar capillary permeability causing interstitial edema. Chest radiography may show multilobar alveolar infiltrates. Treatment is endotracheal intubation with positive end-expiratory pressure ventilation, often with low tidal volumes to protect the lungs from volutrauma. No specific treatment will prevent or resolve ARDS. Noninvasive positive pressure ventilation in the early phases of ARDS288 and continuous renal replacement therapy have also been reported to be useful in the treatment of ARDS in AP.289 After recovery, pulmonary structure and function usually return to normal. 

Cardiovascular Care Cardiac complications of severe AP include heart failure, myocardial infarction, cardiac dysrhythmia, and cardiogenic shock. An increase in cardiac index and a decrease in total peripheral resistance may be present and respond to infusion of crystalloids. If hypotension persists even with appropriate fluid resuscitation, intravenous vasopressors may be required. 

Metabolic Complications Hyperglycemia may present during the first several days of severe pancreatitis but usually disappears as the inflammatory process subsides. Blood sugars fluctuate, and insulin should be administered cautiously. Leptin levels were associated with persistent hyperglycemia early in the course of AP in one study from New Zealand.290 Hypocalcemia is mainly due to a low serum albumin. Serum albumin is lost as albumin-rich intravascular fluid extravasates into peritoneum and retroperitoneum, as well as the negative phase reactant effect on reducing albumin synthesis during the acute illness phase. This albumin loss causes a decrease in the calcium normally bound to the albumin. Because this loss is nonionized, hypocalcemia is largely asymptomatic and requires no specific therapy. However, reduced ionized serum calcium may occur and cause neuromuscular irritability. If hypomagnesemia coexists, it inhibits the release of parathyroid hormone; magnesium replacement should restore serum calcium to normal in such instances. Causes of magnesium depletion include loss of magnesium in the urine, stool, or vomitus or deposition of magnesium in areas of fat necrosis. Once the serum magnesium is normal, signs or symptoms of neuromuscular irritability may require administering IV calcium gluconate, as long as the serum potassium is normal and digitalis is not being given. IV calcium increases calcium binding to myocardial receptors, which displaces potassium and may induce a serious dysrhythmia. 

Antibiotics Antibiotics are sometimes given in AP as prophylactic antibiotics (before a documented infection) or for the treatment of

CHAPTER 58  Acute Pancreatitis

established infection. Necrosis of the pancreas and peripancreatic tissues (necrotizing pancreatitis) can become infected (infected pancreatic necrosis), with increased mortality.291,292 The role of antibiotics in established infection of the pancreas or extrapancreatic sites is not controversial. Imipenem, fluoroquinolones (ciprofloxacin, ofloxacin, pefloxacin), and metronidazole emerged as the drugs that achieved the highest inhibitory concentrations in pancreatic tissue, However, their prophylactic role in predicted moderately severe or severe AP or in established necrotizing pancreatitis is where significant controversy exists. Most recent guidelines do not recommend prophylactic antibiotics.237 Future studies should have a large enough sample size to see assess the benefit of prophylactic antibiotics in either predicted moderately severe or severe or necrotizing pancreatitis. Particular subsets such as extensive necrosis with or without organ failure should be assessed for possible benefit. 

Urgent ERCP The question of early removal of a possibly impacted gallstone in improving the outcome of gallstone pancreatitis remains a controversial issue. Because the obstruction by a stone at the level of ampulla due to a stone is the main mechanism postulated in acute biliary pancreatitis, it is appealing to remove the stone by ERCP to help the patient recover. ERCP in a patient with biliary pancreatitis can be urgent or elective before cholecystectomy. Urgent ERCP has been variously defined as within 24 hours, 48 hours, or 72 hours. For mild biliary AP, same-admission laparoscopic cholecystectomy is the standard therapy, and before such procedure an elective ERCP or intraoperative cholangiography are the choices. The most recent guidelines recommended urgent ERCP within 72 hours for cholangitis and possibly for persistent biliary obstruction defined by elevated liver tests and/or the presence of a stone in the common bile duct on imaging.9,211 One report suggested that in acute biliary pancreatitis, urgent ERCP within 24 to 48 hours is indicated if the patient has cholangitis, total serum bilirubin >5 mg/dL, clinical deterioration (worsening pain and white cell count and worsening vital signs), or a stone documented in the common bile duct on imaging.293 A recent AGA technical review reported a meta-analysis on 8 RCTs of urgent ERCP in acute biliary pancreatitis, comprising 935 patients.237 This report found no benefit of urgent ERCP in acute biliary pancreatitis with regard to single organ failure or multiple organ failure, infected peripancreatic necrosis, occurrence of necrotizing pancreatitis, or mortality. In the only study available with small number of cholangitis patients, there was no difference with urgent ERCP. Most recent studies try to exclude patients with proven cholangitis, as ERCP is the standard of care in those patients. However, the definition and description of cholangitis varied among the studies, making interpretation difficult. There was a slightly reduced hospital stay with urgent ERCP. Hence one could cautiously conclude that the role of urgent ERCP in acute biliary pancreatitis is probably in those patients with cholangitis. In order to obtain good evidence, the report suggested that future trials should be powered to see if urgent ERCP helps in subgroups like those with cholangitis, documented biliary obstruction, and predicted severe AP with clear definition for all the 3 subgroups. 

Nutrition For decades, keeping patients NPO was the rule in the management of patients with AP. However, fasting adversely affects the gut mucosal barrier and facilitates translocation of bacteria from the lumen of the gut to extraluminal tissues, including the inflamed pancreas, with a resultant increase in morbidity and mortality. Thus the concept of gut rousing by nutrition and not gut resting by fasting became the practice in some centers.277 It

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is a common observation that in mild (or interstitial) pancreatitis, most patients are dismissed from the hospital within 5 days. Two reports in patients with mild disease suggested that early refeeding improved outcome and allowed earlier discharge.294,295 On the other hand, a meta-analysis of 3 studies showed that early refeeding prolonged the hospitalization.296 The question of whether an elevated serum amylase or lipase level should influence the clinician to prolong the time until refeeding has been addressed in one study: 116 patients with AP were fed at the clinician’s discretion, and 21% developed pain on refeeding 250 kcal/day.297 If the serum lipase level was more than 3-fold elevated, clinical relapse rate with refeeding was 39%, compared with 16% in those with a lipase 2-fold risk at 5 years.322 Pancreatic

Abdominal compartment syndrome (ACS) is defined as a sustained intra-abdominal pressure greater than 20 mm Hg (typically determined by a pressure-recording catheter in the urinary bladder) that is associated with the development of organ dysfunction or failure.324 The incidence of ACS in AP may be increasing because of the more widespread use of aggressive IV volume repletion, allowing more fluid to sequestrate into the peritoneum.249 A systematic review found that 38% of patients with AP developed ACS325; 11% of these received percutaneous drainage as initial treatment, and 74% received decompressive laparotomy. ACS is associated with increased morbidity and mortality in AP. Another review suggested that the ACS is an epiphenomenon observed in severe AP patients with organ failure rather than the cause of organ failure.326 

Miscellaneous Complications Pancreatic encephalopathy consists of a variety of central nervous system symptoms occurring in patients with AP, including agitation, hallucinations, confusion, disorientation, and coma. A similar syndrome may be due to alcohol withdrawal, and other causes are possible, such as electrolyte disturbances (e.g., hyponatremia) or hypoxia. Purtsher retinopathy (discrete flame-shaped hemorrhages with cotton wool spots) can cause sudden blindness.181 It is thought to be due to microembolization in the choroidal and retinal arteries. Full references for this chapter can be found on www.expertconsult.com 

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323. Das SL, Singh PP, Phillips AR, et al. Newly diagnosed diabetes mellitus after acute pancreatitis: a systematic review and meta-analysis. Gut 2014;63:818–31. 324. Das SL, Kennedy JI, Murphy R, et al. Relationship between the exocrine and endocrine pancreas after acute pancreatitis. World J Gastroenterol 2014;20:17196–205. 325. Cheatman ML, Malbrain ML, Kirkpatrick A, et al. Results from the international conference of experts on intra-abdominal hypertension and abdominal compartment syndrome II. Recommendations. Intensive Care Med 2007;33:951–62. 326. Van Brunschot S, Schut AJ, Bouwense SA, et al. Abdominal compartment syndrome in acute pancreatitis: a systematic review. Pancreas 2014;43:665–74. 327. Trikudanathan G, Vege SS. Current concepts of the role of abdominal compartment syndrome in acute pancreatitis-an opportunity or merely an epiphenomenon. Pancreatology 2014;14:238–43.

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59

Chronic Pancreatitis Chris E. Forsmark

CHAPTER OUTLINE EPIDEMIOLOGY. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 917 PATHOLOGY. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 918 PATHOPHYSIOLOGY. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 918 ETIOLOGY. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 920 Alcohol. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 920 Tobacco . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 921 Tropical Pancreatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 921 Genetic. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 921 Autoimmune Pancreatitis. . . . . . . . . . . . . . . . . . . . . . . . 921 Obstructive. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 926 Miscellaneous. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 926 Idiopathic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 927 CLINICAL FEATURES. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 927 Abdominal Pain. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 927 Steatorrhea (Exocrine Pancreatic Insufficiency). . . . . . . . 929 Diabetes Mellitus (Pancreatic Endocrine Insufficiency). . . 929 PHYSICAL EXAMINATION . . . . . . . . . . . . . . . . . . . . . . . . . 930

DIAGNOSIS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 930 Tests of Pancreatic Function . . . . . . . . . . . . . . . . . . . . . . 931 Tests of Pancreatic Structure (Imaging). . . . . . . . . . . . . . 932 DIAGNOSTIC STRATEGY . . . . . . . . . . . . . . . . . . . . . . . . . . 936 TREATMENT. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 936 Abdominal Pain. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 936 Maldigestion and Steatorrhea . . . . . . . . . . . . . . . . . . . . . 941 Diabetes Mellitus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 942 COMPLICATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 942 Pseudocyst. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 942 GI Bleeding. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 943 Pseudoaneurysm. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 943 Variceal Bleeding From Splenic Vein Thrombosis. . . . . . . 944 Bile Duct Obstruction. . . . . . . . . . . . . . . . . . . . . . . . . . . . 944 Duodenal Obstruction . . . . . . . . . . . . . . . . . . . . . . . . . . . 945 Pancreatic Fistulas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 945 Malignancy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 945 Dysmotility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 946

Chronic pancreatitis is a syndrome, encompassing a spectrum of conditions which culminate in a similar phenotype. The traditional definition of chronic pancreatitis has been based on histology, demonstrating chronic and irreversible damage to the pancreas. Chronic inflammation, fibrosis, and eventual destruction of ductal, exocrine (acinar cell), and endocrine (islets of Langerhans) tissue (Fig. 59.1) characterize the histology of chronic pancreatitis, producing varying degrees of symptoms and structural and functional derangements of the gland. This definition, using histologic criteria, is of very limited clinical value. Pancreatic tissue is rarely available to clinicians. Some patients may have histologic evidence of chronic pancreatitis, and yet have no symptoms or complications from the disease. In addition, the histologic features of chronic pancreatitis are often focal, such that a small biopsy, even if available, might miss the disease. Finally, the histologic features that are seen in chronic pancreatitis are not unique, and may be seen in other conditions (such as normal aging, social use of alcohol, smoking, longstanding diabetes, and others). Chronic pancreatitis may also be defined based on clinical features (abdominal pain, exocrine insufficiency [steatorrhea], or endocrine insufficiency [diabetes mellitus]) or on imaging techniques including US, CT, EUS, MRI, MRCP, and ERCP. Defining chronic pancreatitis on the basis of imaging studies is also imperfect, because the morphologic changes detected by these modalities may take years to develop. Indeed, many of the findings of these imaging studies can be normal or near normal early in the clinical course. Early diagnosis of chronic pancreatitis, at a time when some effective therapy might be administered, is therefore often difficult or impossible.1 Diagnostic criteria that rely on imaging findings are a mixture of diagnostic and staging criteria, determining both

presence and severity of disease. These staging systems also tend to lump together all etiologies, thereby obscuring differences that might be important to clinicians. These definitions have also made an implicit assumption, that acute pancreatitis and chronic pancreatitis are entirely separate entities, when in fact there is now abundant evidence documenting the evolution in many patients from acute to chronic pancreatitis (see Chapter 58). In modern paradigms of pathogenesis, acute pancreatitis is a necessary first step to developing chronic pancreatitis. It is most accurate to think of the 2 conditions as separate ends of the same spectrum; acute pancreatitis is an event, whereas chronic pancreatitis is an ongoing process of variable tempo and outcome. Chronic pancreatitis is best defined as a syndrome, recognizing the importance of etiology, the difficulty of obtaining pancreatic tissue, and the lack of sensitivity of currently available diagnostic tools.1,2 The syndrome is characterized by a constellation of features including exposure to known risk factors, genetic background, symptoms, derangements in pancreatic exocrine or endocrine function, structural changes visible on imaging studies, and, if available, histology. The features may vary from patient to patient, and like all syndromes the presence of just one feature is often insufficient for diagnosis.

EPIDEMIOLOGY Chronic pancreatitis can be demonstrated in up to 5% of autopsies.3,4 Similar, though less pronounced, histologic features are seen even more commonly.5,6 Determining the prevalence of chronic pancreatitis from this type of autopsy data is misleading because these individuals may not have had clinical symptoms of

917

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PART VII  Pancreas

chronic pancreatitis is influenced by the presence of tobacco and alcohol abuse.14,17 In one large multicenter study, the standardized mortality ratio was 3.6:1 (i.e., those with a diagnosis of any form of chronic pancreatitis died at 3.6 times the rate of agematched controls), and older subjects, those who smoked, and those with alcoholic chronic pancreatitis had the most significant reduction in survival.31 Continuing alcohol use raised mortality risk by an additional 60%. Similar rates of increased mortality have been observed in other studies.17,32 Overall, 10-year survival in patients with chronic pancreatitis is about 70%, and 20-year survival about 45%. The cause of death in patients with chronic pancreatitis usually is not the pancreatitis itself but other medical conditions commonly associated with smoking, continued alcohol abuse, pancreatic carcinoma, and postoperative complications.14,32 

PATHOLOGY Fig. 59.1  Histology of chronic pancreatitis. Note the destruction of acinar tissue with replacement by extensive fibrosis and relative sparing of pancreatic islets. (Hematoxylin and eosin.)

chronic pancreatitis during life. Long-standing alcohol use, even in moderate amounts, can lead to histologic changes of chronic pancreatitis without symptoms or clinical features of chronic pancreatitis.7-9 Similarly, aging, smoking, chronic kidney disease, and long-standing diabetes mellitus can induce histologic changes within the pancreas that are difficult to distinguish from those of chronic pancreatitis.5,6,10 Making a diagnosis solely on the basis of histology or autopsy data will therefore overestimate the rate of clinically significant chronic pancreatitis. Estimates of annual incidence of chronic pancreatitis in several retrospective studies range from 5 to 12 cases per 100,000 population.11-16 In the USA, the incidence rate is approximately 5 to 8/100,000,14,17,18 and appears to be increasing over time. The prevalence of chronic pancreatitis is about 50/100,000.14-20 In most studies, alcohol abuse accounts for one-half or more of all cases of chronic pancreatitis.14 These epidemiologic data demonstrate substantial geographic variation.14,18,20 The variation may partly be due to differences in alcohol consumption in different populations, but another part of the variation in incidence rates may merely reflect different diagnostic approaches and different diagnostic criteria. Chronic pancreatitis is more common in men and is most commonly a disease of middle age, with most patients diagnosed above the age of 40.14-17 Chronic pancreatitis accounts for substantial morbidity and health care costs. Approximately 26,000 hospital admissions to non-federal hospitals with a first-listed diagnosis of chronic pancreatitis occur yearly; in more than 80,000 yearly admissions, chronic pancreatitis is listed as one of the discharge diagnoses.14,19,21-24 The prognosis of chronic pancreatitis is variable and is driven largely by the presence of ongoing alcoholism in persons with chronic alcoholic pancreatitis and equally by concomitant tobacco use.14,17,19 One can estimate prognosis from such features as need for medical care or hospitalization or from the development of complications, reduced quality of life, or mortality. Data on the quality of life of patients with chronic pancreatitis25-30 document that the presence of abdominal pain and consequences of ongoing alcohol abuse (in those with alcoholic chronic pancreatitis) are the dominant negative influences on quality of life and that, not surprisingly, quality of life is substantially worse for such patients than for the general population.30 Pain is a dominant cause of reduced quality of life, and continuous pain, even if of lesser severity than episodic pain, is associated with the greatest negative impact.29,30 Mortality in patients with

The different etiologies of chronic pancreatitis usually produce similar pathologic findings (see Fig. 59.1), particularly as the disease progresses. In early chronic pancreatitis the damage is varying and uneven. Areas of interlobular fibrosis are seen, with the fibrosis often extending to the ductal structures. Infiltration of the fibrotic area and lobules with lymphocytes, plasma cells, mast cells, and macrophages is seen.33,34 The ducts may contain eosinophilic protein plugs. In affected lobules, acinar cells are surrounded and replaced by fibrosis. The islets are usually less severely damaged until very late in the course of the disease. Features of acute pancreatitis also may be seen, such as edema, acute inflammation, and acinar cell or fat necrosis. As the disease progresses, fibrosis within the lobules and between lobules becomes more widespread. The pancreatic ducts become more abnormal with progressive fibrosis, stricture formation, and dilation. The ductal protein plugs may calcify and obstruct major pancreatic ducts. Ductal epithelium may become cuboidal, may develop atrophy or squamous metaplasia, or may be replaced by fibrosis entirely. Activated pancreatic stellate cells may be identified in close association with fibrosis. These histologic features are found in most forms of longstanding chronic pancreatitis. Many of these changes, in particular perilobular fibrosis and ductal metaplasia, are also commonly seen in patients of advanced age without chronic pancreatitis, and in patients with long-standing diabetes mellitus.5,6,10 Obstructive chronic pancreatitis (associated with obstruction of the main pancreatic duct by a tumor or stricture) can differ slightly, in that the histologic changes are limited to the gland upstream of the obstruction and protein precipitates and intraductal stones are not usually seen.34 Autoimmune chronic pancreatitis can demonstrate 2 unique histological patterns.35-38 In one form (Type 1) a more robust lymphoplasmacytic infiltrate, including plasma cells, is seen and these are usually positive when stained for immunoglobulin G subtype 4 (IgG4). Obstructive phlebitis affecting the major and minor veins and a whorled (storiform) fibrosis pattern are also characteristic, a pattern termed lymphoplasmacytic sclerosing pancreatitis. Type 1 autoimmune pancreatitis (AIP) is considered a manifestation of IgG4-related disease.39 A second pattern (Type 2) termed idiopathic duct-centric chronic pancreatitis is characterized by neutrophilic infiltration and the absence of IgG4 positive plasma cells.37 With time, the pattern may assume a more end-stage chronic pancreatitis appearance and become indistinguishable from other forms of chronic pancreatitis. 

PATHOPHYSIOLOGY The pathophysiology of chronic pancreatitis remains incompletely understood. The pathophysiologic processes must ultimately account for the features of chronic pancreatitis, including

CHAPTER 59  Chronic Pancreatitis

loss of parenchymal cells, self-sustaining chronic inflammation, and fibrosis. Any proposed mechanism must therefore include explanations for cellular necrosis or apoptosis, initiation and maintenance of inflammatory cell activation, and fibrogenesis by pancreatic stellate cells.2 The pancreas, like all other organs, has a limited repertoire of responses to injury and although it is not likely that all of the various etiologies share a similar pathophysiology, the end histologic result is similar. The study of mechanisms of disease is hampered by the difficulty of obtaining tissue in humans and the relative lack of animal models of chronic pancreatitis, as opposed to acute pancreatitis.40 Alcoholic chronic pancreatitis has been most extensively studied.41-44 No single theory explains adequately why less than 5% of heavy alcohol users develop chronic pancreatitis.14,45 Genetic differences may certainly play an important role (Chapter 57). Alcohol is metabolized by the liver and the pancreas. In the liver the main end product of oxidative alcohol metabolism is acetaldehyde. In the pancreas, an alternative pathway produces fatty acid ethanol esters (FAEEs). Alcohol and its metabolites like FAEE have direct injurious effects on pancreatic acinar cells. Increased membrane lipid peroxidation, a marker of oxidative stress and free radical production, can be seen in animal models and human alcoholic chronic pancreatitis. In addition FAEEs are able to induce sustained elevations in cytosolic calcium in acinar cells, a mechanism shared by other experimental causes of pancreatitis.40 Alcohol may also lead to pathologic increases in acinar cell sensitivity to physiologic stimuli such as cholecystokinin (CCK),40 or to other pathologic exposures such as smoking.45,46 The interaction of smoking and alcohol exposure is an increasingly recognized risk factor for chronic pancreatitis.14,45 Chronic alcohol ingestion in animal models also alters expression of multiple genes in acinar cells, which could increase the sensitivity to physiologic stress and up-regulate the expression and activity of enzymes involved in cell death. Alcohol can promote the inflammatory responses involved in pancreatitis.41-42 These multiple effects of alcohol on the acinar cell are complemented by alcohol injury to ductal cells. Finally, alcohol and its metabolites appear to stimulate the pancreatic stellate cell.41,45,47-49 These cells, as in the liver, appear to be the final common pathway for fibrosis.48,49 Pancreatic stellate cells are found in association with the acini. They are typically found in the periacinar space, with long cytoplasmic processes extending to the acini themselves, but are also present in smaller numbers in association with blood vessels and ducts. Quiescent pancreatic stellate cells are recognized by the presence of vitamin A lipid droplets in the cytoplasm. When activated, they assume a stellate or myofibroblastic appearance, express smooth muscle actin, and lose the lipid droplets. This activation is necessary for the cell to begin to secrete extracellular matrix and produce fibrosis within the gland. Activation of pancreatic stellate cells can occur by alcohol or one of its metabolites, but also occurs in response to both inflammatory cytokines that are released following pancreatic acinar cell necrosis and to reactive oxygen species.47-49 In addition, growth factors (platelet-derived growth factor, transforming growth factor-β1), hormones, intracellular signaling molecules, transcription factors, and angiotensin II can activate pancreatic stellate cells. Activated pancreatic stellate cells are found in areas of extensive necrosis and inflammation in acute pancreatitis, in human as well as animal tissues. These activated pancreatic stellate cells produce autocrine factors that maintain the activated phenotype. In addition to their role in secretion and modulation of the extracellular matrix, pancreatic stellate cells can proliferate in response to stimulation, migrate to areas of inflammation, and participate in phagocytosis. Activation of pancreatic stellate cells is likely occurring through multiple mechanisms in alcoholic (and other forms of) chronic pancreatitis. Chronic alcohol ingestion may produce chronic pancreatitis by additional mechanisms. Longtime alcohol use leads

919

to the secretion of a pancreatic juice rich in protein and low in volume and bicarbonate. These characteristics favor the formation of protein precipitates, which are present early in the evolution of alcoholic chronic pancreatitis. These precipitates may calcify, leading to the formation of pancreatic ductal stones and producing further ductal and parenchymal injury upstream from these stones. In most patients, however, these protein precipitates and ductal stones do not appear to cause the initial pancreatic injury but may facilitate disease progression. There have been several hypotheses for the pathophysiology of chronic pancreatitis that attempt to interweave these observations into a coherent paradigm. One hypothesis focuses on the concept that ductal obstruction (from strictures or stones) is the cause rather than the effect of chronic pancreatitis. This hypothesis, the ductal obstruction hypothesis, is not consistent with most clinical and experimental evidence and with few exceptions (such as the rare condition of obstructive chronic pancreatitis) is not applicable to human chronic pancreatitis. A second paradigm, the toxic-metabolic hypothesis, focuses primarily on the role of alcohol and its metabolites (or smoking or other toxins) and their ability to damage the pancreas and activate pancreatic stellate cells. A third model that has been proposed is the necrosis-fibrosis hypothesis, which holds that the occurrence of repeated or severe episodes of acute pancreatitis with cellular necrosis or apoptosis eventually leads to the development of chronic pancreatitis as the healing process replaces necrotic tissue with fibrosis. This last hypothesis has significant supporting evidence from some natural history studies that document the more common development of chronic pancreatitis in patients with more severe and more frequent acute attacks of alcoholic pancreatitis.50-53 The concept that multiple clinical or subclinical attacks of acute pancreatitis lead to chronic pancreatitis is certainly being reinforced by observations in both animal models40 and in humans.1,2 It is not clear why only a small subset (10 cells/HPF) IgG4-positive cells Fibroinflammatory process may extend to peripancreatic region

Lymphoplasmacytic and neutrophilic infiltration around ducts Destruction of duct epithelium by neutrophils (granulocytic epithelial lesion) Obliterative phlebitis rare No IgG4-positive cells

Average age at presentation

60-70 years

40-50, but may present in young adults and even children

Gender predominance

Male

Equal

Usual clinical presentations

Obstructive jaundice (75%) Acute pancreatitis (15%)

Obstructive jaundice (50%) Acute pancreatitis (33%)

Pancreatic imaging

Diffuse pancreatic enlargement (40%) Focal pancreatic enlargement (60%)

Diffuse pancreatic enlargement (15%) Focal pancreatic enlargement (85%)

IgG4

Elevated in serum (≈2⁄3 of patients) Positive in staining of involved tissues

Not associated

Other organ involvement

Biliary strictures Sialoadenitis Retroperitoneal fibrosis Pseudotumors Kidney Lung Others

Not associated

Associated diseases Long-term outcome

IBD Frequent relapses

Rare or no relapse

Ig, Immunoglobulin G.

is densely infiltrated with immune cells including plasma cells and CD4-positive T-cells. In Type 1 AIP, many of these plasma cells (Fig. 59.2A) express IgG4 on their surface. Elevations in serum levels of IgG-4 can also be seen in many patients with Type 1 AIP. IgG-4 is unable to crosslink antigens and does not activate the classical complement cascade, and no specific target of the IgG-4 has been consistently identified. It is not clear that the IgG-4 is involved in the pathogenesis of disease, and some data suggest it may be anti-inflammatory in patients with AIP and the related condition of IgG4-related disease.105 Experimental evidence suggests a complex mechanism involving both humoral and cellular immunity.35,39,103 Fibrosis, sclerosis, and obliterative phlebitis are characteristically seen in the pancreas in association with the dense chronic inflammatory infiltrate in Type 1 AIP.35-38 Although this inflammatory infiltrate is present in the pancreas, similar infiltrates may be seen in the bile duct, salivary glands, retroperitoneum, lymph nodes, kidney, prostate, ampulla, and occasionally organs.39,103,106-108 More than 10 IgG4-positive plasma cells per high power field in biopsy specimens of the pancreas is consistent with the diagnosis of Type 1 AIP,36-38,103,108 but this number varies depending on the organ that is biopsied. The fibrosis is usually storiform, or present in a whirling pattern resembling the spokes of a wheel. Venous channels are obliterated by the dense inflammatory infiltrate. This pattern has been termed lymphoplasmacytic sclerosing pancreatitis. Type 1 AIP may occur in an isolated pancreatic form but is more commonly associated with extra-pancreatic manifestations, in a condition termed IgG4-related disease (Figs. 59.2 and 59.3).39,103,106-108 The most common extra-pancreatic conditions identified include biliary strictures, hilar lymphadenopathy, sclerosing sialadenitis, retroperitoneal fibrosis, and tubulointerstitial

nephritis.107,108 Biopsies of these organs will reveal a similar inflammatory infiltrated rich in IgG4-positive plasma cells. Involvement of other organs occurs in at least 60% of patients with Type 1 AIP103,107,108 and may occur before, after, or at the same time as the pancreatic disease. A number of conditions are now included as a manifestation of IgG4-related disease including Mikulicz syndrome (in which a massive IgG4-positive mononuclear infiltrate is seen in the salivary and lacrimal glands), Küttner tumor (submandibular glands), Riedel thyroiditis, eosinophilic angiocentric fibrosis (orbits and upper respiratory tract), multifocal fibrosclerosis, inflammatory pseudotumors, mediastinal and retroperitoneal fibrosis, periaortitis, inflammatory aortic aneurysm, and idiopathic hypocomplementemic tubulointerstitial nephritis.39,106-108 A second form of AIP, termed Type 2, is characterized by a different histologic pattern termed idiopathic duct centric pancreatitis. Type 2 AIP is more common in western countries but even here is less common than Type 1, accounting for less than 20% of all cases of AIP.103 Type 2 AIP demonstrates neutrophilic infiltration in the pancreas with microabscesses (granulocyte-­epithelial lesions), and obliterative phlebitis is rare(Table 59.1).36,37 Type 2 AIP is limited to the pancreas and is not associated with an infiltration of IgG4positive plasma cells in the pancreas nor with elevations in serum levels of IgG4. Type 2 AIP may however be seen in association with underlying IBD (15% to 30% of patients with Type 2 AIP). Type 1 AIP is seen more commonly in men (2:1) and usually manifests in middle age or beyond.39,103 More than 85% of patients present after the age of 50 years and the mean age of presentation is 70. Type 2 AIP presents at a younger age and may even present in young adults and children. The most common initial presentation for both forms of AIP is painless obstructive jaundice due to obstruction of the intrapancreatic bile duct

CHAPTER 59  Chronic Pancreatitis

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A

B

C

D Fig. 59.2  Autoimmune pancreatitis. A, Histopathology of a pancreatic resection specimen demonstrating a robust lymphoplasmacytic infiltrate involving the larger pancreatic ducts. (Hematoxylin and eosin.) B, Cholangiogram demonstrating a smooth stricture involving the intrapancreatic portion of the bile duct. C, CT shows a dilated pancreatic duct without pancreatic parenchymal atrophy. D, Pancreatogram reveals a moderately dilated pancreatic duct with diffuse areas of irregularity and alternating areas of stenosis and dilatation. There is an area of more dominant stricture in the pancreatic head. (Courtesy of C. Mel Wilcox, MD, Birmingham, AL.)

(see Fig. 59.2B). Jaundice may occur from compression of the bile duct by the enlarged pancreas or by infiltration of the biliary tree (IgG4 cholangitis). A less common initial presentation is acute pancreatitis, and this is most common in those with Type 2 AIP. Additional symptoms may include weight loss, vomiting, and glucose intolerance. Although pain is not frequently present, abdominal and referred back pain may occur. These clinical features, coupled with imaging studies demonstrating diffuse or focal pancreatic enlargement (see Fig. 59.2C), often raise the suspicion of pancreatic adenocarcinoma. In studies in patients who underwent pancreatic resection for presumed pancreatic carcinoma but were found to have no malignancy in the resected specimen, up to 10% show evidence of AIP.109,110 In Type 1 AIP, jaundice or cholestasis may also occur due to additional strictures of the proximal biliary tree. A pattern similar to that seen in PSC is seen, with a predilection for involvement of the hilar region. The pattern may mimic not only PSC but also cholangiocarcinoma. The disease, unlike classic PSC, is not typically associated with inflammatory bowel disease and is steroid-responsive. Additional common clinical manifestations of Type 1 AIP include a sclerosing sialadenitis (usually presenting as bilateral symmetrical swelling

of the salivary glands), retroperitoneal fibrosis (most commonly presenting as hydronephrosis due to entrapment of the ureters), renal mass, tubulointerstitial nephritis, lymphadenopathy (particularly mediastinal, cervical, and abdominal), prostatitis, sclerosing cholecystitis, interstitial pneumonia, and pseudotumors of the liver, lung, prostate, and pituitary.103,108 The radiographic features of the pancreas are similar for Type 1 and Type 2 AIP. Abdominal US usually shows a diffusely enlarged and hypoechoic pancreas. The appearance on EUS is similar. CT most commonly reveals a diffusely enlarged sausageshaped pancreas (see Fig. 59.2C) in which enhancement with the intravenous contrast agent is delayed and prolonged35,38,103,109,111 some patients may have a capsule-like low-density rim around the pancreas in delayed images. Focal swelling can also occur, mimicking a pancreatic mass. Additional CT findings, such as contiguous fibrosis and inflammation extending into the retroperitoneum or surrounding the retroperitoneal vessels, can also raise a suspicion of carcinoma. MRI of the pancreas also may reveal this diffuse pancreatic enlargement, typically with decreased T1-weighted intensity and increased T2-weighted intensity.103,111 MRCP can be very helpful in identifying the

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PART VII  Pancreas

A

B

C

D Fig. 59.3  Lymphoplasmacytic sclerosing pancreatitis, the most common form of autoimmune pancreatitis. A, Cuff-like periductal lymphoplasmacytic infiltration with normal surrounding pancreatic parenchyma. (Hematoxylin and eosin, ×20.) B, Prominent periductal infiltrate. (Hematoxylin and eosin, ×200.) C, Plasma cell-rich, mixed infiltrate around bile ducts. (Hematoxylin and eosin, ×200.) D, Another example of a cuff-like infiltrate with periductal fibrosis. (Hematoxylin and eosin, ×20.) (Courtesy Dr. Pamela Jensen, Dallas, TX.)

biliary strictures and in visualizing the pancreatic duct, which is also abnormal in AIP.38,108,111,112 EUS may demonstrate a diffusely enlarged and hypoechoic gland.113 The use of EUS-guided fine-needle aspiration of the gland is usually not diagnostic,114 although there are case-reports of EUS-guided core biopsy being diagnostic.115 One of the hallmarks of both types of AIP is diffuse or segmental irregularity and narrowing of the pancreatic duct (see Fig. 59.2D). The duct may be diffusely narrowed and thread-like, or may instead demonstrate alternating areas of stricture and normal caliber or dilated duct.38,103,111,116 MRCP is often able to identify the pancreatic duct abnormalities but may not be able to visualize the duct if it is thread-like and diffusely affected. ERCP is better able to visualize the pancreatic duct,116 but carries more risk and cost than MRCP. Some patients may have a more focal segmental or isolated area of pancreatic duct narrowing, in a pattern more suggestive of malignancy. Some studies in which a second ERCP has been performed note progression from a segmental form to diffuse form in the absence of glucocorticoid treatment. With time, and particularly in those with untreated or relapsing disease, the disease may burn out and lead to pancreatic gland atrophy and calcification. At that point, it is indistinguishable from other forms of chronic pancreatitis. Studies from Japan note that up to 6% of all patients evaluated for chronic pancreatitis have AIP, and the overall prevalence is estimated to be 4.6 per 100,000 persons.39,117 Very few other epidemiologic estimates exist.

The disease is usually suspected based on clinical and imaging features. In Type 1 AIP, laboratory evaluation may reveal elevations in serum immunoglobulins, seen in one half to two thirds of cases, especially in IgG4. Although various cut-offs have been used, current consensus diagnostic guidelines use levels of IgG4 more than 2 times the upper limit of normal.38,103 Elevation in serum IgG4 is not specific for AIP and may also be seen in occasional patients with pancreatic adenocarcinoma. A variety of other autoantibodies have also been reported, including antinuclear antibodies, anti-lactoferrin antibodies, anti-carbonic anhydrase II antibodies, anti-smooth muscle antibodies, rheumatoid factor, and antimitochondrial antibody. These autoantibodies do not have the sensitivity of IgG4 and hence are inferior for diagnostic purposes. These serologic markers of disease are absent in those with Type 2 AIP. There are several systems for diagnosis of Type 1 AIP. An international consensus conference developed criteria which are now widely used across the world.38 The proposed international consensus criteria are included in Table 59.1. They use 5 criteria including imaging of the pancreas and pancreatic duct, serology, other organ involvement, histology (if available), and response to steroid trial. This system allows patients to be categorized as definitive or probable Type 1 AIP, depending on the mix of criteria present. It should be noted that whereas Type 1 AIP can be diagnosed with reasonable accuracy without a pancreatic biopsy, the diagnosis of Type 2 AIP almost always requires

CHAPTER 59  Chronic Pancreatitis

925

TABLE 59.1  International Consensus Diagnostic Criteria for Type 1 Autoimmune Pancreatitis Criteria

Level 1 Evidence

Level 2 Evidence

P: Parenchymal imaging

Typical imaging: Diffuse enlargement of pancreas with delayed enhancement With or without rim-like enhancement or pancreas

Indeterminate imaging: Segmental or focal enlargement of pancreas With delayed enhancement

D: Ductal imaging (ERCP or MRCP) Long (>1⁄3 of the length of pancreatic duct) stricture, or Multiple strictures without upstream dilation of pancreatic duct

Segmental or focal narrowing of pancreatic duct Without marked (>5 mm) upstream dilation of pancreatic duct

S: Serology

IgG4 >2 × upper limit of normal

IgG4 1-2 × upper limit of normal

OOI: Other organ involvement

Histology of extrapancreatic organ involvement (at least 3 of 4 below) Marked lymphoplasmacytic infiltration with fibrosis Storiform fibrosis Obliterative phlebitis Abundant IgG4-positive cells OR Imaging evidence of extrapancreatic organ ­involvement (any) Segmental/multiple proximal or proximal and distal bile duct strictures Retroperitoneal fibrosis

Histology of extrapancreatic organ involvement, including bile duct or ampullary biopsies Marked lymphoplasmacytic infiltration and Abundant IgG4-positive cells OR Physical or radiologic evidence Symmetrically enlarged salivary or lacrimal glands Renal involvement consistent with AIP

H: Histology of pancreas

Lymphoplasmacytic sclerosing pancreatitis on core biopsy or resection specimen (at least 3) Periductal lymphoplasmacytic infiltrate without granulocytic infiltration Obliterative phlebitis Storiform fibrosis Abundant (>10 cells/HPF) IgG4-positive cells

Lymphoplasmacytic sclerosing pancreatitis on core biopsy (at least 2) Periductal lymphoplasmacytic infiltrate without granulocytic infiltration Obliterative phlebitis Storiform fibrosis Abundant (>10 cells/HPF) IgG4-positive cells

Rt: Response to steroids

Rapid (2 wk) radiologically demonstrable resolution or marked improvement in pancreatic/extrapancreatic manifestations

Diagnosis

Primary Basis of Diagnosis

Imaging Evidence

Definitive type 1 AIP

Histology Imaging

Typical/indeterminate Typical Indeterminate Indeterminate

Response to steroids Probable Type 1 AIP

Indeterminate

Collateral Evidence Any non-D level 1/level 2 Two or more from level 1 Level 1 S/OOI or level 1 D +level 2 S/ OOI/H Level 2 S/OOI/H + Rt

  

The diagnosis of Type 2 AIP requires typical imaging with either histologic confirmation or both the presence of IBD and a response to steroids. AIP, Autoimmune pancreatitis; IgG4, immunoglobulin G subtype 4. From Chari ST, Kloeppel G, Zhang L, et al. Histopathologic and clinical subtypes of autoimmune pancreatitis: the Honolulu consensus document. Pancreatology 2010; 10:664–72; Shimosegawa T, Chari ST, Frulloni L, et al. International consensus diagnostic criteria for autoimmune pancreatitis: Guidelines of the International Association of Pancreatology. Pancreatology 2011; 40:352–8.   

pancreatic biopsy or resection. Making an accurate diagnosis of AIP requires that it be differentiated from pancreatic cancer.109,110,118-120 This is particularly important, as pancreatic cancer is far more common than AIP. Features which are especially concerning for malignancy include a dilated pancreatic duct, a single high-grade pancreatic duct stricture with upstream atrophy of the gland, or a low-density focal mass on CT imaging. These imaging features are unfortunately not highly sensitive and specific, and making the distinction between AIP and pancreatic cancer may require a pancreatic core biopsy, a trial of steroids, or a pancreatic resection. Prior to initiating a trial of glucocorticoid therapy, vigorous efforts should be made to exclude malignancy. In some cases this is not possible, and some possibility of underlying malignancy may remain. A typical scenario might be a middle-aged man with obstructive jaundice and an enlargement of the pancreatic head, in whom ERCP and EUS with tissue sampling have been inconclusive. In this setting, there may be concern in delaying the ultimate diagnosis of malignancy for a therapeutic trial of glucocorticoids. Response to glucocorticoid therapy, however, is usually obvious within 2 to 4 weeks and such a trial is not unreasonable if follow-up is close.

Autoimmune chronic pancreatitis may progress rapidly, from the initial symptoms to end-stage chronic pancreatitis, within months. There is some evidence that early therapy with glucocorticoids may prevent subsequent disease complications.103,121 Glucocorticoid therapy usually produces rather dramatic improvement with rapid resolution of both symptoms and radiographic abnormalities. There are no clear recommendations for glucocorticoid dose, although 0.6 to 1 mg/kg has been suggested. 103,108,121 A common starting dose is 40 mg of prednisone daily. Repeat pancreatic imaging at 2 to 4 weeks is prudent, to assess for clinical and radiographic response. Once a response is clear-cut (usually by 4 weeks), tapering of the prednisone dose at a rate of 5 to 10 mg/week is typical, for a total treatment duration of 10 to 12 weeks. Complete serologic response (normalization of serum IgG4) may not be apparent for several months, although decreases may be seen within 4 weeks. Between 30% and 50% of patients with Type 1 AIP experience a relapse after glucocorticoid therapy.103,121 Relapse usually involves recurrent biliary obstruction with cholestatic liver chemistries or frank jaundice. Patients with Type 2 AIP relapse very rarely, if at all. Relapse in Type 1 AIP may be managed by a repeat course of glucocorticoids followed by maintenance at a low dose of prednisone (e.g., 5 to 10 mg/day).

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Immunomodulators, such as azathioprine, have been used with variable success in steroid-dependent patients to allow steroids to be tapered and stopped.121 In those that relapse on azathioprine or in those who cannot tolerate it, continuing the steroids is effective and Rituximab may be used in especially refractory cases.103,108,121 Glucocorticoid therapy may improve not only the structural abnormalities of the pancreas but also exocrine and endocrine pancreatic function (and salivary function if it is affected). Improvement in function is variable, depending on the level of fibrosis and atrophy already established when therapy is initiated. Clinical relapses after resection (e.g., pancreaticoduodenectomy) are rare. 

Obstructive Chronic obstruction of the main pancreatic duct by tumors, scars, ductal stones, duodenal wall cysts, or stenosis of the papilla of Vater or the minor papilla can produce chronic pancreatitis in the parenchyma upstream of the obstruction. Obstruction of the pancreatic ducts may also be an important contributor to other forms of chronic pancreatitis (i.e., obstruction of small or large ductal branches by protein precipitates in alcohol-induced chronic pancreatitis). Obstructive chronic pancreatitis, however, refers to a distinct entity produced by a (generally) single dominant narrowing or stricture of the main pancreatic duct. A number of entities can produce obstructive chronic pancreatitis. Acquired strictures of the main pancreatic duct can occur as a consequence of tumor obstruction from adenocarcinoma, islet cell tumor, intraductal papillary mucinous tumors, or ampullary neoplasms (see Chapter 60). Benign strictures may also develop after a severe attack of acute pancreatitis, particularly an episode associated with significant pancreatic necrosis (see Chapter 58). Blunt and penetrating trauma to the pancreas can lead to pancreatic duct strictures, most commonly in the midbody of the gland where the duct crosses the spine. Each of these processes can be associated with chronic pancreatitis in the gland upstream from the obstruction. The pathology in obstructive chronic pancreatitis is one of diffuse interlobular and intralobular fibrosis, usually equally and symmetrically distributed in the affected region. Pancreas divisum is a common normal variant, occurring in approximately 4% to 11% of the population (see Chapter 55). In rare patients with this anomaly, the minor papilla may be inadequate to allow free flow of pancreatic juice into the duodenum, possibly causing acute episodes of pancreatitis. Pancreas divisum is not considered a primary cause of chronic pancreatitis. Large natural history studies have failed to identify a clear link between pancreas divisum and either acute or chronic pancreatitis. Patients with pancreas divisum who do develop pancreatic disease often have coexistent underlying genetic mutations that may explain the pancreatitis, rather than the effect of divisum.122,123 Dysfunction of the sphincter of Oddi, like pancreas divisum, is most often proposed as a cause of acute or recurrent acute pancreatitis rather than chronic pancreatitis. The response to sphincter ablation in patients with chronic pancreatitis and presumed sphincter of Oddi dysfunction or pancreas divisum is unpredictable, but generally poor. Surgical textbooks have long cautioned against sphincteroplasty as sole therapy for chronic pancreatitis, recognition of the general lack of efficacy of sphincter ablation in this situation. 

Miscellaneous Recurrent or Severe Acute Pancreatitis Chronic pancreatitis can develop after a severe attack of acute pancreatitis, usually with associated pancreatic necrosis, or the need for debridement. Recurrent milder episodes of acute pancreatitis of any etiology may also eventually lead to the development of a chronic inflammatory response within the pancreas,

the activation of pancreatic stellate cells, and chronic pancreatitis. One example of this is hypertriglyceridemia. Elevations of serum triglyceride values greater than 1000 mg/dL can produce acute pancreatitis, which is often severe. Many of these patients will have repeated clinical and subclinical attacks of acute inflammation, and some will ultimately develop chronic pancreatitis.124,125 It appears that after an initial attack of acute pancreatitis, around 10% of patients will be diagnosed with chronic pancreatitis.14,52 Predictors of chronic pancreatitis include multiple relapsing attacks, smoking, and alcohol use.14,50-53 In patients with any etiology of severe acute pancreatitis complicated by substantial pancreatic necrosis, features of chronic pancreatitis may also develop (see Chapter 58).14,126-129 Of note pancreatic exocrine and endocrine insufficiency may develop even more commonly. Around 25% of patients will develop pancreatic exocrine insufficiency after an attack of acute pancreatitis, with alcohol etiology and severe and necrotizing pancreatitis being the major predictors.129 Diabetes mellitus or prediabetes develops in around one third of patients after an attack of acute pancreatitis, although the risk factors for this are not as well established as for exocrine pancreatic insufficiency.130 Taken together these data suggest a higher rate of subsequent chronic pancreatitis after acute pancreatitis than is commonly appreciated. Chronic pancreatitis, including exocrine and endocrine insufficiency, can develop after significant pancreatic necrosis and especially in those undergoing necrosectomy. In one study, patients with necrotizing biliary pancreatitis who did not undergo necrosectomy had exocrine insufficiency and endocrine insufficiency less commonly than those who did (13% vs. 58% and 26% vs. 75%, respectively, for exocrine and endocrine insufficiency).126 Thus, even in the absence of necrosectomy, severe necrotizing pancreatitis may lead to chronic pancreatitis and to exocrine and endocrine insufficiency. Persistent decreases in pancreatic function testing may be seen in up to 80% of patients after recovery from necrotizing pancreatitis.126 Residual strictures of the pancreatic duct are also not uncommon after severe acute pancreatitis, and they may also contribute to the development of chronic pancreatitis in glands upstream from the stricture. In others, a prolonged and smoldering clinical course ultimately leads to chronic pancreatitis. 

Asymptomatic Pancreatic Fibrosis There are several situations in which histologic evidence of chronic pancreatitis, and specifically fibrosis, may be seen in the absence of clinical chronic pancreatitis. Older adults may develop histologic changes within the pancreas that resemble chronic pancreatitis.3-6 ERCP may also demonstrate changes in the pancreatic duct consistent with chronic pancreatitis in these patients.131,132 These structural changes do not usually correspond to functional disturbances of pancreatic function or to clinical features of chronic pancreatitis.132 Chronic alcohol users who do not have clinical chronic pancreatitis commonly have histologic evidence of chronic pancreatitis.7,8 The incidence of acute pancreatitis is increased in patients undergoing hemodialysis, and some evidence suggests that chronic pancreatitis may also be seen with greater frequency in this population. Imaging and autopsy data note changes consistent with chronic pancreatitis in up to 1 in 5 individuals in the absence of clinical.133,134 Chronic renal failure appears to frequently produce asymptomatic pancreatic fibrosis. Changes in pancreatic morphology and function are also common in patients with long-standing diabetes.10 The pancreas is smaller than normal, particularly in patients with Type 1 diabetes.10,135 The pancreatic duct is abnormal in 40% to 50% of diabetic patients when studied by ERCP, with abnormalities suggestive of chronic pancreatitis.136,137 Pancreatic function, as defined by fecal elastase

CHAPTER 59  Chronic Pancreatitis

measurements10,138 or by more formal direct pancreatic function testing,139 is abnormal in 40% to 50% of patients. The reason for these associations is not clear, whether the diabetes is causing the changes in the pancreas or vice versa. Because insulin is a trophic factor for the exocrine pancreas, and because diabetes can produce microvascular angiopathy, insulin deficiency and longstanding diabetes together could explain the pancreatic damage. Although these measures of pancreatic structure and function may be present, they are usually not responsible for symptoms and these patients do not routinely merit treatment with pancreatic enzymes.10 Smoking is a strong risk factor for chronic pancreatitis, and autopsy studies reveal that smoking also produces pancreatic fibrosis,140 particularly intralobular fibrosis. These observations may be combined to suggest that a wide variety of disease states and normal wear and tear (e.g., normal aging, chronic alcohol ingestion, smoking) on the pancreas may produce damage that by histologic criteria resembles chronic pancreatitis, but is not sufficient to cause symptoms and is not severe enough to cross the diagnostic threshold of labeling that patient as having this disease. This concept will be discussed further under “Diagnosis.” 

Idiopathic Idiopathic pancreatitis accounts for 10% to 30% of all cases of chronic pancreatitis,14,59,62,141,142 but this varies depending on the population and location. Idiopathic disease is particularly common in women; in some studies it is the most common etiology in women.141 However, many patients are probably mislabeled as having idiopathic disease. Given that there is no reliable method of determining alcohol ingestion and that there is not an absolute threshold of ingestion for pancreatitis, some of these patients certainly suffer from at least some toxicity from alcohol. Similarly, some of these idiopathic cases occur in patients with known and unknown genetic abnormalities,98,100-102,143,144 particularly those with onset in young adulthood.144 Some of what we formerly labeled idiopathic is instead autoimmune. In many previous studies, smoking was not included as a potential etiologic agent and so smoking may also account for a significant proportion of these patients. Interpreting the literature on idiopathic chronic pancreatitis is therefore difficult because most studies of this entity are probably dealing with cases with several different etiologies. Idiopathic chronic pancreatitis appears to occur in 2 forms, an early-onset type that manifests in the late second or third decade of life and a late-onset form that appears in the sixth or seventh decade of life.69,142 Early-onset idiopathic chronic pancreatitis has a mean age at onset of around 20 years. There appears to be an equal gender distribution. Pain is the predominant feature of this disease, occurring in up to 96% of patients, a higher rate than in either alcoholic or late-onset chronic pancreatitis. Pancreatic calcifications, exocrine insufficiency, and endocrine insufficiency (i.e., diabetes) are extremely rare at presentation (30 years), exocrine insufficiency will ultimately develop in 75%, endocrine insufficiency in 50% to 60%, and diffuse pancreatic calcifications in 90% of patients.69,145 The disease therefore tends to be one of a comparatively painless course associated with the frequent development of pancreatic calcifications, exocrine insufficiency, and endocrine insufficiency. Aging itself can be associated with the development of structural changes within the pancreatic parenchyma and duct that are indistinguishable from those seen in late-onset chronic pancreatitis,132 so the distinction between normal aging and late-onset idiopathic chronic pancreatitis may not always be clear. 

CLINICAL FEATURES Abdominal Pain Abdominal pain is the most common clinical problem in patients with chronic pancreatitis, and the symptom that most detracts from quality of life.25-30,146 Severe pain decreases appetite and limits food consumption, contributing to weight loss and malnutrition. Chronic severe pain leads to a dramatic reduction in quality of life,25-30,146 loss of social functioning, the potential for addiction to narcotic analgesics,147,148 and increased rates of suicide.149 In the USA, about half of all patients with chronic pancreatitis are treated with opioids.147 Intractable pain is the most common reason for hospitalization, endoscopic intervention, and surgery in patients with chronic pancreatitis. There is no single characteristic pain pattern. Pain is most commonly described as being felt in the epigastrium, often with radiation to the back. Pain is usually described as boring, deep, and penetrating and is often associated with nausea and vomiting. Pain may be relieved by sitting forward or leaning forward, by assuming the knee-chest position on one side, or by squatting and clasping the knees to the chest. Pain may worsen after a meal and often is nocturnal. The natural history of abdominal pain varies and is difficult to predict. As an example, many patients with chronic pancreatitis initially present with episodes of pain interspersed with periods of feeling relatively well. During these more acute episodes of pain, such a patient may be labeled as having acute relapsing pancreatitis. As time passes, pain may become more continuous, and the diagnosis of chronic pancreatitis more obvious. Of note, elevations in levels of amylase or lipase may not occur with painful flares, especially in long-standing chronic pancreatitis. Some patients may present with the more gradual onset of constant abdominal pain, and some may have no pain. Once pain develops, it commonly changes over time in character, severity, and timing. Depending on the etiology of chronic pancreatitis, 50% to 90% of patients experience pain during the course of the disease.14,25-30,150-154 Some of these observational studies document a decrease in pain over time in some patients, although the timing and the magnitude of this decrease vary among the studies. In one study, pain relief appeared to occur most commonly at the time of development of diffuse pancreatic calcifications, exocrine insufficiency, and endocrine insufficiency.68 Other studies have not found this same correlation, but many have noted a less pronounced tendency for pain to “burn out” over time.69,70,150-154 Pain may eventually decrease in around half of patients. Some of the pain relief is due to surgery for pain or complications, but pain relief over very long follow-up is also seen in medically treated patients in approximately similar proportions.68,155 The pain pattern in an individual patient, however, is not accurately predictable, and the pain may worsen, stabilize, or improve over

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time. The judgment of therapeutic efficacy for any treatment for chronic pancreatitis must take into account this extremely varying natural history of pain.156-159 The proposed causes of pain in chronic pancreatitis are varied but can be distilled to the following 2 primary mechanisms: (1) increased pressure, ischemia, and inflammation in the pancreas, and (2) injury to and alterations in function of peripheral and central nociceptive nerves. In many chronic pain conditions, including chronic pancreatitis, one can also classify pain as nociceptive pain (due to actual or threatened damage to non-neural tissue, and the activation of nociceptors) and neuropathic pain (pain caused by a lesion or disease of the somatosensory nervous system).156,157,160

Increased Pressure with Ischemia and Inflammation One proposed mechanism of pain is tissue ischemia, driven by increased pressure within the pancreatic duct or parenchyma. Several lines of clinical and experimental evidence point to increased pressure within the pancreatic duct or parenchyma as being important in the genesis of pancreatic pain. Pancreatic ductal and tissue pressures are usually elevated in patients with chronic pancreatitis undergoing surgery for chronic pain.161-163 Elevations in pancreatic ductal pressure measured during ERCP have also been documented in some patients with painful chronic pancreatitis.164,165 Surgical drainage of the pancreatic duct leads to a reduction in pressure to normal levels and is associated with pain relief.161-163 However, pancreatic duct pressures may not be different in those with and without pain,165 and a reduction in pressure after endoscopic stenting does not correlate with pain relief.166 Increased pressure within the pancreatic duct would be expected to be related to obstruction of the pancreatic duct, either in the main duct or in side branches. The presence of a pancreatic duct stricture and upstream pancreatic duct dilation might be an accurate indicator of a group of patients with increased pressure and therefore pain. However, there is not a relationship between pancreatic duct strictures or ductal dilation and pain.156,157,167,168 Nonetheless, patients with a dilated pancreatic duct or pancreatic duct stricture are most likely to experience pain relief from endoscopic or surgical therapy. The mechanism by which increased pressure could cause pain is speculative but may be related to pancreatic tissue ischemia. In animal models of chronic pancreatitis, increased pancreatic pressure is associated with reductions in pancreatic blood flow, tissue oxygen tension, and interstitial pH. In these models pancreatic secretagogues lead to a further decrease in pancreatic blood flow (rather than the normally expected increase), decreased capillary filling, and worsening tissue ischemia. These observations are consistent with those seen in a compartment type syndrome.162 Small studies in humans with chronic pancreatitis undergoing surgery also demonstrate lower pancreatic tissue pH than patients without chronic pancreatitis.169 Pancreatic blood flow, measured at ERCP with the use of platinum electrodes, is also lower in patients with chronic pancreatitis compared with controls.170 Tissue ischemia that is worsened by secretory stimulation of the pancreas may therefore be the mechanism by which elevations in tissue pressure cause pain. Inflammation in the pancreas, with the release of inflammatory mediators, also likely contributes to pain. In particular, trypsin released from damaged acinar cells and tryptase released from resident mast cells can activate proteinase activated receptor 2 (PAR-2) and sensitize the response of transient receptor vanilloid active fibers, releasing substance P as a key molecule in pain signaling.156,160 It is noteworthy that during painful flares, there may not be elevations in serum levels of lipase or amylase or imaging evidence of acute pancreatic inflammation. 

Alterations in Peripheral and Central Nociceptive Nerves The perception of pain requires signaling through nociceptive neurons. Morphologic studies in patients with chronic pancreatitis demonstrate increases in the diameter and number of intrapancreatic nerves, foci of inflammatory cells associated with nerves and ganglia, and damage to the perineural sheath.156,160,171,172 The disruption of the perineural sheath may allow inflammatory mediators to gain access to the neural elements. Regardless of the local events in and around the pancreas causing pain, perception of the pain message requires communication with the central nervous system. The innervation of the pancreas is complex, with both visceral somatic and autonomic nerves. Dendrites of the pancreatic nociceptive sensory afferents travel with sympathetic nerves from the pancreas and reach the celiac ganglia, although no synapse is made there. These dendritic fibers continue, bundled as the left and right greater splanchnic nerves, to the sympathetic trunk ganglia, before reaching the first cell body, located in the dorsal root ganglia in spinal cord segments T5 through T9-T10. Projections of these dorsal root neurons often traverse upward and downward for several spinal segments before entering the dorsal horn of the spinal cord. Afferent pain fibers may cross the midline in several of these connections, accounting for the midline perception of pancreatic pain. Axons from the first-order dorsal root ganglion cell bodies have 2 distinct pathways. Some project to the dorsal horn of the spinal cord and may release a variety of mediators including substance P, calcitonin gene-related peptide, and glutamate onto second-order neurons that project to the thalamus via the spinothalamic white matter columns. These may then synapse with third-order neurons that project to the somatosensory cortex (for cognitive integration of pain) and to the limbic system and hypothalamus (for affective and autonomic integration of pain). A second pathway for projections involves synapses within the same level of the spinal cord with sympathetic efferent cell bodies that project back down the splanchnic nerves to the celiac plexus, with second-order sympathetic neurons projecting back to the pancreas. Vagal afferents may also carry noxious stimuli from the pancreas (especially for stretch). Noxious stimulation of these pathways can occur through a variety of mechanisms. Pressure, ischemia, inflammation, heat, and other classic stimuli can activate these pathways. The accumulation of inflammatory mediators and nerve injury can sensitize the nerve, making it hyper-responsive.156,160,173 There is an increase in nociceptive neurotransmitters (e.g., substance P, calcitonin gene-related peptide) in interlobular and intralobular nerve bundles in patients with chronic pancreatitis.160,173 The close spatial relationship between intrapancreatic nerves and inflammatory cells supports the additional mechanism of neuroimmune interaction. Expression of nerve growth factor and one of its receptors (TrkA) is seen in patients with painful chronic pancreatitis and in animal models of chronic pancreatitis.173,174 Nerve growth factor is one of the key molecules involved in sensitization.173,174 Endogenous proteases, like trypsin, can also activate and sensitize sensory neurons in the pancreas, a process mediated through the protease- activated receptor-2 (PAR-2). Another activator of PAR-2 is tryptase, a mast cell product.160,173 Interestingly, mast cells are seen commonly in pancreatic tissue specimens from patients with chronic pancreatitis. The exact mechanisms by which the inflammatory cells and their products and intrapancreatic neurons interact in chronic pancreatitis remain to be fully clarified, although the data suggest that the production of sensitizing factors near pancreatic nerves alters sensory neuron form and function. In addition, there is substantial evidence from studies of other types of chronic pain that chronic peripheral nerve injury or inflammation leads to changes in nociceptive processing that involve both the spinal cord and central nervous system.

CHAPTER 59  Chronic Pancreatitis

Chronic pain can produce a centrally sensitized pain state in which elimination of the original source of pain may not relieve pain.156,160,175,176 In this situation, pain may occur in response to innocuous or physiologic stimuli (allodynia) or may respond in an exaggerated fashion to stimuli that are painful (hyperalgesia). These phenomena depend on changes at both the spinal cord level and the brain. A number of studies document changes in central nervous system structure and function in patients with chronic pancreatitis.156,160,177,178 These changes include altered central processing of nociceptive inputs, altered pain thresholds, and altered brain micro- and macrostructure. Some examples of these changes in patients with chronic pancreatitis compared to normal healthy controls include reorganization of the insula, secondary somatosensory cortex, and cingulate cortex, with abnormal neuronal excitability of these neural networks.160 Numerous structural changes can also be documented including reduced thickness of cortical volume in areas of visceral pain processing, abnormal EEGs, and abnormal functional MRI of the brain.156,160 The central nervous system reorganization and plasticity underlying hyperalgesia and allodynia are likely major factors limiting the effectiveness of treatments for pain. Nowhere is this fact made more obvious than in the patient who continues to have pancreatic pain after a total pancreatectomy. Pain is complex, and no single mechanism is likely to be present in all patients, implying that no single therapy will be effective. 

Other Causes of Pain In addition to these 2 main mechanisms, a variety of other contributors to pain should be considered. Complications of chronic pancreatitis may cause pain in their own right. These complications include duodenal obstruction, bile duct obstruction, a pseudocyst, and secondary pancreatic carcinoma. These usually have specific therapy. Hyperstimulation of the pancreas via CCK has also been postulated as a potential cause of pain because serum levels of CCK may be elevated in chronic pancreatitis and stimulation of the pancreas by CCK could increase pressure within the gland or facilitate basolateral rather than apical secretin of enzymes. Reducing serum CCK levels is the proposed mechanism for the use of non-enteric coated pancreatic enzymes to reduce pain. 

Steatorrhea (Exocrine Pancreatic Insufficiency) The human pancreas has substantial exocrine reserve. Steatorrhea does not usually occur until pancreatic lipase secretion is reduced to less than 10% of the maximum output.179 Steatorrhea is therefore a feature of far-advanced chronic pancreatitis, in which most of the acinar cells have been injured or destroyed, but may also be seen with blockage of the pancreatic duct, after pancreatic surgery, and after an attack of necrotizing acute pancreatitis. With advanced chronic pancreatitis, maldigestion of fat, protein, and carbohydrates will occur. Azotorrhea (protein maldigestion) also occurs when secretion of proteases is less than 10% of normal. Affected patients may present with diarrhea and weight loss. Some patients may note bulky foul-smelling stools or may even note the passage of frank oil droplets. Unlike in small bowel diseases associated with malabsorption, watery diarrhea, excess gas, and abdominal cramps are less common in patients with chronic pancreatitis. This difference may be due to better-preserved carbohydrate absorption and small bowel and colonic function in patients with chronic pancreatitis and exocrine insufficiency than in those with small intestinal diseases such as celiac disease. Even when there is significant loss of fat in stool, most patients pass only 3 or 4 stools daily and some may pass only one. In general, fat maldigestion occurs earlier and is more severe than protein or carbohydrate maldigestion. There are several

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explanations for this phenomenon. First, fat digestion depends primarily on pancreatic lipase and colipase, although gastric lipase is able to hydrolyze up to 20% of dietary fat. Second, lipase output decreases earlier and more substantially as chronic pancreatitis progresses compared with the secretion of other pancreatic enzymes such as trypsin or amylase. Third, lipase is more sensitive to acid destruction than other pancreatic enzymes. As bicarbonate secretion decreases in chronic pancreatitis and duodenal pH drops, lipase in particular is inactivated. Fourth, in addition to lipase inactivation, the low duodenal pH also predisposes to precipitation of bile salts, thereby preventing the formation of mixed micelles and further interfering with lipid digestion and absorption. Fifth, lipase is more sensitive to digestion and degradation by pancreatic proteases than other digestive enzymes. The median time to development of exocrine insufficiency in chronic pancreatitis has been reported to be as low as 5 years,68 but most studies report longer duration of disease prior to development of steatorrhea. In one large natural history study, the median time to development of exocrine insufficiency was 13.1 years in patients with alcoholic chronic pancreatitis, 16.9 years in patients with late-onset idiopathic chronic pancreatitis, and 26.3 years in patients with early-onset idiopathic chronic pancreatitis.69 With very long follow-up, approximately 50% to 80% of patients with chronic pancreatitis eventually have exocrine insufficiency.68-70,145 Significant weight loss is uncommon despite maldigestion. Patients generally increase their caloric intake to compensate for stool losses. In addition, gastric lipase (acid stable) may partially compensate for the loss of pancreatic lipase.180 Weight is usually maintained despite the fact that the resting energy expenditure is generally increased in patients with chronic pancreatitis. Weight loss is most commonly seen during painful flares that prevent adequate oral intake because of pain, nausea, or vomiting. Weight loss may also occur as a result of the development of a concomitant disease such as small bowel bacterial overgrowth (SIBO, see Chapter 105) or pancreatic or extra-pancreatic malignancy. Finally, weight loss may occur in patients who develop financial difficulties, suffer from chronic severe alcoholism, or lose social support because these may contribute to inadequate caloric and protein intake. Substantial weight loss should lead to an investigation of these potential causes. More subtle weight loss and other complications of maldigestion are more common.181-186 Deficiencies of fat-soluble vitamins develop in patients with chronic pancreatitis and steatorrhea.182-187 Significant vitamin D deficiency and osteopenia and osteoporosis occur in patients with chronic pancreatitis.185-189 These studies demonstrate osteopenia in 40% of patients and osteoporosis in another 25% of patients with chronic pancreatitis and steatorrhea.188 Deficiencies of water-soluble vitamins and micronutrients are less common and generally seen only as a consequence of inadequate intake. Despite the fact that vitamin B12 absorption requires intact pancreatic function to degrade R-factor from dietary cobalamin, vitamin B12 deficiency is quite rare in patients with chronic pancreatitis. The presence of exocrine insufficiency, in addition to the metabolic consequences noted above, is also associated with increased overall mortality in patients with chronic pancreatitis. 190,191 

Diabetes Mellitus (Pancreatic Endocrine Insufficiency) Like exocrine insufficiency, endocrine insufficiency is a consequence of long-standing chronic pancreatitis and is especially common after pancreatic resection and in tropical (fibrocalcific) pancreatitis. Islet cells appear to be relatively resistant to destruction in chronic pancreatitis (see Fig. 59.1).192 When diabetes develops, the mechanism is more complex than just a simple loss of beta cells due to the progressive destruction of islets.193-197

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Various factors make diabetes due to chronic pancreatitis (and pancreatic cancer) different than either classic type 1 or type 2 diabetes, and pancreaticogenic diabetes is defined as type 3c diabetes.197 Type 3c diabetes is characterized by low levels of insulin and counter-regulatory hormones (particularly glucagon and pancreatic polypeptide), rare ketosis, and frequent treatment induced hypoglycemia.193-197 About half of patients with chronic pancreatitis who develop diabetes will require insulin.195 Unlike type 1 diabetes, insulin-producing beta cells and glucagon-producing alpha cells are both injured. This combination increases the risk of prolonged and severe hypoglycemia with overvigorous insulin treatment, owing to the lack of a compensatory release of glucagon.194,198 Diabetes mellitus appears to be almost as common as steatorrhea in patients with far-advanced chronic pancreatitis. In one study the median times to development of diabetes in patients with alcoholic, late-onset idiopathic, and early-onset idiopathic chronic pancreatitis were 19.8, 11.9, and 26.3 years, respectively.69 Other studies have noted shorter median times of 6 to 10 years.68,70,199,200 Ultimately with long-term follow-up, 40% to 80% of patients with chronic pancreatitis have diabetes, depending on etiology.68,69 Those with chronic pancreatitis who undergo pancreatic surgery have higher rates of both exocrine and endocrine insufficiency.201-203 Microangiopathic complications are as common in patients with diabetes associated with chronic pancreatitis as in patients with type 1 diabetes with similar duration of disease.194,204 

PHYSICAL EXAMINATION Very few of the physical examination findings are diagnostic or specific for chronic pancreatitis. Patients may appear undernourished with sarcopenia, and may demonstrate mild to moderate abdominal tenderness. In those with more advanced disease, weight loss and malnutrition may be more evident. Rarely, a palpable mass is found, indicating a pseudocyst. Jaundice may be observed in the presence of coexistent alcoholic liver disease or bile duct compression within the head of the pancreas. A palpable spleen may also rarely be found in patients with thrombosis of the splenic vein as a consequence of chronic pancreatitis or in patients with portal hypertension due to coexistent chronic liver disease. In some patients with AIP, evidence of a coexistent autoimmune feature, such as salivary gland enlargement or lymphadenopathy, may be found. 

DIAGNOSIS A variety of diagnostic tests for chronic pancreatitis are available. These diagnostic tests are usually separated into those that are designed to detect abnormalities of pancreatic function and those that detect abnormalities of pancreatic structure (Table 59.2). Before considering these tests in more detail, it is useful to remember that in almost all patients, chronic pancreatitis is a slowly progressive disease. In the early stages within the pancreas, chronic inflammation, cellular necrosis and apoptosis, and activation of pancreatic stellate cells have all developed, but these features of chronic pancreatitis remain visible only on histology. With progressive fibrosis and loss and destruction of tissue, the disease becomes more evident. Abnormalities of pancreatic structure or function may take years or even decades to develop, or may not develop at all.1,2,67-70,104,205 All available diagnostic tests are most accurate in far-advanced disease, when obvious functional or structural abnormalities have developed. Conversely, to greater or lesser degrees, all diagnostic tests are less accurate in less advanced or early chronic pancreatitis. Functional abnormalities in chronic pancreatitis include exocrine insufficiency (maldigestion and steatorrhea) and endocrine insufficiency (type 3c diabetes mellitus). In addition, some

TABLE 59.2  Available Diagnostic Tests for Chronic Pancreatitis* Tests of Pancreatic Structure

Tests of Pancreatic Function

EUS

Direct hormonal stimulation (with pancreatic stimulation by secretin or cholecystokinin or both): Using oroduodenal tube Using endoscopy

MRI with MRCP, with or without secretin stimulation

Fecal elastase

CT

Serum trypsinogen (trypsin)

ERCP

Fecal chymotrypsin

Abdominal US

Fecal fat

Plain abdominal x-ray

Blood glucose level

  

*Ranked in estimated order of decreasing sensitivity for each category.

  

diagnostic tests measure maximum stimulated secretory capacity of the pancreas, which appears to become abnormal before there is failure of exocrine or endocrine function.205,206 Structural abnormalities that can be diagnostic include changes within the main pancreatic duct (dilation, strictures, irregularity, pancreatic ductal stones), side branches of the pancreatic duct (dilation, irregularity), or pancreatic parenchyma (lobularity of the gland, alterations in echogenicity, cysts, stones, atrophy, and others). Patients with alcoholic chronic pancreatitis, hereditary chronic pancreatitis, tropical pancreatitis, and late-onset idiopathic chronic pancreatitis are most prone to development of these abnormalities of function or structure, although the process may still take several years. These changes develop particularly slowly, and sometimes not at all, in patients with early-onset idiopathic chronic pancreatitis.1,67,69,205 The determination of the sensitivity, specificity, and accuracy of any of these diagnostic tests requires that the test result be compared with some gold standard, a test that gives reliable and certain evidence as to the presence or absence of disease. In the case of chronic pancreatitis, this gold standard has been pancreatic histology (see Fig. 59.1). Unfortunately, the histologic changes are not uniform throughout the gland,33 so that findings in a biopsy specimen may be misleading. Even more important, obtaining pancreatic tissue carries risk and is seldom performed solely for diagnosis. In addition, similar histologic findings may be encountered in patients without clinical features of chronic pancreatitis, such as with aging, social alcohol use, smoking, and diabetes.4-10,132 Given the lack of a functional gold standard, substitutes for the gold standard include other diagnostic tests or long-term followup. Most studies have not monitored patients diagnosed with early chronic pancreatitis or possible early chronic pancreatitis (patients in whom diagnostic tests are not unequivocally positive) for long enough to establish the presence or absence of chronic pancreatitis with certainty. Another potential substitute for the gold standard is some other diagnostic test, and in fact, new diagnostic tests are often compared with such modalities as ERCP, EUS, CT, MRI, and pancreatic function tests, or composites of these. In patients with chronic pancreatitis and far-advanced structural or functional abnormalities, little else can mimic these abnormalities, and essentially all diagnostic tests are accurate. The situation is quite different in patients with early or less advanced or minimal-change chronic pancreatitis, and even more so in patients with suspected or possible chronic pancreatitis, in whom these easily identifiable structural or functional abnormalities are lacking.1,205,207 In this situation, only tests of maximum sensitivity have a chance of enabling a diagnosis, and the lack of a gold standard can lead to diagnostic confusion and difficult decision making. In addition to choosing a diagnostic test on the basis of sensitivity and specificity, clinicians must consider the

CHAPTER 59  Chronic Pancreatitis

availability, cost, and risk of each of these tests to maximize diagnostic information and minimize risk. These issues are discussed here in relation to each of the available diagnostic tools. 

Tests of Pancreatic Function Tests of pancreatic function can be divided into those that directly measure pancreatic function by measuring the output of enzymes or bicarbonate from the pancreas and those that measure the released enzymes indirectly (through its action on a substrate or its level in blood or stool).

Direct Tests Direct hormonal stimulation tests are believed to be the most sensitive function tests for chronic pancreatitis.1,205-208 These tests require placement of a tube or endoscope in the duodenum, stimulation of pancreatic secretions (usually with secretin, but in some cases with CCK), and collection of pancreatic secretions for analysis (bicarbonate concentration in the case of secretin infusion, enzyme secretion in the case of CCK). A few studies have compared the results of these hormonal stimulation tests with pancreatic histology with overall sensitivities ranging from 67% to 88%.209-211 The largest study compared histology with combined secretin-CCK testing in 108 patients.209 There was a linear correlation of stimulated bicarbonate output with histologic severity of chronic pancreatitis. Although mean peak bicarbonate concentration was in the normal range (>80 mEq/L) in 69 patients with normal or equivocal histology, mean bicarbonate concentration was 70, 63, and 50 mEq/L in those with mild, moderate, and severe histologic chronic pancreatitis, respectively. The overall sensitivity of hormonal stimulation testing in this study was 67%, with a specificity of 90% and overall accuracy of 81%. When the analysis was restricted to the 29 patients with moderate or severe histologic changes of chronic pancreatitis, the sensitivity of hormonal stimulation testing rose to 79%. In this same group of 29 patients, the sensitivity of ERCP was 66%. In comparisons with ERCP, direct hormonal stimulation tests appear to be somewhat more sensitive for the diagnosis of chronic pancreatitis. The values for sensitivity of pancreatic function testing range from 74% to 97%, with specificity ranging from 80% to 90%.208-217 In these studies the 2 tests agree in about 3 quarters of patients, although some studies note higher rates of concordance. Most studies also note a general correlation between increasing structural abnormalities and progressive abnormalities of hormone stimulation test results, although the relationship is not exact. Most of these studies also identify patients with discordant results—patients with abnormal ERCPs and normal hormonal stimulation test results as well as those with normal ERCPs and abnormal hormonal stimulation test results. In 4 studies the percentage of patients with an abnormal hormonal stimulation test result and a normal ERCP ranged from 3% to 20%.210-215 Three small studies have followed such patients whose diagnosis was based solely on an abnormal hormonal stimulation test result and found development of chronic pancreatitis on follow-up in 90% of patients.217-219 These data point out that direct pancreatic function testing appears to be able to identify a group of patients with chronic pancreatitis who have functional abnormalities of stimulated secretion but who do not (yet) have ERCP-identifiable structural abnormalities. Conversely, most of these studies also report patients with normal hormonal stimulation test results and abnormal ERCPs. This group of patients is generally less common, averaging less than 10% in several studies. Long-term follow-up in a small group of such patients noted development of chronic pancreatitis in 0% to 26%.217-219 These studies point out that in situations in which results of the 2 tests disagree, hormonal stimulation testing appears to be somewhat more sensitive and specific than ERCP.220,221

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Some experts have suggested that the pancreas has such reserve that 30% to 50% damage to the gland is necessary before direct pancreatic function tests yield reliably positive results. Despite their theoretical advantages, direct pancreatic function tests have a number of limitations. First, they have not been well standardized across institutions offering the test. Second, they are available at only a very few referral centers and so are not available to the majority of clinicians seeing patients with chronic pancreatitis. Third, it can be difficult for patients to tolerate unsedated placement of an oroduodenal tube for the hour or more required for the test. Fourth, accurate measurement of bicarbonate concentrations or enzyme output may be challenging. False-positive results have been reported in patients who have undergone Billroth II gastrectomy, in patients with diabetes, celiac disease, and cirrhosis, and in patients recovering from a recent attack of acute pancreatitis. A direct pancreatic function test is most useful in patients with presumed chronic pancreatitis in whom easily identifiable structural and functional abnormalities have not been demonstrated on more widely available diagnostic modalities such as CT or MRI, or when these imaging studies are equivocal. This type of test is most useful in ruling out chronic pancreatitis in patients who present with a chronic abdominal pain syndrome suggestive of chronic pancreatitis, saving these patients the label of chronic pancreatitis with its negative repercussions and the risk of such diagnostic tests as ERCP.1,205,207,220 There are variations of direct pancreatic function tests that may be easier for patients to tolerate (by sedating them) and might be able to be made more widely available. One variation is to collect pancreatic secretions at the time of ERCP by placement of a catheter directly in the pancreatic duct (the so-called intraductal secretin test). This test typically samples pancreatic output for only 15 minutes, to minimize the likelihood of ERCPinduced pancreatitis. It is not standardized and does not appear to be as accurate as standard direct pancreatic function testing222 probably because of the rather brief collection time. A common variation of pancreatic function testing is to use sedation and a standard upper endoscope to take the place of the usual oroduodenal tube, with analysis of bicarbonate output using the regular hospital laboratory. This variation attempts to bypass the difficulties limiting the widespread application of standard direct pancreatic function tests, such as passage of the collection tube in unanesthetized patients and need for a dedicated laboratory to measure the bicarbonate concentration by back-titration. Unlike the intraductal secretin test, this endoscopic variation appears to be nearly, although not quite, as accurate as standard direct pancreatic function testing.206,220,223-225 The initial descriptions of this test used a 60-minute collection with timed aspirates of duodenal fluid every 15 minutes. This is a long time to keep a patient sedated and an endoscopy room occupied, although it may be possible to shorten the test and only collect samples at 30 and 45 minutes after secretin injection206,226,227 with only minimal loss of sensitivity. Another variation of the test is to measure lipase output rather than bicarbonate output, with CCK as the secretagogue.228 This variation appears to be less accurate than secretin-based pancreatic function testing. Like traditional pancreatic function testing, endoscopic-based pancreatic function tests have been compared to alternative diagnostic tests like ERCP,229 with an overall agreement in 86% of patients and a high negative predictive value for endoscopic pancreatic function testing. The value of pancreatic function tests, whether traditional or endoscopic, lies in their high sensitivity and consequent ability to rule out chronic pancreatitis.205,220,225,230 Current practice is to administer 0.2 μg/kg of recombinant secretin, with samples collected via a Dreiling tube or endoscope over 45 to 60 minutes, in 15-minute aliquots or samples. The fluid samples are analyzed for bicarbonate concentration; an abnormal test is defined as all samples with bicarbonate concentration less than 80 mEq/L. 

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Indirect Tests The desire to develop indirect tests of pancreatic function is an outgrowth of the complexity, discomfort, and limited availability of direct pancreatic function testing. Indirect tests generally measure pancreatic enzymes in blood or stool. Tests that measure the effect of pancreatic enzymes on an orally administered substrate with collection of metabolites in blood, breath, or urine are of historical interest or only available as research tools. Serum Trypsinogen Serum trypsinogen (often called serum trypsin) can be measured in blood and provides a rough estimation of pancreatic function. Abnormally low levels of serum trypsinogen can be seen in patients with advanced chronic pancreatitis with steatorrhea.231 Serum trypsin is not decreased in patients with other forms of steatorrhea, but low levels of serum trypsinogen may be seen in patients with pancreatic ductal obstruction, including malignant obstruction. The test is available through commercial laboratories, but each have different normal ranges.  Pancreatic Enzymes in Stool Low concentrations of chymotrypsin or elastase in stool can reflect inadequate delivery of these pancreatic enzymes to the duodenum. Both can be measured on random samples of stool. Fecal chymotrypsin is low in most patients with chronic pancreatitis and steatorrhea. Fecal chymotrypsin is available from commercial laboratories. False-positive results have been reported in other malabsorptive conditions (celiac disease, Crohn disease), in diarrheal diseases in which the stool is diluted, and in severe malnutrition. Because the test is usually normal in patients without steatorrhea, it is reliably positive only in advanced chronic pancreatitis. Fecal elastase-1 has significant advantages over fecal chymotrypsin in that it is much more stable in passage through stool and is easier to measure. Levels less than 200 μg/gram of stool are considered abnormal and suggestive of exocrine pancreatic insufficiency. Levels less than 100 μg/gram of stool are considered evidence of exocrine pancreatic insufficiency. The test is reasonably accurate in more advanced chronic pancreatitis.191,207,232,233 Fecal elastase-1 can be falsely low due to dilution in other diseases causing diarrhea, such as short bowel syndrome and small bowel bacterial overgrowth. The test should be performed on a solid or semi-solid stool specimen. Fecal elastase measurement is available through reference laboratories in the USA.  Fecal Fat Excretion Maldigestion of fat occurs after 90% of pancreatic lipase secretory capacity is lost. An evaluation of pancreatic lipase action is the measurement of fecal fat excretion during a 72-hour collection of stool. Although theoretically quite simple, the test is difficult to perform in practice. The patient must follow a diet containing 100 g/day of fat for at least 3 days before the test and the 3 days after the test, and complete collection of the sample is difficult to achieve. In health, less than 7 g of fat (7% of the ingested dose) should be present in stool. Measuring fecal fat requires that the dietary content of fat be known exactly, which is difficult to ascertain. A qualitative analysis of fecal fat can also be performed with a Sudan III stain of a random specimen of stool. The finding of more than 6 globules per high-power field is considered a positive result, but as with fecal fat excretion, the patient must be ingesting adequate fat to allow measurable steatorrhea. Sudan III staining of stool is positive only in patients with substantial steatorrhea.207,208 

Tests of Pancreatic Structure (Imaging) Plain Abdominal Radiography The finding of diffuse (but not focal) pancreatic calcifications on plain abdominal films is quite specific for chronic pancreatitis.

Focal calcifications may be seen in cystic and islet cell tumors of the pancreas, and in peripancreatic vascular calcifications. Calcifications occur late in the natural history of chronic pancreatitis and may take from 5 to 25 years to develop.69,70,145 Calcifications are most common in alcoholic, late-onset idiopathic, hereditary, and tropical pancreatitis and far less common in early-onset idiopathic pancreatitis. Acceleration of the clinical course of chronic pancreatitis, and subsequent calcifications, are particularly common in patients who smoke.53-58,84,85,234 Calcifications are not static once they develop and may in fact wax and wane over time.234,235 

Abdominal US US has been widely studied as a diagnostic tool for chronic pancreatitis. This modality is limited in that the pancreas (and particularly the pancreatic head) cannot be adequately visualized in many patients owing to overlying bowel gas or body habitus. Ultrasonographic findings indicative of chronic pancreatitis include dilation of the pancreatic duct, shadowing pancreatic ductal stones, gland atrophy, irregular gland margins, pseudocysts, and changes in the parenchymal echotexture (see Table 59.2). Most studies suggest a sensitivity of 50% to 80% with a specificity of 80% to 90%.236 In a study comparing transabdominal ultrasonography with CT, ERCP, and EUS, the accuracy of US was 56%.237 In this study, some abnormality (such as changes in parenchymal echotexture) was noted on US in 40% of patients who had a normal pancreas as defined by the other diagnostic tests. A large screening study of transabdominal US in Japan encompassing 130,000 examinations found increased echogenicity, mild dilation of the pancreatic duct, small cystic cavities, and even ductal calcification in the absence of clinical features of chronic pancreatitis.238 The majority of these abnormalities could not be attributed to chronic pancreatitis and were instead attributed to aging. These studies would suggest that there is a large spectrum of ultrasonographic findings in normal individuals and that it can be difficult to distinguish normal (or age-related) variability from chronic pancreatitis if the visualized changes are mild. Although relatively inexpensive and safe, transabdominal US is not generally useful in the evaluation of patients with suspected chronic pancreatitis. The finding of a normal pancreas or moderate to marked changes of advanced chronic pancreatitis can be diagnostic, but mild changes of chronic pancreatitis are less specific and must be interpreted in light of the clinical history and the patient’s age. US can be useful in screening for complications of chronic pancreatitis (e.g., pseudocyst or bile duct obstruction) and in evaluating for other conditions that might mimic the symptoms of chronic pancreatitis (i.e., biliary tract disease). 

CT The overall sensitivity of CT for chronic pancreatitis is between 75% and 90%, with a specificity of 85% or more.236,237,239 CT is able to image the pancreas in essentially all patients and hence has a substantial advantage over US. Table 59.3 outlines the diagnostic abnormalities seen on CT in chronic pancreatitis. Most studies of diagnostic CT in chronic pancreatitis have not used state-of-theart CT technology. Like all diagnostic tests, CT is most accurate in advanced chronic pancreatitis after substantial structural changes have developed (Fig. 59.4). Although CT is more expensive than US and exposes the patient to ionizing radiation, it is more sensitive and more specific. One finding of unknown significance is the presence of fatty replacement of the pancreas.240,241 This condition, variously termed fatty pancreas, pancreatic lipodystrophy, non-alcoholic fatty pancreas disease, and others, may be related to metabolic syndrome, obesity, aging, or other unknown factors and is in itself not a specific finding of chronic pancreatitis. 

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TABLE 59.3  Grading of Chronic Pancreatitis by US or CT Grade Normal

59

US or CT Findings No abnormal findings on a good-quality study visualizing the entire gland

Equivocal

One of the following: Mild dilatation of the pancreatic duct (2-4 mm) in the body of the gland Gland enlargement ≤2-fold normal

Mild-moderate

One of the preceding findings plus at least one of the following: Pancreatic duct dilatation (>4 mm) Pancreatic duct irregularity Cavity (ies) 10 mm Intraductal filling defects Calculi/pancreatic calcification Ductal obstruction (stricture) Severe duct dilatation or irregularity Contiguous organ invasion

  

Adapted from Sarner M, Cotton PB. Classification of pancreatitis. Gut 1984; 25:756.

Fig. 59.4  CT demonstrating several large, densely calcified stones (arrows) within a markedly dilated pancreatic duct in long-standing chronic pancreatitis.

  

MRI MRI, coupled with MRCP is as accurate, and probably more so, than CT in patients with chronic pancreatitis.236,239,242 MRCP results agree with ERCP results in about 90% of cases.220,225 Agreement between MRCP and ERCP is less common in areas where the pancreatic duct is small (tail of pancreas and side branches) or when the ductal changes are more subtle. Improved visualization of the pancreatic duct can be achieved by administering secretin.236,242-245 In addition, signal intensity (usually on T1 imaging) and arterial enhancement ratios can be obtained, using gadolinium as a contrast agent, which may improve the ability to image the gland.242,246 Finally, a qualitative or semi-quantitative assessment of fluid output from the pancreas to the duodenum can be made during MRCP after secretin injection (S-MRCP), which may allow estimation of pancreatic secretory function.242,247,248 Secretin-MRCP has been compared with endoscopic-based pancreatic function testing.248 Abnormalities on MRCP were seen in 8/23 patients with a normal pancreatic function test, suggesting secretin-MRCP may have a significant false-positive rate. Some analyses suggest that just measuring volume after secretin stimulation, instead of bicarbonate concentration, is too inaccurate to be clinically useful.249 One study also compared MRI findings with histology in a group of patients undergoing total pancreatectomy for non-calcific chronic pancreatitis.250 Using a cut-off of ≥ 2 MRI features only reached 65% sensitivity, and 89% specificity. The strongest predictors of chronic pancreatitis were pancreatic duct irregularity, T1-weighted signal intensity, and duodenal filling after secretin. Advancements in MR image analysis will continue to improve the image quality of MRCP, which in the future will equal ERCP in accuracy. Like ERCP, however, MRCP will be inaccurate in patients without significant ductal abnormalities. Although MRI is widely available, not all centers have the capacity to perform high-quality MRCP or S-MRCP. 

ERCP Pancreatography has been considered the most specific and sensitive test of pancreatic structure. It also has the advantage over all

previously discussed tests in that therapy (e.g., pancreatic duct stenting, stone extraction) may be administered. The disadvantage, however, is that ERCP is the riskiest diagnostic test, with complications occurring in at least 5% of patients (in as many as 20% of certain subgroups) and a mortality rate of 0.1% to 0.5%. In most studies in patients with chronic pancreatitis, the sensitivity of ERCP is between 70% and 90%, with a specificity of 80% to 100%.221,236,237 Thus, chronic pancreatitis can exist in the absence of any visible changes within the pancreatic duct.1,209,219, 221,229,236,251,252

The diagnostic features of chronic pancreatitis on ERCP are listed in Table 59.4. These were developed at an international consensus conference held more than 30 years ago.253,254 The diagnosis is based on abnormalities seen in the main pancreatic duct and the side branches. ERCP is highly sensitive and specific in patients with advanced disease. The appearance of a massively dilated pancreatic duct with alternating strictures (the chain-oflakes appearance) is characteristic of the most advanced chronic pancreatitis (Fig. 59.5). Less dramatic pancreatographic changes are less definitive and specific (Fig. 59.6). The accurate interpretation of an ERCP requires a study of adequate quality (filled to the second generation of the side branches and without significant movement artifact) and the capability to obtain radiographic images of high resolution. Many pancreatograms do not meet these criteria for an adequate study.221 An underfilled pancreatic duct can appear to have an irregular duct margin (leading to overdiagnosis of chronic pancreatitis) or might not delineate changes within the inadequately filled side branches (leading to underdiagnosis of chronic pancreatitis). The pancreatic duct abnormalities characteristic of chronic pancreatitis can be seen in other conditions. The most common is the effect of aging on the pancreatic duct. Although pancreatic function is well preserved in normal aging, impressive abnormalities may develop in the pancreatic duct. They include focal or diffuse dilatation of the main pancreatic duct and its side branches, the development of cystic cavities, and even ductal calculi.131,132,221,255,256 In the large screening US study mentioned previously, 50% of all calcification and more than 80% of ductal dilation and cystic lesions seen were believed to be attributable to aging, not chronic pancreatitis.238 Whether these changes represent the consequences of

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TABLE 59.4  Cambridge Grading of Chronic Pancreatitis on Endoscopic Retrograde Pancreatography Grade

Main Pancreatic Duct

Side Branches

Normal

Normal with filling of duct to side branches

Normal

Equivocal

Normal

10 mm) Obstruction or stricture Filling defect(s) Severe dilatation or irregularity

≥3 Abnormal

  

Adapted from Axon ATR, Classen M, Cotton PB, et al. Pancreatography in chronic pancreatitis: international definitions. Gut 1984; 25:1107–12.   

Fig. 59.6  Endoscopic retrograde pancreatogram demonstrating subtle changes limited to the side branches (arrows) in a patient in whom a direct pancreatic function (secretin) test indicated chronic pancreatitis. These subtle findings are generally not sufficient for a definitive diagnosis of chronic pancreatitis.

Fig. 59.5  Endoscopic retrograde pancreatogram showing a markedly dilated pancreatic duct with alternating strictures and dilatation. This “chain-of-lakes” appearance is diagnostic of chronic pancreatitis.

the normal wear and tear on the pancreas during life is not known. Temporary changes in the pancreatic duct may also occur after an episode of acute pancreatitis and may take months to resolve.221 Pancreatic carcinoma may produce changes within the pancreatic duct that resemble those of chronic pancreatitis. Finally, the placement of pancreatic duct stents can produce new abnormalities within the pancreatic duct that mimic chronic pancreatitis and that may not entirely resolve after stent removal.221,257,258 Pancreatic stents are placed to prevent post-ERCP pancreatitis. These temporary, very small-caliber stents used for these purposes appear to rarely produce these ductal changes.259 There is significant potential for substantial interobserver and intraobserver variability in the interpretation of ERCP.221 The initial consensus conference identified some abnormalities such as a dilated pancreatic duct, abnormal duct contour, and abnormal side branches but did not define absolute criteria to differentiate normal from abnormal or normal variant.254 In one study, 74 postmortem pancreatograms were submitted to 6 experienced endoscopists.131 They were asked to judge whether the pancreatogram demonstrated chronic pancreatitis, and the severity of the abnormalities. The pancreas was then examined for histologic correlation. All 6 endoscopists correctly identified the 5 subjects with chronic pancreatitis. In the remaining 69 subjects, there was

no histologic evidence of chronic pancreatitis. Depending on the observer, between 42% and 98% of these pancreatograms were read as demonstrating chronic pancreatitis, largely based on mild abnormalities within the main duct and side branches. The mistaken interpretations were felt to be due to age-related changes within the pancreas. Another study attempted to estimate intraobserver variability by submitting 51 pancreatograms to 4 expert endoscopists on 3 separate occasions.260 Each endoscopist was consistent in his or her own 3 reports in 47% to 95% of cases (yielding a rate of intraobserver variability as high as 53%). Much of the intraobserver and interobserver variability in ERCP evaluations is related to the interpretation of mild or subtle pancreatographic changes rather than dramatic abnormalities. This is the most substantial clinical problem related to ERCP as a diagnostic tool; subtle or minor abnormalities of the pancreatic duct are quite nonspecific and are not reliable markers of chronic pancreatitis. Given the risk of ERCP and the availability of alternative methods to image the pancreatic duct (MRCP or EUS), ERCP should not be used as a diagnostic tool in patients with presumed chronic pancreatitis. ERCP should only be used when therapy is planned. 

EUS EUS allows a highly detailed examination of pancreatic parenchyma and the pancreatic duct by overcoming the imaging problems in transabdominal US (such as intervening gas in the bowel lumen). The traditional diagnostic system (MST or minimal standard terminology) is based on the presence of abnormalities in the pancreatic duct and the parenchyma (Table 59.5). These features may be individually classified as none, minimal, moderate, or extensive but in practice are generally only graded as present or absent, and the total number of features is used as the score. The sensitivity and specificity of the test is determined by the threshold total score used to define chronic pancreatitis. A large range of threshold scores have been used, ranging from 1 to 6. Most studies have used the presence of 3 or more features to define a positive result.236,251,261-263 A second diagnostic system termed the Rosemont criteria is also used for EUS diagnosis of chronic pancreatitis (see Table 59.5). This was developed

CHAPTER 59  Chronic Pancreatitis

935

TABLE 59.5  Diagnosis of Chronic Pancreatitis on EUS Standard MST EUS Grading System

Rosemont Criteria for EUS Diagnosis

Parenchymal abnormalities

Hyperechoic foci Hyperechoic strands Lobularity of contour Cysts

Major features

Hyperechoic foci with shadowing (Major A) Main pancreatic duct calculi (Major A) Lobularity with honeycombing (Major B)

Ductal abnormalities

Main duct dilatation Main duct irregularity Hyperechoic ductal walls Visible side branches Calcification

Minor features

Lobularity without honeycombing Hyperechoic foci without shadowing Stranding Cysts Irregular main pancreatic duct contour Main pancreatic duct dilation Hyperechoic duct margin Dilated side branches

In the standard EUS system, each finding counts equally and the score is the total number of findings. In the Rosemont system, the diagnostic strata are as follows: Most consistent with chronic pancreatitis

1 Major A feature and ≥3 minor features or 1 Major A feature and 1 Major B feature or 2 Major A features

Suggestive of chronic pancreatitis

1 Major A feature and 5 mm) and an obstructing stricture or stone in the head of the pancreas. The endoscopic treatment of complications such as bile duct strictures and pseudocysts is discussed latert and in Chapter 61. 

Surgical Therapy Surgical therapy in chronic pancreatitis is most commonly considered for intractable abdominal pain for which medical therapy has failed. Other indications for surgery in these patients are complications involving adjacent organs or structures (duodenal, splenic venous, or biliary complications), failure of endoscopic or radiologic management for pseudocysts, internal pancreatic fistulas, and exclusion of malignancy despite an extensive evaluation. Surgical options for pain are pancreatic ductal drainage, resection of all or part of the pancreas, and both. The choice of surgical procedure depends in large part on the ductal anatomy, presumed pathogenesis of pain, and associated complications as well as local surgical preferences and expertise.285,323-325 Ductal drainage procedures are the least technically demanding and preserve the most pancreatic parenchyma. The rationale for these procedures is to relieve ductal obstruction and reduce pancreatic pressures, thereby relieving pain. Pancreatic ductal drainage procedures generally require dilation of the pancreatic duct to more than 5 mm, a diameter that allows relatively easy identification and anastomosis.323 This operation is considered

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in patients with a dilated pancreatic duct but without an inflammatory mass in the head of the pancreas. The most commonly performed procedure is the lateral pancreaticojejunostomy or Partington-Rochelle modification of the Puestow procedure. In this procedure the pancreatic duct is opened longitudinally and anastomosed to a defunctionalized limb of small bowel, which is connected with a Roux-en-Y anastomosis. This limb also can be used to decompress any coexisting pseudocysts. At the time of the operation, ductal strictures can be incised and stones can be readily removed as needed. The procedure also can be performed in the absence of a dilated pancreatic duct (normal duct Puestow procedure or “V-plasty”), but the efficacy for relieving pain is believed to be less.324 The procedure can be performed laparoscopically. The operative mortality for a modified Puestow procedure is extremely low.323 No randomized trials comparing a modified Puestow procedure with other surgical therapies have been conducted. Immediate pain relief is seen in approximately 3 quarters of carefully selected patients.323-325 With long-term follow-up, about half continue to experience pain relief. The explanation for this decline in effectiveness is unknown but may reflect closure of the anastomosis, pain originating in the undrained segments of the head of the pancreas, or the development of other sources of pain (neural inflammation, central nervous system sensitization, duodenal or bile duct obstruction, etc.). There is thus a tradeoff between the simplicity and low risk of this procedure and the gradual deterioration of pain relief over time. Exocrine and endocrine functions are generally unaffected by this surgical procedure per se but appear to continue to deteriorate as in unoperated patients. In an attempt to overcome the modest early and substantial late failure rates of simple drainage procedures, approaches combining resection of the pancreas with drainage of the pancreatic duct have been developed. These have focused particularly on the head of the pancreas because this is felt to be the pacemaker of the disease by many surgeons. A routine longitudinal pancreaticojejunostomy does not completely decompress the ducts in the head of the gland, the duct of Santorini, and the small ducts draining the uncinate process. Some patients may have an associated inflammatory mass of the head of the pancreas, making drainage of the pancreatic duct within the head of the pancreas more difficult. In addition, resection of the head of the pancreas may be necessary in patients with a large inflammatory mass of the head that compresses and obstructs the duodenum or the bile duct. Options to deal with these problems include resection of the head of the pancreas (pancreaticoduodenectomy [Whipple operation], duodenum-preserving Whipple operation, or duodenum-preserving pancreatic head resections [DPPHR]) and combinations of ductal drainage with local resection of all or part of the pancreatic head.325 It should be noted that improved pain relief after these surgical procedures involving pancreatic resection may be partially explained by the denervation of visceral pancreatic afferent nerves during more extensive dissection rather than better drainage of the pancreatic ducts in the head of the pancreas. Whipple resection or duodenum-preserving Whipple resection produces pain relief in 65% to 95% of patients.285,323 Whipple operations are generally considered in patients with disease limited to the head of the pancreas, particularly those with a large inflammatory mass of the pancreas in whom malignancy is also being considered. Associated biliary or duodenal obstruction, seen more commonly in these patients with inflammatory masses of the head of the pancreas, can also be treated at the time of the resection. These operations have higher morbidity and mortality than simple ductal drainage operations. Although the mortality in high-volume centers is less than 3%, early postoperative complications (primarily disruptions of normal motility and pancreatic duct leaks) can occur in up to half of cases. Surgical mortality is

higher if the inflammatory mass occludes or compresses major arteries or veins. Several procedures have been developed to resect all or part of the head of the pancreas without the disruptions of GI physiology seen with traditional Whipple operations and to limit the amount of pancreatic tissue removed. The DPPHR, variant developed by Beger, is performed by resecting the pancreatic head but sparing the duodenum, and covering the site with a defunctionalized Roux-en-Y jejunal limb to allow drainage of pancreatic and biliary secretions.326 Modifications of this procedure were subsequently developed to avoid dissecting around the portal and superior mesenteric veins (and the associated bleeding risk) and to limit the amount of pancreatic tissue (in particular islet cells) that is removed. In one modification, developed by Frey, less of the head of the pancreas is cored out, leaving the bile duct and peripancreatic vessels undisturbed.327 This approach is coupled with a longitudinal incision of the pancreatic duct in the body and tail of the pancreas and the overlaying of a long jejunal anastomosis covering both the opened duct and the cored-out head. A third operation, termed the Berne procedure, uses a pancreatic head resection without longitudinal duct incision, but leaves a narrow layer of pancreatic tissue against the duodenum and retropancreatic vessels.328 There have been several randomized trials and meta-analyses comparing one of the Whipple operations with DPPHR (either the Frey or Beger procedure).323,329,330 In short-term follow-up, these procedures appear to have equivalent efficacy in relieving pain, with more diabetes seen in those undergoing Whipple procedures. In long-term follow-up this advantage of a DPPHR may be lost. Randomized trials comparing the Beger with the Frey operations however show similar rates of postoperative complications, efficacy, and long-term quality of life. Postoperative complications are more common than with a simple modified Puestow procedure, but both short- and long-term pain relief is superior. In the USA a limited number of surgeons are trained in these variations of DPPHR. Laparoscopic and robotic-assisted approaches are possible for most of these operative approaches for both benign and malignant pancreatic diseases.331,332 The complications occurring after surgery for chronic pancreatitis vary with the operation chosen. They include pancreatic fistula, wound infection, delayed gastric emptying, intra-abdominal abscess, pancreatitis, cholangitis, and bile leak. The optimal timing of surgery is not known. In the past, surgery was considered a last option and considered when other therapy (medical and endoscopic) has failed to provide sufficient pain relief. Some analyses have suggested earlier surgery, before patients have developed hyperalgesia and/or opiate dependence, would be preferable.333,334 A randomized trial is in process to assess this.335 The surgical therapy of chronic pancreatitis may also involve some less commonly used operations. In some patients with disease limited to the body and tail of the pancreas, typically after trauma to the pancreatic duct in the body of the pancreas with upstream obstructive chronic pancreatitis, resection of the body and tail may be considered. Total or near-total pancreatectomy with concomitant islet cell auto-transplantation is being performed more frequently. It is most commonly considered in patients with intractable pain and a non-dilated pancreatic duct. It is imperative that these patients are accurately diagnosed as having chronic pancreatitis, as they often do not have clear-cut imaging evidence of chronic pancreatitis prior to surgery.220,230,250,268 Islet cell auto-transplantation, if successful, can salvage sufficient islets to avoid diabetes. In practice, insulin independence is achieved in about 40% of patients, with pain relief in 80% of patients.336,337 The risk of postoperative diabetes is dependent on the yield of islet cells at the time of the pancreatectomy. Islet yields are reduced in those patients with previous pancreatic surgery.336-338

CHAPTER 59  Chronic Pancreatitis

Total pancreatectomy with islet cell autotransplantation is also used in pediatric pancreatitis (particularly genetic forms). At the current time, it remains mainly a salvage operation for patients with overwhelming pain, in whom other options have failed. In caring for patients who have undergone surgery for chronic pancreatitis, it is important to remember that exocrine insufficiency and endocrine insufficiency can develop as a consequence of the surgery as well as the ongoing disease process. Exocrine insufficiency in particular may escape detection because symptoms may be mild. Steatorrhea can develop in 30% to 40% of patients undergoing simple drainage procedures and in up to two thirds of those undergoing pancreatic resections.191,339 The use of pancreatic enzyme supplements after pancreatic surgery leads to better absorption of nutrients and should be considered for most (or all) patients after surgery for chronic pancreatitis. The development of endocrine insufficiency (diabetes) after surgery for chronic pancreatitis is also common but not invariable, occurring as a consequence of pancreatic resection and progressive disease. 

Nerve Blocks and Neurolysis The celiac plexus transmits visceral afferent impulses from the upper abdominal organs, including the pancreas. The greater, lesser, and least splanchnic nerves travel from the celiac plexus and then pass through the diaphragm to reach the spinal cord. Attempts to block the transmission of nociceptive stimuli have met with limited success. Celiac plexus block (usually using a combination of a glucocorticoid and a long-acting local anesthetic like bupivacaine) and celiac plexus neurolysis (using an injection of absolute alcohol) can be administered by CT- or EUSguided techniques, but EUS guidance is safer, more effective, and more long-lasting than that delivered under CT guidance.340-342 Despite that advantage, EUS-guided celiac plexus block is used infrequently due to the unpredictable response and short-lived effect.343 Celiac plexus neurolysis has been used in pancreatic carcinoma, but is not recommended for patients with chronic pancreatitis. Current guidelines do not recommend celiac plexus block or neurolysis for painful chronic pancreatitis.156,207,285 Interfering with nerve transmission through the splanchnic nerves might also block central perception of nociceptive inputs. This generally involves sectioning the greater splanchnic nerve on one or both sides. This can be performed through a thoracoscopic approach. Pain relief after thoracoscopic splanchnicectomy averages about 50% at 1 year and drops to 25% with longer follow-up.344,345 The lack of response might be explained by the multiple spinal levels that receive input from the splanchnic nerves and the tremendous variation in the number of splanchnic roots, which makes complete neurotomy difficult. This therapy is rarely performed. Another approach to minimizing nociception focuses on the central nervous system and pain perception. This has included therapy with centrally acting agents like SSRIs and gabapentinoids as discussed above, but also spinal cord stimulation and trans-cranial magnetic stimulation of pain centers in the brain.156,346,347 These are novel approaches, but their overall effectiveness remains to be determined. 

Treatment of Pain There are a variety of approaches to managing pain. The first step is to make sure the diagnosis is correct, which may be challenging in less-advanced chronic pancreatitis. It is prudent to assess for specifically treatable complications that might cause pain, such as gastric, duodenal, or biliary obstruction, pseudocyst, or secondary cancer.207,348 Before beginning therapy, it is helpful to quantify the severity, character, and temporal nature of pain, and the impact on quality of life. For most patients, an attempt at

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medical therapy utilizing formal structured alcohol and smoking abstinence programs and low-potency analgesics should be tried first. The addition of pancreatic enzymes and antioxidants as part of medical therapy may be tried, although the data supporting their effectiveness in reducing pain is limited. In those with an inadequate response, more potent narcotic analgesics coupled with an adjunctive agent (SSRI or gabapentinoid) should be considered. If this is ineffective, the next therapeutic decision hinges on whether the pancreatic duct is dilated greater than 5 mm. In those with a dilated pancreatic duct, endoscopic or surgical therapy should be considered. The choice of endoscopic or surgical therapy, and the type of surgical therapy, depends on patient choice, available expertise, and pancreatic anatomy. In those with a non-dilated pancreatic duct, continued medical therapy is appropriate, with consideration of total pancreatectomy and islet cell autotransplantation only for very selected patients. 

Maldigestion and Steatorrhea Although patients with chronic pancreatitis may maldigest fat, protein, and carbohydrates, it is fat maldigestion that is the principal clinical problem. It has been estimated that 90,000 USP units of lipase delivered to the intestine with each meal should be sufficient to eliminate steatorrhea.179,191,207 This corresponds to approximately 10% of the normal lower limit of pancreatic output of lipase. A number of factors limit the effectiveness of commercially available enzyme supplements. Pancreatic enzyme supplements vary in enzyme content. The lipase content of commercially available preparations ranges from 3000 to 40,000 USP units of lipase per pill or tablet. Five brand-name products are now available (see Table 59.6), and generic forms of pancreatic enzymes are not available. Much of the lipase may not reach the small bowel in an active form, being denatured by gastric acid or destroyed by proteases. Most commercially available enteric-coated enzyme preparations use a microsphere size that is too big to empty from the stomach in synchrony with the food. These enteric-coated microspheres may also not release their enzyme contents until they reach the distal jejunum or ileum, too distal for efficient fat digestion and absorption. Finally, the enzyme preparations are of relatively low potency, so many pills or tablets must be taken with each meal and snack. This requirement can have a major negative influence on compliance. Finally, these are costly agents and can cost patients up to $2000/monthly. These factors all interfere with the effective treatment of steatorrhea. Even in clinical studies, correction of fat digestion to normal levels is uncommon.349 The goal of managing steatorrhea is to assure that at least 90,000 USP units of lipase are present with each meal in the prandial and postprandial phase. It may not be necessary to administer that amount in every patient, as many patients still have some residual pancreatic secretion and because gastric lipase may partially compensate for the loss of pancreatic lipase.180 A starting dose of 40,000 to 50,000 is common, with upward titration based on effect. Many patients are under-treated,191,350-352 including those who are at highest risk after pancreatic surgery or resection for chronic pancreatitis.339 If the non–enteric-coated preparation is chosen, concomitant suppression of gastric acid with a histamine-2 receptor antagonist or proton pump inhibitor is necessary. The effectiveness of enzyme supplementation is generally gauged by clinical parameters, including improvement in stool consistency, loss of visible fat in the stool, and gain in body weight. Performing a 72-hour fecal fat analysis before the start of and during therapy, to prove effectiveness, is rarely needed but can be considered in those who do not show the expected response. It is important to periodically evaluate for deficiencies of fat-soluble vitamins, particularly vitamin D, and to assess for the presence of osteopenia or osteoporosis with a bone mineral density test.182-191,207,352 Appropriate enzyme therapy improves

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nutritional status, body weight, quality of life, and, possibly, mortality.190 There are numerous dietary recommendations for chronic pancreatitis, usually using very low-fat diets. There is no evidence that these diets are less likely to cause pain than other diets, and very low-fat diets may lead to worsening fat-soluble vitamin deficiencies. A heart-healthy or Mediterranean diet is reasonable, with avoidance of foods which cause symptoms. There are several potential explanations for failure of enzyme therapy for steatorrhea. The most common is inadequate dose, often due to patient noncompliance with the number of pills, or the cost of pills, that must be taken. Changing to a more potent preparation to reduce the number of pills taken can be helpful. It is also important to make sure that acid suppression has been prescribed and is being used by patients on the non–enteric-coated preparation. The enteric-coated preparations are not typically co-administered with an agent to reduce gastric acid. In some patients, the enteric-coated preparations may release enzymes in the mid or distal small bowel and this delayed release may not be sufficient to effectively treat steatorrhea. Adding an agent to suppress gastric acid can force these enteric-coated preparations to open more proximally in the small intestine and improve fat digestion in some patients, and can be considered in those that are not responding to therapy. The enzymes should be taken spread out over the course of the meal.191,352 It is occasionally useful to change from one formulation to another (e.g., changing from enteric-coated preparations to a combination of a non– enteric-coated preparation plus an agent to suppress acid) or to raise the dose higher than 90,000 USP units of lipase per meal, if the response is still not satisfactory. If all these measures fail to achieve the desired effect, it is appropriate to search for alternative diagnoses that could also produce malabsorption, such as celiac disease, or SIBO which may be a particular problem in these patients.353,354 The mechanism of SIBO in these patients is unknown but is likely related to abnormalities in small bowel motility (induced by the disease or by narcotic analgesics); the common use of proton pump inhibitor therapy, which facilitates bacterial overgrowth in the stomach; previous pancreatic and intestinal surgery; and possibly a decrease in the bactericidal capacity of pancreatic juice. Finally, if all these measures fail, one can replace dietary fat with medium-chain triglycerides, which do not require lipolysis (and hence lipase) for absorption. 

Diabetes Mellitus Periodic monitoring for the development of diabetes is appropriate in patients with chronic pancreatitis. A yearly fasting glucose level and hemoglobin A1C are appropriate.194,207 Residual functional β-cell mass can be estimated by measuring C-peptide levels. Although many patients may have diabetes as a consequence of islet destruction, about half of the risk of diabetes in these patients are typical risk factors for Type 2 DM.355 Diabetes mellitus is an independent predictor of mortality in patients with chronic pancreatitis. Morbidity and mortality due to diabetes mellitus may occur from progressive microangiopathic complications or from more dramatic complications, such as treatment-induced hypoglycemia (in those with inadequate glucagon reserve and particularly in those who are malnourished). 193-196 Ketoacidosis is unusual. Some patients show response to the use of an oral hypoglycemic, such as a sulfonylurea, thiazolidinedione, metformin, or other agents. Metformin is preferred, as there is circumstantial evidence that it may lower the risk of secondary pancreatic carcinoma.195 Insulin is often needed, however, and patients with chronic pancreatitis tend to have lower insulin requirements than patients with type 1 diabetes mellitus.195,196 Overvigorous attempts at tight control of blood glucose value may be associated with disastrous complications of treatment-induced hypoglycemia.198 Attempts at tight control of blood glucose value are indicated in one subgroup,

however—patients with hyperlipidemic pancreatitis—in whom the diabetes is usually a primary illness and tight control of blood glucose makes control of serum lipids possible. In long-standing diabetes, appropriate monitoring for nephropathy, retinopathy, and neuropathy is indicated. 

COMPLICATIONS Pseudocyst Pseudocysts are fluid-filled and walled-off cavities containing pancreatic fluid. They occur in about 25% of patients with chronic pancreatitis, and are most commonly seen in alcoholic chronic pancreatitis.356-359 The most common symptom associated with a pseudocyst is abdominal pain, which occurs in the majority of symptomatic patients. Less common manifestations are a palpable mass, nausea and vomiting (due to compression of the stomach or duodenum), jaundice (due to compression of the bile duct), and bleeding. Some patients are asymptomatic. Elevations in serum lipase and amylase values are found in at least one half of patients, and a persistent elevation in serum lipase or amylase can be a clue to the presence of a pseudocyst. The diagnosis of pseudocyst is generally made through imaging studies, including US, CT, MRI, and EUS. The advantages of CT and MRI in this setting are visualization of the capsule of the pseudocyst, which can be used to gauge the maturity of the collection, and determination of the relation of the pseudocyst to the stomach and duodenum, which can be useful in the choice of therapy. MRI can also give some additional information on the character of the contents of the collection, in particular whether it is mainly fluid or a mixture of fluid and solid material. Pseudocysts occur outside the pancreas and contain very little solid material.360 This differentiates them from walled-off necrosis, containing fluid and solid material and replacing the normal pancreas. ERCP is not required for diagnostic purposes, although around 70% of pseudocysts communicate with the pancreatic duct.357,358 ERCP is associated with an approximately 15% chance of infection of a previously uninfected pseudocyst, so this procedure should be undertaken only after antibiotics have been administered and therapy is imminent. The natural history of pseudocysts in chronic pancreatitis is not fully defined. Overall, complications of pseudocysts occur in 20% to 40% of cases. Complications include compression of large peripancreatic vessels, stomach, or duodenum; infection; hemorrhage; and development of a fistula. Many pseudocysts will remain without symptoms or complications. Unlike fluid collections and pseudocysts associated with acute pancreatitis, those occurring in a background of chronic pancreatitis resolve far less commonly. Despite that, treatment is not necessary in all patients. Patients who have minimal or no symptoms and no complications should be managed conservatively.357,358,361 Symptomatic or complicated pseudocysts require therapy. Pseudocysts occurring in the setting of chronic pancreatitis are generally mature at the time of their diagnosis (they have a visible capsule of granulation tissue surrounding them on CT or MRI), and a delay in therapy is not needed to allow the pseudocyst capsule to mature. Therapy for symptomatic, complicated, or rapidly enlarging pseudocysts can be surgical, percutaneous, or endoscopic. Percutaneous tube drainage of pseudocysts is possible if a safe tract to the collection can be identified. Percutaneous drainage of pancreatic pseudocysts complicating chronic pancreatitis is discouraged owing to the widely held view that such cysts are frequently associated with ductal obstruction downstream from the fluid collection, making the risks of fistula formation along the tract and of pseudocyst recurrence or chronic fistula after removal of the tube unacceptably high. The long-term success of percutaneous drainage is still unknown but is certainly relatively low. Re-accumulation of the collection after tube removal

CHAPTER 59  Chronic Pancreatitis

is the rule. Complications, which occur in less than 10% to 15% of cases, include bleeding, infection of the cavity, and formation of a draining fistula along the tube tract. Endoscopic therapy of pseudocysts is possible if the fluid collection can be accessed through the papilla or through the wall of the stomach or duodenum. The route chosen depends on the location of the pseudocyst. Transpapillary drainage is possible for smaller pseudocysts in the head of the gland that communicate with the pancreatic duct. All others that are amenable to endoscopic therapy are better managed with endoscopic cystogastrostomy or cystojejunostomy, depending on their location. Success rates of 80% to 90% are routinely reported.361-364 Many centers use endoscopic therapy as first-line therapy. The complication rate is about 10%.361-364 Most complications are related to transmural stent placement and include bleeding (which may occasionally be massive), perforation, and infection of previously uninfected collections. Using EUS to assess for large vessels between the gut lumen and the pseudocyst, and a direct EUSguided puncture to avoid nearby vessels reduces complications. Antibiotic coverage and readily available surgical backup are essential if endoscopic therapy is undertaken. Typically, stents are left in place for several weeks, or longer, to allow the pseudocyst to decompress. Most, but not all pseudocysts are amenable to endoscopic therapy. The long-term success rate of endoscopic therapy is not well defined but appears to be as good as surgical techniques. Surgical therapy usually involves cyst decompression into a loop of small bowel or stomach, often coupled with a pancreatic ductal drainage procedure (e.g., modified Puestow procedure). Surgical therapy has a long-term success rate of around 90% and an operative mortality of less than 3%.365 Although pseudocysts recur after surgery in only about 10% of cases, pain may return in up to one half with long-term follow-up. This is true of all therapies for pseudocysts, in that pain from the underlying chronic pancreatitis may also occur in the absence of a pseudocyst. Surgical therapy is also necessary in patients who experience severe complications of less-invasive endoscopic or percutaneous treatments. Cystogastrostomy and cystojejunostomy can be performed with laparoscopic techniques.365 One small prospective randomized trial compared EUS-guided pseudocyst drainage to open surgical cystogastrostomy, and found no difference in pseudocyst recurrence and that endoscopic therapy was associated with shorter hospital stays, better quality of life, and lower costs.366 No studies have directly compared laparoscopic with endoscopic techniques.367,368 It has been noted that failure of percutaneous drainage of pseudocysts is often associated with a stricture of the pancreatic duct downstream (toward the duodenum) from the pseudocyst or a significant disruption of the duct. These features predict prompt recurrence after the tubes are removed. Endoscopic therapy is prone to a similar problem unless these anatomic problems are dealt with. MRCP can be used to identify patients with pancreatic duct strictures or major disruptions who are at increased risk of recurrence. Although not a routine practice at all centers, performance of ERCP in association with (immediately before or after) EUS-guided pseudocyst drainage may be considered.363,364 The goal of the ERCP is to identify a pancreatic duct stricture or large duct disruption and treat this with a bridging stent. This might reduce the risk of pseudocyst recurrence after removal of the transenteric pseudocyst stents. In some patients in whom this is not possible, trans-enteric stents have been left in place indefinitely362-364 but the long-term safety of this approach is not known. Pseudocysts account for 90% of all cystic collections associated with the pancreas. Areas of walled-off pancreatic necrosis (in the setting of acute pancreatitis) can appear cystic on CT scans, but have a different therapeutic approach than a pseudocyst.360 A number of other cystic collections can mimic the appearance of a pseudocyst, in particular cystic neoplasms (Box 59.3, and see Chapter 60). 

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BOX 59.3 Cystic Collections within the Pancreas Pseudocyst (70%-90%) Cystic neoplasms (10%-15%)

Mucinous cystadenoma and ­cystadenocarcinoma Intraductal papillary mucinous neoplasm Serous cystadenoma Serous cystadenocarcinoma Solid pseudopapillary tumor Acinar cell cystadenocarcinoma Choriocarcinoma Teratoma Islet cell tumors with cystic ­degeneration Pancreatic ductal adenocarcinoma

True cysts (rare)

Polycystic disease of the pancreas (isolated or associated with ­polycystic disease of the kidneys) von Hippel-Lindau disease Simple true cyst Dermoid cyst

Miscellaneous cystic lesions (very rare)

Lymphoepithelial cyst Endometrial cyst Macrocyst associated with cystic fibrosis Retention cyst Parasitic cyst (Echinococcus ­granulosus or Taenia solium)

GI Bleeding GI bleeding in the setting of chronic pancreatitis may develop from a variety of causes. Some are not related to chronic pancreatitis, such as bleeding from a Mallory-Weiss tear, esophagitis, peptic ulcer disease, and varices from concomitant alcoholic cirrhosis. Others occur as a direct result of the pancreatitis, most notably bleeding from a pancreatic pseudocyst, pseudoaneurysm, and portal or splenic vein thrombosis. Bleeding may occur from the wall of a pseudocyst. Bleeding occurs from small vessels (venous, capillary, or arteriole) in the wall, which can lead to expansion of the pseudocyst and further rupture of these small vessels.369 Blood may remain in the pseudocyst or may reach the gut via a spontaneous pseudocyst decompression into the GI lumen or into the pancreatic duct (hemosuccus pancreaticus).370 Bleeding from small vessels in the wall of the pseudocyst is generally of low volume but is often associated with increased abdominal pain due to expansion of the pseudocyst. 

Pseudoaneurysm Pseudoaneurysms form as a consequence of enzymatic and pressure digestion of the muscular wall of an artery by a pseudocyst. The pseudoaneurysm may rupture either into the pseudocyst (converting the pseudocyst into a larger pseudoaneurysm) or directly into an adjacent viscus, peritoneal cavity, or pancreatic duct. Pseudoaneurysmal bleeding may complicate 5% to 10% of all cases of chronic pancreatitis with pseudocysts, although pseudoaneurysms may be seen in up to 21% of patients with chronic pancreatitis undergoing angiography.369,371,372 Pseudoaneurysms are also seen after pancreatic surgery. Many visceral arteries may be involved, the splenic artery being most common, followed by gastroduodenal or pancreaticoduodenal arteries. Once bleeding occurs, the mortality is at least 40%

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being related both to the severity of the blood loss and to the presence of coexisting conditions. Although death from a pseudocyst is rare, more than half the overall mortality of pseudocysts is due to hemorrhage. Bleeding from a pseudoaneurysm may be slow and intermittent or acute and massive. Common presentations are abdominal pain (due to the enlargement of the pseudocyst), unexplained anemia, and overt GI bleeding (if the blood can reach the gut lumen through the pseudocyst or through the pancreatic duct). In many cases, an initial self-limited bleed occurs (so-called sentinel bleed), followed hours or days later by a massive exsanguinating hemorrhage. The initial self-limited nature of the bleed may be due to transient tamponade of the bleeding within the confines of the pseudocyst. The presence of unexplained blood loss or any amount of GI bleeding in a patient with pancreatitis or a known pseudocyst should immediately raise the possibility of a pseudoaneurysm. If a pseudoaneurysm is suspected in the setting of upper GI blood loss, an urgent upper endoscopy should be undertaken. If no obvious bleeding site is seen, pseudoaneurysm formation should be considered. Rarely, blood may be seen issuing from the ampulla (hemosuccus pancreaticus), but the absence of this finding does not rule out pseudoaneurysm. The next step in the evaluation should be an emergency CT scan with intravenous contrast. The finding of high-density material within a pseudocyst on the initial noncontrast images is highly suggestive of a pseudoaneurysm, as is a circular opacifying structure within the low-attenuation pseudocyst after the intravenous administration of contrast agent (Fig. 59.9). It is prudent to avoid oral administration of a contrast agent so that it will not interfere with angiography if required. In most centers, such a CT finding is followed immediately by angiography to define and embolize the pseudoaneurysm. Once a pseudoaneurysm has been identified, it should be treated whether or not it has caused bleeding. Angiographic embolization or stentgraft placement has largely replaced primary surgery371,372 which is reserved for cases in which these therapies have failed. 

Fig. 59.9  CT scan demonstrating a pseudocyst containing a pseudoaneurysm (arrow) that is opacified following intravenous injection of contrast agent.

Variceal Bleeding From Splenic Vein Thrombosis Variceal bleeding may complicate chronic pancreatitis because of either associated alcoholic cirrhosis or thrombosis of the splenic (and, less commonly, portal) vein. Thrombosis of the splenic vein is most common and produces a segmental or left-sided portal hypertension.373 Decompression of splenic venous outflow occurs through the short gastric veins to the coronary vein, producing prominent variceal channels in the gastric cardia and fundus. Depending on the venous anatomy, esophageal varices may also be produced, although they are generally smaller than the gastric varices. The natural history of gastric varices in this setting is not known, but the overall risk of bleeding is less than with esophageal varices due to cirrhosis.369 The risk of gastric variceal bleeding is around 10% or less.373 Therapy is therefore not required in the absence of bleeding. Should bleeding occur, splenectomy is curative. Endoscopic control of bleeding is possible with gastric varices, utilizing cyanoacrylate injection or other techniques. 

Bile Duct Obstruction The distal bile duct is enclosed within the posterior portion of the head of the pancreas. Inflammatory and fibrotic conditions of the head of the pancreas, as well as cancer or a pseudocyst in this location, can compress this intrapancreatic bile duct, leading to abnormal liver chemistry values, jaundice, biliary pain, or cholangitis. Symptomatic bile duct obstruction occurs in about 10% of patients. The ductal stricture can be suspected from cholestatic liver chemistry values, CT or US findings of biliary ductal dilation, or both. ERCP characteristically demonstrates a long tapered stenosis of the distal bile duct (Fig. 59.10).

Fig. 59.10  A retrograde cholangiogram showing a smooth stricture of the bile duct (arrows) as it passes through the head of the pancreas in a patient with chronic pancreatitis.

The occurrence of cholangitis is an absolute indication for therapy. The presence of abnormal liver chemistry values or jaundice is not so straightforward because those most affected are alcoholic patients, and alcoholic (and other intrinsic) liver disease can also produce substantial abnormalities in liver chemistry values. The clinical, biochemical, and even radiologic features are not always sufficient to distinguish biliary stenosis from intrinsic liver disease.374 Liver biopsy may be necessary to determine the choice of therapy. An asymptomatic stenosis of the intrapancreatic bile duct, in the absence of symptoms, jaundice, or progressive abnormalities in liver chemistry values, can often be followed conservatively. If there is a concern about the development of secondary biliary cirrhosis, a liver biopsy should be performed. In patients with jaundice or biliary pain, in the absence of alternative explanations (i.e., intrinsic liver disease), therapy should be undertaken. Definitive therapy of bile duct obstruction usually involves surgical biliary bypass with choledochojejunostomy or choledochoduodenostomy. Many of these patients may have a large inflammatory mass of the head

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of the pancreas and undergo concomitant resection (Whipple operation or duodenum preserving pancreatic head resection). One study suggested that hepatic fibrosis due to chronic biliary obstruction may actually decrease after successful surgical decompression.375 Although endoscopic plastic stent therapy for biliary obstruction due to chronic pancreatitis is generally temporarily effective (see Chapter 61), the long-term success is relatively low.376 Placement of one or more plastic stents to treat bile obstruction is relatively simple, but the long-term management is complicated by the need for multiple stent exchanges over many months to years, and stent migration and obstruction are common. Long-term endoscopic stent therapy usually requires the use of either multiple plastic stents, or a fully-coated metal stent, with treatment times of 6 to 12 months.377,378 Long-term response is far less than surgical biliary bypass. The development of a bile duct stenosis in a patient with chronic pancreatitis may also signal the development of a pancreatic malignancy.110 EUS is useful in this setting to attempt to differentiate benign from malignant strictures. 

Duodenal Obstruction Approximately 5% of patients with chronic pancreatitis experience symptomatic duodenal stenosis. Fibrosis in the head of the pancreas, often associated with an inflammatory mass, is the most common explanation. Pancreatic malignancy superimposed on chronic pancreatitis can present in the same manner.110 Symptoms of duodenal obstruction include nausea, vomiting, weight loss, and abdominal pain. Coexistent obstruction of the bile duct may occur. The diagnosis is best made with CT using oral contrast or an upper GI barium study, because the extent of duodenal stenosis is often underestimated at the time of endoscopy. Because the degree of stenosis may improve with resolution of some of the inflammation, a trial of conservative therapy may be worthwhile. Surgical therapy is required for those in whom conservative management fails. The simplest approach is a bypass with a gastrojejunostomy, which may be performed with laparoscopic techniques. This may be coupled with drainage of the bile duct and/or pancreatic duct (lateral pancreaticojejunostomy). Resection of the head of the pancreas with a duodenum preserving pancreatic head resection or Whipple procedure may also be considered in select patients with a large inflammatory mass of the head of the pancreas,323-325 or in those in whom malignancy is also being considered. 

Pancreatic Fistulas External Fistulas External pancreatic fistulas occur most commonly as a consequence of surgical or percutaneous therapy for chronic pancreatitis or pseudocyst.379,380 It has been estimated that perhaps half of such fistulas heal with complete bowel rest and parenteral hyperalimentation. The most common complications are abscess and bleeding. There is some evidence that the addition of octreotide, in a dosage of 100 μg subcutaneously every 8 hours, can hasten closure of such fistulas. Successful medical treatment, even with octreotide, can take many weeks. The placement of an endoscopic stent across the site of ductal disruption is effective at closing the fistula rapidly. Up to 75% of pancreaticocutaneous fistulas may be effectively treated with endoscopic techniques,379,380 although this approach may need to be coupled with percutaneous drainage of intra-abdominal fluid collections. In patients in whom endoscopic therapy fails or cannot be performed, surgical treatment can involve pancreatic resection (if the fistula is in the tail) or a fistulojejunostomy, in which the fistula tract is “capped” with a defunctionalized limb of jejunum.379 

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Internal Fistulas Internal pancreatic fistulas occur mainly in the setting of chronic pancreatitis after rupture of a pseudocyst or after pancreatic trauma. The fluid may track to the peritoneal cavity (pancreatic ascites) or into the pleural space (pancreatic pleural effusion) or rarely to an adjacent hollow organ (stomach or duodenum or colon). The site and track of the fistula can usually be appreciated on MRCP. Affected patients may not complain of symptoms of chronic pancreatitis but may instead note abdominal distention or shortness of breath, depending on the site of fluid accumulation. Although such fistulas occur in advanced chronic pancreatitis there may not be a clear-cut history of recent symptomatic pancreatitis. The diagnosis can be established through documentation of high levels of amylase within the respective fluid, typically more than 4000 U/L. Conservative treatment, consisting of complete bowel rest, parenteral hyperalimentation, paracentesis or thoracentesis, and octreotide, is effective in some internal pancreatic fistulas.379 If the leak is in the body or head of the pancreas, a pancreatic duct stent covering the fistula site is highly effective. In some cases, merely bridging the ampulla with a short pancreatic duct stent may be enough to heal the fistula. Endoscopic therapy is less effective but still worthwhile if the leak is from the tail, but is ineffective if the leak is present upstream from a complete blockage of the pancreatic duct (excluded pancreatic tail syndrome). In this situation, resection or surgical drainage of the distal pancreas is required, and MRCP is used preoperatively to delineate the ductal anatomy for surgical planning. 

Malignancy The risk of pancreatic cancer is higher with all forms of chronic pancreatitis (see Chapter 60). The lifetime risk for pancreatic cancer in patients with chronic pancreatitis is about 4%, with an estimated relative risk of 13.14,31,32,381 The risk of pancreatic cancer is highest in patients with hereditary pancreatitis, those who smoke, and those who have coexistent diabetes.14,197,381-384 At present, there is no completely reliable way to differentiate chronic pancreatitis alone from chronic pancreatitis complicated by adenocarcinoma.110 The symptoms and signs may be similar (abdominal pain, weight loss, jaundice). In the absence of widespread metastases, imaging studies such as CT, US, and even ERCP may be unable to establish the diagnosis. EUS is most accurate, but finding a small hypoechoic tumor within a diseased gland with preexisting altered echotexture can be difficult. However, EUS is superior to CT for detection of coexistent malignancy particularly when the lesion is small. EUS also has the substantial advantage of allowing directed tissue biopsy of any suspicions lesions. Tumor markers may be helpful in attempting to differentiate chronic pancreatitis from cancer. CA 19-9, the tumor marker most commonly used for pancreatic adenocarcinoma, is elevated in the serum in 70% to 80% of patients with adenocarcinoma of the pancreas.385 Biliary obstruction and cholangitis can also raise CA 19-9 levels. The use of any of these techniques for surveillance is not cost-effective in the general population of patients with chronic pancreatitis, although they may be useful in families with hereditary pancreatic cancer and hereditary pancreatitis. In some patients, laparoscopy or laparotomy is required to determine the presence or absence of coexistent pancreatic carcinoma. In those with a benign pseudotumor who undergo resection to rule out malignancy, a variant of autoimmune chronic pancreatitis is often found.38,110 Extra-pancreatic cancers are also increased in patients with chronic pancreatitis, These cancers, particularly those of the upper digestive tract and lungs, are probably related to the effect of concomitant tobacco use.14,17,31,32 

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Dysmotility Gastroparesis and antroduodenal dysmotility are seen in patients with chronic pancreatitis,386,387 as a consequence of perigastric inflammation, hormonal changes associated with chronic pancreatitis (e.g., increases in plasma CCK), pancreatic surgery with reconstruction, or a side effect of narcotic analgesics. Gastroparesis is clinically important because it may produce

symptoms occasionally indistinguishable from those of the disease and may interfere with the effective delivery of pancreatic enzymes.387 Gastroparesis should be considered in patients with early satiety, nausea, vomiting, and weight loss. Full references for this chapter can be found on www.expertconsult.com 

.

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322. Ahmed Ali U, Pahlplatz JM, Nealon WH, et al. Endoscopic or surgical intervention for painful obstructive chronic pancreatitis. Cochrane Database Syst Rev 2015 Mar 19;(3):CD007884. 323. Zhao X, Cui N, Wang X, Cui Y. Surgical strategies in the treatment of chronic pancreatitis: an updated systematic review and meta-analysis of randomized controlled trials. Medicine (Baltim) 2017;96:e6220. 324. Plagemann S, Welte M, Izbicki JR, Bachman K. Surgical treatment for chronic pancreatitis: past, present, and future. Gastroenterol Res Pract 2017:8418372. 325. Dua MM, Visser BC. Surgical approaches to chronic pancreatitis: indications and techniques. Dig Dis Sci 2017;62:1738–44. 326. Beger HG, Schlosser W, Friess HM, et al. Duodenum-preserving head resection in chronic pancreatitis changes the natural course of the disease: a single-center 26-year experience. Ann Surg 1999;230:512–9. 327. Frey CF, Reber HA. Local resection of the head of the pancreas with pancreaticojejunostomy. J Gastrointest Surg 2005;9:863–8. 328. Gloor B, Freiss H, Uhl W, et al. A modified technique of the Beger and Frey procedure in patients with chronic pancreatitis. Dig Surg 2001;18:21–5. 329. Diener MK, Huttner FJ, Kieser M, et al. Partial pancreatodudenectomy versus duodenum-preserving pancreatic head resection in chronic pancreatitis: the multicenter, randomized, controlled, double-blind ChroPac trial. Lancet 2017;390:1027–37. 330. Gurusamy KS, Lusuku C, Halkias C, Davidson BR. Duodenumpreserving pancreatic resection versus pancreaticoduodenectomy for chronic pancreatitis. Cochrane Database Syst Rev 2016 Feb 3;2:CD011521. 331. Strijker M, van Santvoort HC, Besselink MG, et al. Robot-assisted pancreatic surgery: a systematic review of the literature. HPB 2013;15:1–10. 332. de Rooj T, Klompmaker S, Hilal MA, et al. Laparoscopic pancreatic surgery for benign and malignant disease. Nat Rev Gastroenterol Hepatol 2016;13:227–38. 333. Yang CJ, Bliss LA, Schapira EF, et al. Systematic review of early surgery for chronic pancreatitis: impact on pain, pancreatic function, and re-intervention. J Gastrointest Surg 2014;18:1863–8. 334. Ke N, Jia D, Huang W, et al. Earlier surgery improves outcomes from painful chronic pancreatitis. Medicine (Baltim) 2018;97:e0651. 335. Ahmed Ali U, Issa Y, Bruno MJ, et al. Early surgery versus optimal current step-up practice for chronic pancreatitis (ESCAPE): design and rationale of a randomized trial. BMC Gastroenterol 2013;13:49. 336. Bramis K, Gordon-Weeks AN, Friend PJ, et al. Systematic review of total pancreatectomy and islet autotransplantation for chronic pancreatitis. Br J Surg 2012;99:761–6. 337. Wu Q, Zhang M, Qin Y, et al. Systematic review and meta-analysis of islet autotransplantation after total pancreatectomy in chronic pancreatitis patients. Endocrin J 2015;62:227–34. 338. Bellin MD, Freeman ML, Gelrud A, et al. Total pancreatectomy and islet autotransplantation in chronic pancreatitis: recommendations from PancreasFest. Pancreatology 2014;14:27–35. 339. Sabater L, Ausania F, Bakker OJ, et al. Evidence-based guidelines for the management of pancreatic exocrine insufficiency after pancreatic surgery. Ann Surg 2016;264:949–58. 340. Gress F, Schmidt C, Sherman S, et al. A prospective randomized comparison of endoscopic ultrasound- and computed tomographyguided celiac plexus block for managing chronic pancreatitis pain. Am J Gastroenterol 1994;94:900–5. 341. Santosh D, Lakhtakia S, Gupta R, et al. Clinical trial: a randomized trial comparing fluoroscopy guided percutaneous technique vs. endoscopic ultrasound guided technique for celiac plexus block for treatment of pain in chronic pancreatitis. Aliment Pharmacol Ther 2009;29:979–84. 342. Kaufman M, Singh G, Das S, et al. Efficacy of endoscopic ultrasound-guided celiac plexus block and celiac plexus neurolysis for managing abdominal pain associated with chronic pancreatitis and pancreatic cancer. J Clin Gastroenterol 2010;44:127–34. 343. Michaels AJ, Draganov PV. Endoscopic ultrasonography guided celiac plexus neurolysis and celiac plexus block in the management of pain due to pancreatic cancer and chronic pancreatitis. World J Gastroenterol 2007;13:3575–80. 344. Baghdadi S, Abbas MH, Albouz F, Ammori BJ. Systematic review of the role of thoracoscopic splanchnicectomy in palliating the pain of patients with chronic pancreatitis. Surg Endosc 2008;22:580–8.

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345. Buscher HC, Schipper EE, Wilder-Smith OH, et al. Limited effect of thoracoscopic splanchnicectomy in the treatment of severe chronic pancreatitis: a prospective long-term analysis of 75 cases. Surgery 2008;143:715–22. 346. Fregni F, Freedman SD, Pascual-Leone A. Recent advances in the treatment of chronic pain with non-invasive brain stimulation techniques. Lancet Neurol 2007;6:188–91. 347. O’Connell NE, Marston L, Spencer S, DeSouza LH, Wand BM. Non-invasive brain stimulation techniques for chronic pain. Cochrane Database Syst Rev 2018 Mar 16;3:CD008208. 348. Chauhan S, Forsmark CE. Pain management in chronic pancreatitis: a treatment algorithm. Best Pract Res Clin Gastroenterol 2010;24:323–35. 349. De la Iglesia-Gasrcia D, Huang W, Szatmary P, et al. Efficacy of pancreatic enzyme replacement therapy in chronic pancreatitis: systematic review and meta-analysis. Gut 2017;66:1474–86. 350. Sikkens EC, Cahen DL, van Eijck C, et al. The daily practice of pancreatic enzyme replacement therapy after pancreatic surgery: a northern European survey: enzyme replacement after surgery. J Gastrointest Surg 2012;16:1487–92. 351. Sikkens EC, Cahen DL, van Eijck C, et al. Patients with exocrine insufficiency due to chronic pancreatitis are undertreated: a Dutch national survey. Pancreatology 2012;12:71–3. 352. Dominguez-Munoz JE. Diagnosis and treatment of pancreatic exocrine insufficiency. Curr Opin Gastroenterol 2018;34:349–54. 353. Ni Chonchubhair HM, Bashir Y, Dobson M, et al. The prevalence of small intestine bacterial overgrowth in non-surgical patients with chronic pancreatitis and pancreatic exocrine insufficiency. Pancreatology 2018;18:379–85. 354. DiMagno MJ, Forsmark CE. Chronic pancreatitis and small intestinal bacterial overgrowth. Pancreatology 2018;18:360–2. 355. Bellin MD, Whitcomb DC, Abberbock J, et al. Patient and disease characteristics associated with the presence of diabetes mellitus in adults with chronic pancreatitis in the US. Am J Gastroenterol 2017;112:1457–65. 356. Aghdassi A, Mayerle J, Kraft M, et al. Diagnosis and treatment of pancreatic pseudocysts in chronic pancreatitis. Pancreas 2008;36:105–12. 357. Baillie J. Pancreatic pseudocysts (part I). Gastrointest Endosc 2004;59:873–9. 358. Baillie J. Pancreatic pseudocysts (part II). Gastrointest Endosc 2004;60:105–13. 359. Ramsey ML, Conwell DL, Hart PA. Complications of chronic pancreatitis. Dig Dis Sci 2017;62:1745–50. 360. Banks PA, Bollen TL, Dervenis C, et al. Classification of acute pancreatitis—2012: revision of the Atlanta classification and definitions by international consensus. Gut 2013;62:102–11. 361. Chauhan SS, Forsmark CE. Evidence-based treatment of pancreatic pseudocysts. Gastroenterology 2013;145:511–3. 362. Elmunzer BJ. Endoscopic drainage of pancreatic fluid collections. Clin Gastroenterol Hepatol 2018;16:1851–63. 363. Teoh AYB, Dhir V, Kida M, et al. Consensus guidelines on the optimal management in interventional EUS procedures: results from the Asian EUS group RAND/UCLA panel. Gut 2018;67:1209–28. 364. Samuelson AL, Shah RJ. Endoscopic management of pancreatic pseudocysts. Gastroenterol Clin North Am 2012;41:47–62. 365. Matsuoka L, Alexopoulos SP. Surgical management of pancreatic pseudocysts. Gastrointest Endosc Clin N Am 2018;28:131–41. 366. Varadarajulu S, Bang JY, Sutton BS, et al. Equal efficacy of endoscopic and surgical cystgastrostomy for pancreatic pseudocyst drainage in a randomized trial. Gastroenterology 2013;145:583–90.

367. Aljarabah M, Ammori BJ. Laparoscopic and endoscopic approaches for drainage of pancreatic pseudocysts: a systematic review of published series. Surg Endosc 2007;21:1936–44. 368. Gurusamy KS, Pallari E, Hawkins N, Pereira SP, Davidson BR. Management strategies for pancreatic pseudocysts. Cochrane Database Syst Rev 2016 Apr 14;4:CD011392. 369. Forsmark CE, Wilcox CM, Grendell JH. Endoscopy-negative upper gastrointestinal bleeding in a patient with chronic pancreatitis. Gastroenterology 1992;102:320–9. 370. Yu P, Gong J. Hemosuccus pancreaticus: a mini-review. Ann Med Surg (Lond) 2018;28:45–8. 371. Evans RP, Murad MM, Pall G, Fisher SG, Bramhall SR. Pancreatitis: preventing catastrophic haemorrhage. World J Gastroenterol 2017;23:5460–8. 372. Kirby JM, Vora P, Midia M, Rawlinson J. Vascular complications of pancreatitis: imaging and intervention. Cardiovasc Intervent Radiol 2008;31:957–70. 373. Butler JR, Eckert GJ, Zyromski NJ, et al. Natural history of pancreatitis-induced splenic vein thrombosis: a systematic review and meta-analysis of its incidence and rate of gastrointestinal bleeding. HPB 2011;13:839–45. 374. Lesur G, Levy P, Flejou JF, et al. Factors predictive of liver histopathological appearance in chronic alcoholic pancreatitis with common bile duct stenosis and increased serum alkaline phosphatase. Hepatology 1993;18:1078–81. 375. Hammel P, Couvelard A, O’Toole D, et al. Regression of liver fibrosis after biliary drainage in patients with chronic pancreatitis and stenosis of the common bile duct. N Engl J Med 2001;344:418–23. 376. Kahl S, Zimmermann S, Genz I, et al. Risk factors for failure of endoscopic stenting of biliary strictures in chronic pancreatitis: a prospective follow-up study. Am J Gastroenterol 2003;98: 2448–53. 377. Chan CH, Telford JJ. Endoscopic management of benign biliary strictures. Gastrointest Endosc Clin N Am 2012;22:511–37. 378. Mangiavillano B, Pagano N, Baron TH, Luigiano C. Outcome of stenting in biliary and pancreatic benign and malignant disease: a comprehensive review. World J Gastroenterol 2015;21:9038–54. 379. Blatnik JA, Hardacre JM. Management of pancreatic fistulas. Surg Clin North Am 2013;93:611–7. 380. Malleo G, Pulvirenti A, Marchegiani G, et al. Diagnosis and management of postoperative pancreatic fistula. Langenbeck’s Arch Surg 2014;399:801–10. 381. Lowenfels AB, Maisonneuve P, Cavallini G, et al. Pancreatitis and the risk of pancreatic cancer. N Engl J Med 1993;328:1433–7. 382. Raimondi S, Lowenfels AB, Morselli-Labate AM, et al. Pancreatic cancer in chronic pancreatitis; aetiology, incidence, and early detection. Best Pract Res Clin Gastroenterol 2010;24:349–58. 383. Eibl G, Cruz-Monserrate Z, Korc M, et al. Diabetes mellitus and obesity as risk factors for pancreatic cancer. J Acad Jutr Diet 2018;118:555–67. 384. Andersen DK, Korc M, Petersen GM, et al. Diabetes, pancreatocogenic diabetes, and pancreatic cancer. Diabetes 2017;42:1227–37. 385. Loosen SH, Neumann UP, Trautwein C, Roderburg C, Luedde T. Current and future biomarkders for pancreatic adenocarcinoma. Tuymour Biol 2017;39:1010428317692231. 386. Vu MK, Vecht J, Eddes EH, et al. Antroduodenal motility in chronic pancreatitis: are abnormalities related to exocrine insufficiency? Am J Physiol 2000;278:G458–66. 387. Chowdhury RS, Forsmark CE, Davis RH, et al. Prevalence of gastroparesis in patients with small duct chronic pancreatitis. Pancreas 2003;26:235–8.

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Pancreatic Cancer, Cystic Pancreatic Neoplasms, and Other Nonendocrine Pancreatic Tumors* Bijal Modi, G. Thomas Shires

CHAPTER OUTLINE PANCREATIC CANCER. . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Features. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Staging. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CYSTIC TUMORS OF THE PANCREAS. . . . . . . . . . . . . . . . Mucinous Cystic Neoplasms. . . . . . . . . . . . . . . . . . . . . Serous Cystadenomas. . . . . . . . . . . . . . . . . . . . . . . . . . Intraductal Papillary Mucinous Neoplasms. . . . . . . . . . . Solid Pseudopapillary Tumors. . . . . . . . . . . . . . . . . . . . OTHER PANCREATIC TUMORS. . . . . . . . . . . . . . . . . . . . .

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PANCREATIC CANCER The most common malignancy arising from the pancreas is a ductal adenocarcinoma.1 Pancreatic adenocarcinoma is a highly lethal malignancy representing 3% of all cancer cases in the USA but representing 7% of all cancer deaths. There were approximately 53,760 new cases with 43,090 deaths expected in 2017.2 Despite its relatively low incidence compared with other malignancies, it represents the 4th leading cause of cancer death in men and women and is expected to become the 2nd leading cause of cancer death by 2030.1 The 5-year survival rate for newly diagnosed pancreatic adenocarcinoma remains 8%.3 Numerous factors have made the usual strategies of early detection and better treatment options an ongoing challenge.

Epidemiology Incidence In the period between 2003 and 2014, the incidence rate of pancreatic cancer (PC) remained stable in the USA, with a slight elevation in the white population.4 PC is a disease of aging, with the median age at diagnosis of 71 years, with many cases diagnosed before the age of 65. It is rarely seen before the age of 45, with its incidence rising sharply after the age of 50. There is a slight male predominance with a higher incidence in blacks compared to whites.4 

Populations at Risk There are a number of risk factors associated with the development of PC. Certain risk factors are immutable: advanced age, * Lalan Wilfong contributed to a previous version of this chapter.

male gender, African American race and family history, whereas other risk factors are accrued over time or are environmental (obesity, smoking, alcohol use, chronic pancreatitis). The vast majority of PCs are sporadic in nature. Approximately 5% to 10% of cases are associated with familial PC syndromes, defined as those with 2 or more first-degree family members with PC. Patients with a familial PC syndrome tend to be younger at diagnosis (median age 64 to 65 years).5 Table 60.1 summarizes some of the genetic syndromes associated with an increased risk of PC. Increased risk of PC has been associated with a number of inherited gene mutations: BRCA2, CDKN2A, ATM, mismatch repair enzyme instability as present in Lynch syndrome, PALB2, STK11, PRSS1, and SPINK2. CDKN2A and BRCA2 are the most prominent inherited gene mutations associated with inherited PC, with BRCA2 mutations representing the most common gene mutation.5,6 Familial atypical multiple mole melanoma (FAMMM) is an autosomal dominant condition defined by a mutation of tumor suppressor gene CDKN2A. Normally, CDNKN2A encodes the p16 protein preventing phosphorylation and activation of the retinoblastoma gene. Patients with FAMMM are at risk for melanoma and PC.7 Hereditary pancreatitis (see Chapter 57), commonly caused by an autosomal dominant mutation in the PRSS gene, is associated with a near 50% incidence of PC by age 74.8 Patients with other, non-hereditary forms of chronic pancreatitis also have a higher likelihood of developing PC. Smoking and alcohol use are risk factors that may synergize with chronic pancreatitis to influence tumor development.9 Individuals with Peutz-Jeghers syndrome with STK11 gene mutations, discussed in Chapter 126, have a cumulative risk of PC by age 65 to 70 of 11% to 36%.10 Screening for PC has represented a difficult proposition owing to the low incidence of disease, cost and expertise necessary for imaging, and relatively low sensitivity of imaging modalities. The most efficient mechanism to increase the positive predictive value of screening would be to identify high-risk populations. Currently, family history and the presence of defined gene mutations represent the most effective mechanisms to identify high-risk populations.11 The number of first-degree relatives (FDRs) with PC strongly influences an individual’s cancer risk. The risk of PC is increased 6.4-fold with 2 affected FDRs and 32-fold with 3 FDRs.12 The 2013 International Cancer of the Pancreas Screening (CAPS) consortium has agreed that individuals with 3 or more blood relatives with PC, with at least 1 affected FDR, should be considered for screening. Those with at least 2 affected FDRs should also be considered for screening. Individuals with 2 affected blood relatives with PC, with at least 1 FDR, can be considered for screening. Patients with specific mutations should be considered for screening: Peutz-Jeghers regardless of family history and BRCA2/PALB2/p16/ patients with Lynch syndrome who have an FDR with PC should be considered for screening. Agreed-upon screening modalities include MRI/MRCP and EUS.13 There is no consensus age to initiate screening, although the AGA suggests screening begins at the age of 35 in patients with hereditary pancreatitis or 10 years before the age of the index case in the setting of familial PC.14

947

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PART VII  Pancreas

TABLE 60.1  Historical Features and Genetic Syndromes Associated with an Increased Risk of Pancreatic Cancer History

Mutated Gene

Relative Risk

Individual Risk by Age 70

None

None

1

0.5%

Breast cancer

BRCA2

3.5-10

5%

BRCA1

2

1%

FAMMM syndrome

TP16 (CDKN2A)

20-34

10%-17%

≥3 FDRs with PC

Unknown

32

16%

Hereditary pancreatitis

PRSS1

50-80

25%-40%

Peutz-Jeghers syndrome

STK11/LKB1

132

30%-60%

HNPCC syndrome

MLH1, MSH2, others

Unknown

45 kg/m2) than in nonobese control women. Obesity is associated with increased hepatic secretion of cholesterol into bile, possibly because of higher enzymatic activity of HMG-CoA reductase and increased cholesterol synthesis in the liver. As a result, gallbladder bile is more lithogenic in obese than in nonobese persons, and a higher ratio of cholesterol to solubilizing lipids (bile acids and phospholipids) is observed in the former group. These alterations predispose to cholesterol crystallization and gallstone formation. Gallbladder motility is often impaired in obese persons, thereby promoting mucin secretion and accumulation, as well as cholesterol crystallization. The effect of pronucleating and antinucleating factors on cholesterol crystallization and gallstone formation in gallbladder bile warrants further investigation in obese and nonobese subjects. 

Octreotide The somatostatin analog octreotide increases the prevalence of gallstones when administered to patients as treatment for acromegaly, with approximately 28% of treated acromegalic patients forming gallstones. Acromegalic patients who are treated with octreotide display dysfunctional gallbladder motility, sluggish intestinal transit, and increased colonic deoxycholic acid formation and absorption,52 all of which facilitate formation of cholesterol gallstones. 

Diabetes Mellitus Patients with diabetes mellitus have long been considered to be at increased risk of developing gallstones because hypertriglyceridemia and obesity are associated with diabetes mellitus and because gallbladder motility is often impaired in patients with diabetes mellitus.59 Proving that diabetes mellitus is an independent risk factor for gallstones has been difficult, however. Mice with hepatic insulin resistance induced by liver-specific disruption of the insulin receptor are markedly predisposed to formation of cholesterol gallstones.60 Hepatic insulin resistance promotes hepatic secretion of biliary cholesterol by increasing expression of the hepatic cholesterol transporters Abcg5 and Abcg8 through the forkhead transcription factor FoxO1 pathway. It also reduces expression of the bile salt synthetic enzymes, particularly oxysterol 7α-hydroxylase, thereby resulting in a lithogenic bile salt profile. 

Ceftriaxone The third-generation cephalosporin ceftriaxone has a long duration of action, with much of the drug excreted in the urine. Approximately 40% of the drug, however, is secreted in an unmetabolized form into bile, where its concentration reaches 100 to 200 times that of the concentration in plasma and exceeds its saturation level in bile. Once its saturation level is exceeded, ceftriaxone complexes with calcium to form insoluble salts, thereby resulting in formation of biliary sludge. Up to 43% of children who receive high doses of ceftriaxone (60 to 100 mg/kg/day) have been reported to form biliary sludge, and about 19% of these

Diseases of the Ileum Disease or resection of the terminal ileum has been found to be a risk factor for gallstone formation. For example, intestinal bile salt absorption is often impaired in patients with Crohn disease, who are at increased risk of gallstones.61 The loss of specific bile salt transporters (e.g., ileal apical sodium-dependent bile acid transporter) in the terminal ileum may result in excessive bile salt excretion in feces and a diminished bile salt pool size, presumably with a consequent increase in the risk of cholesterol gallstones. These changes may also lead to formation of pigment gallstones because increased bile salt delivery to the colon enhances

65

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solubilization of unconjugated bilirubin, thereby increasing bilirubin concentrations in bile.62  Spinal Cord Injuries Spinal cord injuries are associated with a high prevalence of gallstones, which have been reported in some 31% of such patients, who have an annual rate of biliary complications of 2.2%. Although the complication rate associated with gallstones in patients with spinal cord injuries is at least 2-fold higher than the rate of gallstones in the general population, the relative risk is still low enough that prophylactic cholecystectomy is probably not justified. The mechanisms responsible for the association between spinal cord injuries and gallstone formation remain unclear. Gallbladder relaxation is impaired in these patients, but gallbladder contraction in response to a meal is normal. Therefore, the increased risk of gallstones is unlikely to be due to biliary stasis alone.  NAFLD Both gallstone disease and NAFLD are highly prevalent in the general population and often co-exist in the same populations (see Chapter 87). These epidemiologic and clinical studies raise the possibility that both disorders could be casually related, similar risk factors influence the natural history of NAFLD and gallstone disease, or NAFLD is indeed an independent risk factor for cholesterol cholelithiasis. Although many clinical studies have investigated the association between NAFLD and gallstone disease, the results have been variable.63-68 The relationship among insulin resistance (evaluated with the homeostatic model assessment), liver fibrosis, NASH, and gallstone disease has been studied in morbidly obese patients with NAFLD before bariatric surgery.67 The prevalence of NASH is 18% in a morbid obese population with gallbladder disease. The third large U.S. National Health and Nutrition Examination Survey (NHANES) between 1988 and 1994 investigated 12,232 subjects by US and reported an association between gallstone disease, with a prevalence of 7.4% for gallstones and 5.6% for cholecystectomy, and NAFLD, with a prevalence of 20.0%.63 The prevalence of NAFLD was significantly higher in the group that underwent cholecystectomy (48.4%) and in the gallstone group (34.4%) than in the gallstone-free group (17.9%). These findings suggest that both conditions are tightly associated with metabolic disturbances such as obesity, insulin resistance, dyslipidemia, and the metabolic syndrome.  Celiac Disease Celiac disease is a chronic, small intestinal, autoimmune enteropathy caused by an intolerance to dietary gluten in genetically predisposed individuals (see Chapter 107). Clinical studies have found that, because of defective CCK release from the proximal small intestine caused by enteropathy in patients with celiac disease before they start a gluten-free diet, gallbladder emptying in response to a fatty meal is impaired.67-72 Lack of CCK markedly enhances susceptibility to cholesterol gallstones via a mechanism involving dysmotility of both the gallbladder and the small intestine.73 Because a gluten-free diet can significantly improve celiac enteropathy, early diagnosis and therapy in celiac patients is crucial for preventing the long-term impact of CCK deficiency on biliary and intestinal function. When gluten is reintroduced in the diet, clinical and histologic relapse often occurs in patients with celiac disease. Moreover, some patients do not respond well to a gluten-free diet. Patients with celiac disease should routinely undergo US to determine whether gallbladder motility function is preserved and whether biliary sludge (a precursor to gallstones) is present in the gallbladder. Impaired intestinal CCK secretion is the link between celiac disease and cholesterol gallstone disease.74 Because neither epidemiologic investigations of gallstone prevalence rates in patients with

celiac disease nor clinical studies of the impact of celiac disease on the pathogenesis of gallstones have been reported, whether celiac disease is an independent risk factor for gallstone disease remains largely unknown. 

Protective Factors Statins Use of statins has been associated with a decreased risk of gallstone disease in 2 large case-control studies. The first study compared 27,035 patients with gallstone disease who required cholecystectomy with 106,531 matched controls and showed a benefit to long-term statin use (>20 prescriptions filled and use of statins for >1.5 years)75; statin use was associated with a decreased risk of gallstone disease requiring cholecystectomy (adjusted odds ratio [OR], 0.64). Similar results were observed in a population study from Denmark of 32,494 patients with gallstone disease matched with 324,925 controls.76 The odds ratios of having gallstone disease in current and prior users of statins (>20 prescriptions filled) were 0.76 and 0.79, respectively, compared with controls. 

Ascorbic Acid The observation that deficiency of ascorbic acid (vitamin C) is associated with the development of gallstones in guinea pigs prompted investigation of the relationship between ascorbic acid levels and gallstones in humans. Serum ascorbic acid levels have been correlated with clinical or asymptomatic gallstones in 7042 women and 6088 men who were enrolled in the third NHANES.77 Among women, but not men, each standard deviation increase in serum ascorbic acid levels was associated with a 13% lower prevalence rate of clinical gallbladder disease. 

Coffee In a 10-year follow-up of 46,000 male health professionals, subjects who consistently drank 2 to 3 cups of regular coffee per day were approximately 40% less likely to develop symptomatic gallstones.78 Drinking 4 or more cups per day was even more beneficial (relative risk 0.55), but there was no benefit to drinking decaffeinated coffee. A similar benefit to regular coffee was noted in a cohort study involving 81,000 women.79 

COMPOSITION AND ABNORMALITIES OF BILE Physical Chemistry of Bile Chemical Composition of Bile Cholesterol, phospholipids, and bile salts are the 3 major lipid species in bile, and bile pigments are minor solutes. Cholesterol accounts for up to 95% of the sterols in bile and gallstones; the remaining 5% of the sterols are cholesterol precursors and dietary sterols from plant and shellfish sources. Concentrations of cholesteryl esters are negligible in bile and account for less than 0.02% of total sterols in gallstones. The major phospholipids are lecithins (phosphatidylcholines), which account for more than 95% of total phospholipids; the remainder consists of cephalins (phosphatidylethanolamines) and a trace amount of sphingomyelin. Phospholipids constitute 15% to 25% of total lipids in bile. Lecithins are insoluble amphiphilic molecules with a hydrophilic zwitterionic phosphocholine head group and hydrophobic tails that include 2 long fatty acyl chains. Biliary lecithins possess a saturated C-16 acyl chain in the sn-1 position and an unsaturated C-18 or C-20 acyl chain in the sn-2 position. The major molecular species of lecithins (with corresponding frequencies) in bile are 16:0 to 18:2 (40% to 60%), 16:0 to 18:1

CHAPTER 65  Gallstone Disease

(5% to 25%), 18:0 to 18:2 (1% to 16%), and 16:0 to 20:4 (1% to 10%). Lecithins are synthesized principally in the endoplasmic reticulum of the hepatocyte from diacylglycerols through the cytidine diphosphate-choline pathway. The common bile salts typically contain a steroid nucleus of 4 fused hydrocarbon rings with polar hydroxyl functions and an aliphatic side chain conjugated in amide linkage with glycine or taurine. In bile, more than 95% of bile salts are 5β,C-24 hydroxylated acidic steroids that are amide-linked to glycine or taurine in an approximate ratio of 3:1. Bile salts constitute approximately two thirds of the solute mass of normal human bile by weight. The hydrophilic (polar) areas of bile salts are the hydroxyl groups and conjugated side chain of either glycine or taurine, and the hydrophobic (nonpolar) area is the ringed steroid nucleus. Because they possess both hydrophilic and hydrophobic surfaces, bile salts are highly soluble, detergentlike, amphiphilic molecules. Their high aqueous solubility is due to their capacity to self-assemble into micelles when a critical micellar concentration is exceeded. The primary bile salts are hepatic catabolic products of cholesterol and are composed of cholate (a trihydroxy bile salt) and chenodeoxycholate (a dihydroxy bile salt) (see Chapter 64). The secondary bile salts are derived from the primary bile salt species by the action of intestinal bacteria in the ileum and colon and include deoxycholate, ursodeoxycholate, and lithocholate. The most important of the conversion reactions is 7α-dehydroxylation of primary bile salts to produce deoxycholate from cholate and lithocholate from chenodoxycholate. Another important conversion reaction is the 7α-dehydrogenation of chenodeoxycholate to form 7α-oxo-lithocholate. This bile salt does not accumulate in bile but is metabolized by hepatic or bacterial reduction to form the tertiary bile salt chenodeoxycholate (mainly in the liver) or its 7β-epimer ursodeoxycholate (primarily by bacteria in the colon). Bile pigments are minor solutes and are formed as a metabolic product of certain porphyrins. They account for roughly 0.5% of total lipids in bile by weight. They are mainly bilirubin conjugates with traces of porphyrins and unconjugated bilirubin. Bilirubin can be conjugated with a molecule of glucuronic acid, which makes it soluble in water. In human bile, bilirubin monoglucuronides and diglucuronides are the major bile pigments. Other bile pigments are monoconjugates and diconjugates of xylose, glucose, and glucuronic acid and various homoconjugates and heteroconjugates of them. Proteins and inorganic salts are also found in bile. Albumin appears to be the most abundant protein in bile, followed by immunoglobulins G and M, apolipoproteins AI, AII, B, CI, and CII, transferrin, and α2-macroglobin. Other proteins that have been identified but not quantitated in bile include EGF, insulin, haptoglobin, CCK, lysosomal hydrolase, and amylase. Inorganic salts detected in bile include sodium, phosphorus, potassium, calcium, copper, zinc, iron, manganese, molybdenum, magnesium, and strontium. 

Physical States of Biliary Lipids Cholesterol is nearly insoluble in water, and the mechanism by which cholesterol is solubilized in bile is complex because bile is an aqueous solution. The 2 main types of macromolecular aggregates in bile are micelles and vesicles, which greatly enhance the solubilization of cholesterol in bile. Bile salts are soluble in an aqueous solution because they are amphiphilic, in that they have both hydrophilic and hydrophobic areas. This unique property of bile salts is dependent on the number and characteristics of the hydroxyl groups and side chains, as well as the composition of the particular aqueous solution. When bile salt concentrations exceed the critical micellar concentration, their monomers can spontaneously aggregate to form simple micelles. The simple micelles (≈3 nm in diameter) are small, disklike, and thermodynamically stable aggregates that can solubilize

1021

cholesterol. They can also solubilize and incorporate phospholipids to form mixed micelles that are capable of solubilizing at least triple the amount of cholesterol compared with that solubilized by simple micelles. Mixed micelles (4 to 8 nm in diameter) are large, thermodynamically stable aggregates composed of bile salts, phospholipids, and cholesterol. Their size depends on the relative proportion of bile salts and phospholipids. The mixed micelle is a lipid bilayer with the hydrophilic groups of the bile salts and phospholipids aligned on the “outside” of the bilayer, interfacing with the aqueous bile, and the hydrophobic groups on the “inside.” Therefore, cholesterol molecules can be solubilized on the inside of the bilayer away from the aqueous areas on the outside. The amount of cholesterol that can be solubilized is dependent on the relative proportions of bile salts, and the maximal solubility of cholesterol occurs when the molar ratio of phospholipids to bile salts is between 0.2 and 0.3. Furthermore, the solubility of cholesterol in mixed micelles is enhanced when the concentration of total lipids in bile is increased. When model and native biles are examined by quasi-elastic light-scattering spectroscopy and electron microscopy, it is found that, besides micelles, vesicles solubilize cholesterol in bile. Biliary vesicles are unilamellar spherical structures that contain phospholipids, cholesterol, and little if any bile salts. Vesicles are substantially larger than either simple or mixed micelles (40 to 100 nm in diameter) but much smaller than liquid crystals (≈500 nm in diameter) that are composed of multilamellar spherical structures. Because vesicles are present in large quantities in hepatic bile, they could be secreted by hepatocytes. Unilamellar vesicles are often detected in freshly collected samples of unsaturated bile and are physically indistinguishable from those identified in supersaturated bile. Dilute hepatic bile, in which solid cholesterol crystals and gallstones never form, is always supersaturated with cholesterol because vesicles solubilize biliary cholesterol in excess of what could be solubilized in mixed micelles. Cholesterol-rich vesicles are remarkably stable in dilute bile, consistent with the absence of cholesterol crystallization in hepatic bile. The unilamellar vesicles can fuse and form large multilamellar vesicles (also known as liposomes or liquid crystals). Solid cholesterol monohydrate crystals may nucleate from multilamellar vesicles in concentrated gallbladder bile. Vesicles are relatively static structures that are affected by several factors, including biliary lipid concentrations and the relative ratios of cholesterol, phospholipids, and bile salts. The relative concentrations of these 3 important lipids in bile are influenced by their hepatic secretion rates, which vary with fasting and feeding. For example, during the fasting period, hepatic output of biliary bile salts is relatively low. As a result, the ratio of cholesterol to bile salts is increased, and more cholesterol is carried in vesicles than in micelles. By contrast, with feeding, hepatic output of biliary bile salts is increased, and more cholesterol is solubilized in micelles than in vesicles. In addition, when the concentration of bile salts is relatively low, especially in dilute hepatic bile, vesicles are relatively stable, and only some vesicles are converted to micelles. By contrast, with increasing bile salt concentrations in concentrated gallbladder bile, vesicles may be converted completely into mixed micelles. Because relatively more phospholipids than cholesterol can be transferred from vesicles to mixed micelles, the residual vesicles are remodeled and may be enriched in cholesterol relative to phospholipids. If the remaining vesicles have a relatively low ratio ( HDL > chylomicron remnants) plus de novo hepatic cholesterol synthesis. Output is related to the amount of cholesterol disposed of within the liver by conversion to cholesteryl ester (to form new VLDL and for storage) minus the amount of cholesterol converted to primary bile salts. An appreciable fraction of cholesterol in bile may also be derived from the diet via apolipoprotein E–dependent delivery of chylomicron remnants to the liver. Under low or no dietary cholesterol conditions, bile contains newly synthesized cholesterol from the liver and preformed cholesterol that reaches the liver in several different ways. Approximately 20% of the cholesterol in bile comes from de novo hepatic biosynthesis, and 80% is from pools of preformed cholesterol within the liver. De novo cholesterol synthesis in the liver uses acetate as a substrate and is mainly regulated by the rate-limited enzyme HMG-CoA reductase. This enzyme can be up- or down-regulated depending on the overall cholesterol balance in the liver. An increase in the activity of this rate-limiting enzyme leads to excessive cholesterol secretion in bile. The major sources of preformed cholesterol are hepatic uptake of plasma lipoproteins (mainly HDL and LDL through their receptors on the basolateral membrane of hepatocytes). Consistent with their central role in reverse cholesterol transport, HDL particles are the main lipoprotein source of cholesterol that is targeted for biliary secretion. Under conditions of a high cholesterol diet, dietary cholesterol reaches the liver through the intestinal lymphatic pathway as chylomicrons and then chylomicron remnants, after chylomicrons are hydrolyzed by plasma lipoprotein lipase and hepatic lipase. The synthesis of

HEPATOCYTE

HMGCR

SR-BI

ABCB4

PL

CMRR ACAT CH ester Esterification

VLDL ABCA1

Canalicular membrane

Biosynthesis

ABCG5/G8 CH

CYP7A1 Catabolism Nascent HDL

BILE

Acetate LDLR

CYP27A1

CH

NPC1L1

BS

Vesicle

ABCB11

BS

Fig. 65.4 Uptake, biosynthesis, catabolism, and biliary secretion of cholesterol at the hepatocyte level. Hepatic uptake of cholesterol is mediated by the LDL receptor (LDLR), by scavenger receptor class B type I (SR-BI) for HDL, and by the chylomicron remnant receptor (CMRR) for chylomicron remnants (CMR). Biosynthesis of hepatic cholesterol (CH) from acetate is regulated by the rate-limiting enzyme 3-hydroxy-3-methylglutarylcoenzyme A reductase (HMGCR). Part of the cholesterol is esterified by acyl-coenzyme A:cholesterol acyltransferase (ACAT) for storage in the liver. Some of the cholesterol is used for the formation of VLDL, which is secreted into the blood. The ABC transporter ABCA1 may translocate, either directly or indirectly, cholesterol and phospholipids to the cell surface, where they appear to form lipid domains that interact with amphipathic α-helices in apolipoproteins. This interaction solubilizes these lipids and generates nascent HDL particles that dissociate from the cell. A proportion of cholesterol is used for synthesis of bile salts (BS) via the classical and alterative pathways, as regulated by 2 rate-limiting enzymes, cholesterol 7α-hydroxylase (CYP7A1) and sterol 27-hydroxylase (CYP27A1), respectively. Hepatic secretion of biliary cholesterol, bile salts, and phospholipids (PL) across the canalicular membrane is determined by 3 lipid transporters, ABCG5/G8, ABCB11, and ABCB4, respectively. The Niemann-Pick C1-like 1 (NPC1L1) protein may have a weak role in taking cholesterol back from hepatic bile to the hepatocyte. A vesicle is shown in the canaliculus.  

1023

65

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PART VIII  Biliary Tract

new cholesterol in the liver is reduced and comprises only about 5% of biliary cholesterol. Overall, the liver can systematically regulate the total amount of cholesterol within it, and any excess cholesterol is handled efficiently. Although biliary phospholipid is derived from the cell membranes of hepatocytes, the composition of biliary phospholipid differs markedly from that of hepatocyte membranes. The membranes of hepatocytes contain phosphatidylcholines (lecithins), phosphatidylethanolamines, phosphatidylinositols, phosphatidylserines, and sphingomyelins. The major source of phosphatidylcholine molecules destined for secretion into bile is hepatic synthesis. A fraction of biliary phosphatidylcholines may also originate in the phospholipid coat of HDL particles. From 10 to 15 g of phospholipids are secreted into bile each day in humans. More than 95% of bile salt molecules, after secretion into bile, return to the liver through the enterohepatic circulation by absorption mostly from the distal ileum via an active transport system such as apical sodium-dependent bile acid transporter and organic solute transporters α and β (see Chapter 64). Consequently, newly synthesized bile salts in the liver contribute only a small fraction (G (rs9514089)

—

+

+

↓ Intestinal bile salt absorption

SLCO1B1 (OATP1B1)

Solute carrier organic anion transporter family, member 1B1

12p12

p.P155Thr (rs11045819)

—

—

+

↓ Intestinal bile salt absorption

TM4SF4

Transmembrane 4

3q25.1

—

TBD

TBD

superfamily member 4

Cholesterol 7α-hydroxylase (Cytochrome P450 7A1)

8q11-q12

Promoter SNP−204A>C

+

—

+

↓ The rate-limiting enzyme for bile salt biosynthesis in the classical pathway

UGT1A1

Bilirubin UDP-glucuronyl transferase

2q37

Promotor A(TA)7TAA

—

—

+

↑ Hepatic bilirubin conjugation

SULT2A1

Sulfotransferase

19q13.33

rs2547231

—

—

+

? sulfate conjugation and detoxification of bile salts family 2A, member 1

GCKR

Glucokinase

2p23.3

rs1260326

—

—

+

↑ Altered glucose homeostasis, ↑ cholesterol synthesis regulatory protein

16q12-q21

RFLP

—

—

+

↑ Hepatic cholesterol uptake from increased HDL catabolism

12q23.1

Promoter SNPs −1G>T and −20647T>G, IVS7−31 A>T

—

—

+

↓ Conversion of cholesterol into bile salts ↑ Biliary cholesterol secretion

11q23-q24

−75G>A, RFLP

—

—

+

↑ Biliary cholesterol secretion secondary to increased reverse cholesterol transport

Lipid Regulatory Enzymes CYP7A1

Intracellular Lipid Regulatory Transporter CETP Cholesteryl ester transfer protein Lipid Regulatory Transcription Factor NR1H4 (FXR) Nuclear receptor 1H4 (Farnesoid X receptor)

Lipoprotein Receptors and Related Genes APOA1 Apolipoprotein A1

APOB

Apolipoprotein B

2p24-p23

c.2488C>T, c.4154G>A

+

—

+

↑ Biliary cholesterol secretion secondary to reduced hepatic VLDL synthesis ↑ Intestinal cholesterol absorption

APOC1

Apolipoprotein C1

19q13.2

RFLP

—

—

+

↑ APOC1 remnant-like particle cholesterol

PART VIII  Biliary Tract

Gene symbol

Chromosome location

LDL receptor–related protein-associated protein 1

4p16.3

Intron 5 insertion/ deletion (rs11267919)

—

—

+

↑ Hepatic cholesterol uptake from chylomicron remnants via LRP

Hormone Receptors CCK1R (CCKAR)

Cholecystokinin 1 receptor (CCK A receptor)

4p15.1-p15.2

RFLP

+

—

+

↓ Gallbladder and small intestinal motility

ESR2 (ERβ)

Estrogen receptor 2

14q23.2

c.1092+3607(CA)n

—

—

+

↑ Hepatic cholesterol biosynthesis

AR

Androgen receptor

Xq12

c.172(CAG)n

—

—

+

↓ Gallbladder motility

ADRB3

β3-Adrenergic receptor

8p12

p.R64W (rs4944)

—

—

+

↓ Gallbladder motility

Black Pigment Stones ANK1

Ankyrin 1

8p11.1

Multiple

—

+

—

Spherocytosis → hemolysis

CFTR (ABCC7)

CF transmembrane regulator

7q31.2

Δq31

+

—

—

↑ Enterohepatic bilirubin circulation ↓ Bile pH ↑ Fecal bile salt excretion

G6PD

Glucose-6-phosphate dehydrogenase

Xq28

Multiple

+

+

+

↑ Hemolysis

GPI

Glucose-6-phosphate isomerase

19q13.1

p.Leu339Pro

TBD

PKLR

Pyruvate kinase

1q21

p.R510Q

TBD

HBA1/2

Hemoglobin alpha chain complex

16p13.3

HbH

HBB

Hemoglobin beta chain complex

11p15.5

p.E26K (HbE) p.E6V (HbS)

UGT1A1

Bilirubin UDP-glucuronyl transferase

2q37

Promotor A(TA)7TAA

—

—

+

↑ Hepatic bilirubin conjugation

Biliary Tract Stones COMT

Catechol-O-methyltransferase

22q11.21

Exon4−76C>G (rs4818)

—

—

+

↑ Estrogen levels

CXCR2

Chemokine (C-X-C motif) receptor 2

2q35

c.811C>T (rs2230054) c.1235T>C (rs1126579)

—

—

+

TBD

IL8

Interleukin-8

4q13-q21

−351A>T (rs4073)

—

—

+

↑ IL8 expression → inflammation

NOS2

Nitric oxide synthase 2

17q11.2-q12

Exon16+14C>T (rs2297518)

—

—

+

TBD

RNASEL

Ribonuclease L

1q25

Exon1−96A>G (rs486907)

—

—

+

TBD

LRPAP1

—

+

TBD TBD +

TBD

α-Thalassemia/ β-thalassemia intermediate/minor/sickle cell disease → hemolysis TBD

CHAPTER 65  Gallstone Disease

  

LRP, Low-density lipoprotein receptor-related protein; RFLP, restriction fragment length polymorphism; SNP, single nucleotide polymorphism; TBD, to be determined; UDP, uridine diphosphate. Adapted with permission from Krawczyk M, Wang DQ, Portincasa P, et al. Dissecting the genetic heterogeneity of gallbladder stone formation. Semin Liver Dis 2011;31:157–72.   

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PART VIII  Biliary Tract

some ethnic groups at high risk of gallstones. This study strongly suggests that inhibiting both hepatic synthesis and intestinal absorption of cholesterol to reduce biliary output of cholesterol may be a therapeutic strategy for genetically defined subgroups of persons at high risk for gallstones.208 The factors that regulate intestinal membrane lipid transporters, lipid regulatory enzymes, intracellular lipid transporters, and lipid regulatory transcription factors may influence the amount of cholesterol of intestinal origin that contributes to biliary secretion by the liver. Direct evidence for the role of intestinal factors in mouse gallstones comes from a study of ACAT2-knockout mice.209 Because of the deletion of the Acat2 gene, the lack of cholesteryl ester synthesis in the small intestine significantly reduces intestinal cholesterol absorption and leads to complete resistance to diet-induced cholesterol gallstones. Furthermore, the potent cholesterol absorption inhibitor ezetimibe prevents gallstones by effectively reducing intestinal absorption and biliary secretion of cholesterol and protects gallbladder motility by desaturating bile in mice.50,210 Moreover, ezetimibe significantly reduces biliary cholesterol saturation and retards cholesterol crystallization in bile of patients with gallstones.50 Therefore, reduced intestinal absorption of cholesterol or hepatic uptake of chylomicron remnants may induce a decrease in biliary cholesterol secretion and saturation. In addition, reduced expression levels of the genes that encode the ileal apical sodium-dependent bile acid transporter (ASBT), the cytosolic ileal lipid binding protein (ILBP), and organic solute transporters α and β (OSTα and β) may contribute to gallstone formation by decreased ileal bile acid reabsorption and an altered bile acid pool and composition in female and nonobese patients with gallstones compared with control subjects (see Chapter 64).211,212 The single nucleotide polymorphism rs9514089 in the ASBT gene (gene symbol SLC10A2) has been identified as a susceptibility variant for cholelithiasis in humans,213 although the effect of rs9514089 genotype on gallstone risk was not replicated in Sorbs.214 Further analyses in larger cohorts are required to evaluate the role of genetic variants of SLC10A2 as a risk factor for gallstone formation. 

PIGMENT STONES Although the pathogenesis of black and brown pigment gallstones is not as well understood as that of cholesterol gallstones, and each type of stone probably has a distinctive pathogenesis, both types of pigment stones result from abnormalities in the metabolism of bilirubin and are pigmented as a result of bilirubin precipitation.215-217 In general, the bile of patients with either type of pigment stones contains an excess of unconjugated bilirubin, analogous to the saturation of bile with cholesterol in patients with cholesterol stones.218 Also, both types of pigment stones are composed primarily of bile pigment and contain a matrix of mucin glycoproteins. In black stones, however, the pigment is predominantly an insoluble highly cross-linked polymer of calcium bilirubinate, whereas in brown stones, the main pigment is monomeric calcium bilirubinate. The 2 types of pigment stones also differ in radiodensity, location within the biliary tract, and geographic distribution. Results of studies of susceptibility genes for pigment stones are summarized in Table 65.1. Several candidate genes enhance the formation of pigment stones by increasing enterohepatic cycling of bilirubin. Persons with Gilbert syndrome have mild, chronic, unconjugated hyperbilirubinemia in the absence of liver disease or overt hemolysis because of reduced expression of bilirubin uridine diphosphate glucuronyl transferase 1 (gene symbol UGT1A1), which is due to an abnormality in the promoter region of the gene for this enzyme (see Chapter 21).219 A genome-wide association study has identified a variant of the UGT1A1 gene as a major risk factor for gallstone disease in

humans.220 The UGT1A1 promoter variant increases the susceptibility to pigment stone formation in patients with sickle cell disease or CF.221-224 A regression analysis has shown that serum bilirubin levels and the prevalence of gallstones are strongly associated with the number of UGT1A1 promoter [TA] repeats in patients with sickle cell disease, with each additional repeat correlating with an increase in serum bilirubin levels of 21% and in cholelithiasis risk of 87%.222 Moreover, UGT1A1 gene variants in linkage disequilibrium with the variant are associated with the risk of developing cholesterol gallstones. These findings imply that the supersaturation of bile with bilirubin may be a risk factor for the formation of both pigment and cholesterol gallbladder stones. As discussed earlier, increased biliary bilirubin levels and enhanced precipitation of calcium bilirubinate in bile provide a critical nidus for cholesterol nucleation and crystallization. The frequency of gallstones in patients with CF is 10% to 30% compared with less than 5% in age-matched control subjects, but biliary cholesterol saturation does not differ between patients with and without gallstones. In fact, gallstones in patients with CF are generally black pigment stones (i.e., composed of calcium bilirubinate with an appreciable cholesterol admixture) but rarely cause symptoms. In a mouse (ΔF508 mutant) model of CF, increased fecal bile salt loss induces more hydrophobic bile salts in hepatic bile and augments enterohepatic cycling of bilirubin.225 These alterations lead to hyperbilirubinbilia and significantly higher levels of all bilirubin conjugates and unconjugated bilirubin, followed by hydrolysis and precipitation of divalent metal salts of unconjugated bilirubin in bile. In addition, lower gallbladder bile pH values and elevated levels of calcium bilirubinate ion products in bile increase the likelihood of supersaturating bile with bilirubin and forming black pigment gallstones. The pancreatic duodenal homeobox gene-1 (Pdx1) is required for proper development of the major duodenal papilla, peribiliary glands, and mucin-producing cells in the bile duct and for maintenance of the periampullary duodenal epithelial cells during the perinatal period (see Chapter 62). Loss of the major duodenal papilla allows duodenobiliary reflux and bile infection, resulting in formation of brown pigment stones in Pdx1-knockout mice, and treatment with antibiotics significantly reduces the frequency of brown pigment stones.226

Black Stones Black pigment stones are formed in uninfected gallbladders, particularly in patients with chronic hemolytic anemia (e.g., β-thalassemia, hereditary spherocytosis, sickle cell disease), ineffective erythropoiesis (e.g., pernicious anemia), ileal diseases (e.g., Crohn disease) with spillage of excess bile salts into the large intestine, extended ileal resections, and liver cirrhosis. These alterations promote formation of black pigment stones because higher colonic bile salt concentrations enhance the solubilization of unconjugated bilirubin, thereby increasing bilirubin concentrations in bile.227 The resulting unconjugated bilirubin is precipitated as calcium bilirubinate to form stones.228 This type of stone is composed of either pure calcium bilirubinate or polymer-like complexes consisting of unconjugated bilirubin, calcium bilirubinate, calcium, and copper. Mucin glycoproteins account for as much as 20% of the weight of black pigment stones. A regular crystalline structure is not present in this type of stone. For hepatic secretion, bilirubin is first mono- or diglucuronidated by UGT1A1 and subsequently secreted by ABC transporter C2 (ABCC2), also called multidrug-resistance associated protein 2 (MRP2) (see Chapters 64 and 77). Under normal physiologic conditions, unconjugated bilirubin is not secreted into bile. Although bilirubin glucuronides are hydrolyzed by endogenous β-glucuronidase, unconjugated bilirubin constitutes

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CHAPTER 65  Gallstone Disease

less than 1% of total bile pigment, primarily because the activity of the enzyme is inhibited by β-glucaro-1,4-lactone in the biliary tract.229,230 The unifying predisposing factor in black pigment stone formation is hepatic hypersecretion of bilirubin conjugates (especially monoglucuronides) into bile. In the presence of hemolysis, hepatic secretion of these bilirubin conjugates increases 10-fold. Unconjugated monohydrogenated bilirubin is formed by the action of endogenous β-glucuronidase, which coprecipitates with calcium as a result of supersaturation. A 1% hydrolysis rate may give rise to high concentrations of unconjugated bilirubin that often greatly exceed the solubility of bilirubin in bile. A defect in acidification of bile may also be induced by gallbladder inflammation or the reduced buffering capacity of sialic acid and sulfate moieties in the mucin gel. The reduction in buffering capacity facilitates supersaturation of calcium carbonate and calcium phosphate that would not occur at a more acidic pH. Gallbladder motility defects are not observed in patients with black pigment stones. 

Brown Stones Brown pigment stones are composed mainly of calcium salts of unconjugated bilirubin, with varying amounts of cholesterol, fatty acids, pigment fraction, and mucin glycoproteins, as well as small amounts of bile salts, phospholipids, and bacterial residues. Brown pigment stones may be easily distinguished grossly from black pigment stones by their reddish brown to dark brown color and lack of brightness. Their shape is irregular or molded and occasionally spherical. Most of the stones are muddy in consistency, and some show facet formation. Brown pigment stones are either smooth or rough without any surface luster and are soft, fragile, and light in comparison with other gallstones. The cut surface is generally a stratified structure (lamellation) or is amorphous without the radiating crystalline structure seen in cholesterol stones. Almost invariably, brown pigment stones have a lamellated cross-sectional surface with calcium bilirubinate-rich layers alternating with calcium palmitate-rich layers. Brown pigment stones are formed not only in the gallbladder but also commonly in other portions of the biliary tract,

Fig. 65.6  Proposed mechanisms for the pathogenesis of brown pigment stones. Under normal physiologic conditions, unconjugated bilirubin is not secreted into bile. Although modest hydrolysis of bilirubin glucuronides by endogenous β-glucuronidase occurs, unconjugated bilirubin constitutes less than 1% of total bile pigment, mostly because the activity of β-glucuronidase is inhibited by β-glucaro-1,4-lactone in the biliary system. The presence of excess bacterial β-glucuronidase, however, overcomes the inhibitory (−) effect of βglucaro-1,4-lactone, which results in hydrolysis of bilirubin glucuronide into free bilirubin and glucuronic acid. Free bilirubinate combines with calcium to yield water-insoluble calcium bilirubinate. In addition, phospholipase A1 liberates free fatty acids such as palmitic and stearic acids from phospholipids, and bile salt hydrolases produce unconjugated bile salts from glycine or taurine-conjugated bile salts. Dead bacteria and/or parasites could act as nuclei that accelerate precipitation of calcium bilirubinate. The mucin gel in the gallbladder can trap these complex precipitates and facilitate their growth into macroscopic stones.

especially in intrahepatic bile ducts. Formation of brown pigment stones requires the presence of structural or functional stasis of bile associated with biliary infection, especially with Escherichia coli.231 These stones are quite prevalent in Asia, where Clonorchis sinensis and roundworm infestations are common, and parasitic elements have been considered to be kernels of brown pigment stone formation (see Chapter 84).232 Bile stasis predisposes to bacterial infection as well as accumulation of mucins and bacterial cytoskeletons in the bile ducts. Bile stasis may be induced by bile duct stenosis and bacterial infection caused by infestation of parasites and their ova.233 As the incidence of biliary infections has decreased in Asian populations prone to development of brown pigment stones, the ratio of cholesterol stones to pigment stones has also changed in these populations. The percentage of brown pigment stones in Japan has fallen from 60% to 24% since the 1950s, and similar changes have been reported from other Asian countries.234-236 Enteric bacteria produce β-glucuronidase, phospholipase A1, and conjugated bile acid hydrolase. Activity of β-glucuronidase results in production of unconjugated bilirubin from bilirubin glucuronide; phospholipase A1 liberates palmitic and stearic acids from phospholipids; and bile acid hydrolases produce unconjugated bile salts from glycine or taurine-conjugated bile salts. Partially ionized saturated fatty acids, unconjugated bilirubin, and unconjugated bile salts may precipitate as calcium salts. Mucin gel can trap these complex precipitates and facilitate their growth into macroscopic brown pigment stones. Fig. 65.6 shows the postulated mechanisms underlying the formation of brown pigment stones. Under normal physiologic conditions, bilirubin in bile exists mainly as bilirubin glucuronide, which is soluble in aqueous media. Bile also contains β-glucuronidase of tissue origin, the activity of which is inhibited by β-glucaro-1,4-lactone, which is also formed in the liver. If infection with E. coli occurs, the concentration of bacterial β-glucuronidase increases significantly and exceeds the inhibitory power of β-glucaro-1,4-lactone. As a result, bilirubin glucuronide is hydrolyzed to produce unconjugated bilirubin and glucuronic acid; the former is water-insoluble and combines with calcium to form calcium bilirubin at its carboxyl radical, thereby leading to the formation of brown pigment gallstones. 

Phospholipids

Bilirubin glucuronides

Conjugated bile salts

-Glucaro-1,4lactone Bacterial -glucuronidase Glucuronic acid

(–)

Phospholipase A1

Bile salt hydrolase

Endogenous -glucuronidase

Free bilirubin

Calcium bilirubinate

Calcium

Free fatty acids

Free unconjugated bile salts

Brown pigment stones

Dead bacteria and/or parasites

Mucin gel

65

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PART VIII  Biliary Tract

NATURAL HISTORY

Symptomatic Stones

The natural history of gallstones is typically described in 2 separate groups of patients: those who have symptoms and those who are asymptomatic. Autopsy studies clearly show that the vast majority of patients with gallstones are asymptomatic and remain so. Ascertaining the true frequency of complications in persons with asymptomatic stones (as well as those with symptomatic stones) is critical to providing rational, cost-effective recommendations regarding therapy (see later). Unfortunately, the information available on the natural history of gallstones has been sparse and somewhat varied.237-239

The cardinal symptom of gallstones is biliary pain (“colic”), which is described as pain in the RUQ often radiating to the back, with or without nausea and vomiting. The pain is usually not true colic (see Chapter 11) and is almost never associated with fever. The natural history of symptomatic gallstones has a more aggressive course than that of asymptomatic stones. The U.S. National Cooperative Gallstone Study showed that in persons who had an episode of uncomplicated biliary pain in the year before entering the study, the rate of recurrent biliary pain was 38% per year.243 Other investigators have reported a rate of recurrent biliary pain as high as 50% per year in persons with symptomatic gallstones.244 As noted earlier, biliary complications are also more likely to develop in persons with symptomatic gallstones. The risk of biliary complications is estimated to be 1% to 2% per year and is believed to remain relatively constant over time.245 Therefore, cholecystectomy should be offered to patients after biliary symptoms develop. In patients with high operative risk, an alternative approach is close observation, because 30% will have no further episodes of biliary pain. 

Asymptomatic Stones The study that changed our understanding of the course and appropriate therapy of gallstone disease was performed by Gracie and Ransohoff.237 They monitored 123 University of Michigan faculty members for 15 years after they had been found to have gallstones on routine screening US. At 5, 10, and 15 years of follow-up, 10%, 15%, and 18% of the patients, respectively, had become symptomatic, and none had experienced serious complications. The investigators suggested that the rate at which biliary pain develops in persons with asymptomatic gallstones is about 2% per year for 5 years and then decreases over time. Biliary complications developed in only 3 patients in this study, and all complications were preceded by episodes of biliary pain. In fact, biliary pain, not a biliary complication, is the initial manifesting symptom in 90% of people with previously asymptomatic gallstones.237 Therefore, in patients with asymptomatic stones, the frequency of complications is low, and prophylactic cholecystectomy is not necessary. Subsequent studies have reported slightly higher rates of biliary pain and complications in patients with initially asymptomatic gallstones,238 but only 1 was a long-term and prospective study.239 The Group for Epidemiology and Prevention of Cholelithiasis (GREPCO) in Rome reported the courses of 151 subjects with gallstones, 118 of whom were asymptomatic on entering the study. In those who were initially asymptomatic, the frequency of biliary pain was 12% at 2 years, 17% at 4 years, and 26% at 10 years, and the cumulative rate of biliary complications was 3% at 10 years.239 In a 1987 study, incidental gallstones were discovered in 285 (21%) of 1371 patients from Norway who had not had a cholecystectomy.240 Twenty-four years later, a follow-up study included 134 of the patients who had gallstones.241 Gallstones were present on US in 25 of 89 patients (28% overall, 31% of women and 25% of men), and there was no correlation between initial size and number of gallstones and persistence of stones on follow-up. Nine of 134 patients (7%) had undergone cholecystectomy, as had 5 of 91 patients who had died prior to follow up (6%). During follow up, abdominal pain developed in 44%, and 29% had what were deemed to be functional abdominal complaints. This study illustrates again both the frequent resolution and relatively benign nature of asymptomatic gallstone disease. 

Stones in Patients With Diabetes Mellitus Diabetic patients have been considered at increased risk of gallstone complications; however, the natural history of gallstones in diabetic patients follows the same pattern observed in nondiabetic persons. A prospective study of patients with insulinresistant diabetes mellitus showed that after 5 years of follow-up, symptoms had developed in 15% of the asymptomatic patients.242 Moreover, the complication and mortality rates were comparable to those in studies of nondiabetic patients with gallstones. Therefore, prophylactic cholecystectomy is not recommended in patients with insulin-resistant diabetes mellitus and asymptomatic gallstones. 

Special Patient Populations The clinical manifestations of gallstones are shown schematically in Fig. 65.7 and summarized in more detail in Table 65.2.246-250 Biliary pancreatitis is discussed in Chapter 58. Although the standard approach to asymptomatic gallstones is observation, some patients with asymptomatic gallstones may be at increased risk of complications and may require consideration of prophylactic cholecystectomy. An increased risk of cholangiocarcinoma and gallbladder carcinoma has been associated with certain disorders of the biliary tract and in some ethnic groups (e.g., Native Americans) (see Chapter 69). Risk factors include choledochal cysts, Caroli disease, pancreaticobiliary malunion (also referred to as anomalous union of the pancreatic and biliary ducts, in which the pancreatic duct drains into the bile duct), large gallbladder adenomas, and porcelain gallbladder (see Chapters 55, 62, and 67). Patients at increased risk of biliary cancer may benefit from prophylactic cholecystectomy. If abdominal surgery is planned for another indication, an incidental cholecystectomy should be performed. Pigment gallstones are common and often asymptomatic in patients with sickle cell disease. Prophylactic cholecystectomy is not recommended, but an incidental cholecystectomy should be considered if abdominal surgery is performed for other reasons. Some authorities recommend combined prophylactic splenectomy and cholecystectomy in young asymptomatic patients with hereditary spherocytosis if gallstones are present. Morbidly obese persons who undergo bariatric surgery are at high risk of complications of gallstones (see Chapters 7 and 8). These patients have a frequency of gallstones of greater than 30%. An incidental cholecystectomy is recommended at the time of surgery. Some investigators have proposed that patients with incidental cholelithiasis who are awaiting heart transplantation undergo a prophylactic cholecystectomy irrespective of the presence or absence of biliary tract symptoms because they are at increased risk of post-transplant gallstone complications.251 A retrospective study that addressed this issue in renal transplant recipients, however, concluded that complications of gallstones could be managed safely after symptoms emerged.252 

DIAGNOSIS Imaging studies play a central role in the diagnosis of gallstones and associated conditions. Table 65.3 shows the wide array of imaging techniques available to evaluate the biliary tract.253-256

CHAPTER 65  Gallstone Disease

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Stone intermittently obstructing Stone impacted in the cystic the cystic duct, causing intermittent duct, causing acute cholecystitis (10%) biliary pain (20%) 3 Stone in the cystic duct 2 compressing or fistulizing into the common hepatic duct, causing 4 Mirizzi syndrome (100% because patients with acute cholecystitis generally have had prior episodes of biliary pain.)

Long-standing cholelithiasis, resulting in gallbladder carcinoma (10 mg/dL suggests malignant obstruction or coexisting hemolysis A transient “spike” in serum aminotransferase or amylase (or lipase) levels suggests the passage of a stone

Leukocytosis in 80%, but the remainder may have a normal WBC count with or without band forms Serum bilirubin level is >2 mg/dL in 80% Serum alkaline phosphatase level is usually elevated Blood cultures are usually positive, especially during chills or a fever spike; 2 organisms are grown in cultures from half of patients

Diagnostic studies (see Table 65.3 for details on imaging studies)

US Oral cholecystography Meltzer-Lyon test (see Chapter 67)

US Hepatobiliary scintigraphy Abdominal CT

ERCP EUS MRC Percutaneous THC

ERCP Percutaneous THC

Natural history

After the initial attack, 30% of patients have no further symptoms Symptoms develop in the remainder at a rate of 6% per year, and severe complications at a rate of 1%-2% per year

50% of cases resolve spontaneously in 7-10 days without surgery Left untreated, 10% of cases are complicated by a localized perforation and 1% by a free perforation and peritonitis

The natural history is not well defined, but complications are more common and more severe than for asymptomatic stones in the gallbladder

A high mortality rate if unrecognized, with death from septicemia Emergency decompression of the BD (usually by ERCP) improves survival dramatically

Treatment (see Chapters 66 and 70)

Elective laparoscopic cholecystectomy, possibly with IOC ERCP for stone removal or BD exploration if IOC shows stones

Laparoscopic cholecystectomy, possibly with IOC if feasible; otherwise open cholecystectomy BD exploration or ERCP for stone removal if IOC shows stones

Stone removal at the time of ERCP, followed in most cases by early laparoscopic cholecystectomy

Emergency ERCP with stone removal or at least biliary decompression Antibiotics to cover gramnegative and possibly anaerobic organisms and Enterococcus spp. Subsequent cholecystectomy

  

aSee Chapter 58 for a discussion of biliary pancreatitis. BD, Bile duct; IOC, intraoperative cholangiography; MRC, magnetic resonance cholangiography; THC, transhepatic cholangiography.

  

CHAPTER 65  Gallstone Disease

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TABLE 65.3  Imaging Studies of the Biliary Tract Technique

Condition Tested For Findings/Comments

US

Cholelithiasis

Stones manifest as mobile, dependent echogenic foci within the gallbladder lumen with acoustic shadowing Sludge appears as layering echogenic material without shadows Sensitivity >95% for stones >2 mm Specificity >95% for stones with acoustic shadows Rarely, a stone-filled gallbladder may be contracted and difficult to see, with a “wall-echo-shadow” sign Best single test for stones in the gallbladder

Choledocholithiasis

Stones are seen in the BD in only ≈50% of cases but can be inferred from the finding of a dilated BD (>6 mm diameter), with or without gallstones, in another ≈25% of cases Can confirm, but not exclude, BD stones

Acute cholecystitis

Sonographic Murphy sign (focal gallbladder tenderness under the transducer) has a positive predictive value of >90% in detecting acute cholecystitis when stones are seen Pericholecystic fluid (in the absence of ascites) and gallbladder wall thickening to >4 mm (in the absence of hypoalbuminemia) are nonspecific findings but are suggestive of acute cholecystitis

EUS

Choledocholithiasis

Highly accurate for excluding or confirming stones in the BD Concordance of EUS with the ERCP diagnosis ≈95%; many studies suggest slightly higher sensitivity rates for EUS than for ERCP Specificity ≈97% Positive predictive value ≈99%, negative predictive value ≈98%, accuracy ≈97% With experienced operators, EUS can be used in lieu of ERCP to exclude BD stones, particularly when the clinical suspicion is low or intermediate Considered for patients with low to moderate clinical probability of choledocholithiasis

Oral cholecystographya

Cholelithiasis

Stones manifest as mobile filling defects in an opacified gallbladder Sensitivity and specificity exceed 90% when the gallbladder is opacified, but nonvisualization occurs in 25% of studies and can result from multiple causes other than stones Opacification of the gallbladder indicates cystic duct patency May be useful in the evaluation of acalculous gallbladder diseases such as cholesterolosis and adenomyomatosis (see Chapter 67)

Cholescintigraphy (hepatobiliary scintigraphy; hydroxyiminodiacetic acid or diisopropyl iminodiacetic acid scan)

Acute cholecystitis

ERCP

Choledocholithiasis

Assesses patency of the cystic duct A normal scan shows radioactivity in the gallbladder, BD, and small bowel within 30-60 min A positive result is defined as nonvisualization of the gallbladder, with preserved hepatic excretion of radionuclide into the BD or small bowel Sensitivity is ≈95% and specificity is ≈90%, with false-positive results seen in fasted critically ill patients With cholecystokinin stimulation, the gallbladder “ejection fraction” can be determined and may help evaluate patients with acalculous biliary pain (see Chapter 67) A normal scan result virtually excludes acute cholecystitis ERCP is the standard diagnostic test for stones in the BD, with sensitivity and specificity of ≈95% Use of ERCP to extract stones (or at least drain infected bile) is lifesaving in severe cholangitis and reduces the need for BD exploration at the time of cholecystectomy Recommended for patients with a high clinical probability of choledocholithiasis

MRCP

Cholelithiasis

When contrast agent flows retrograde into the gallbladder, stones appear as filling defects and can be detected with a sensitivity rate of ≈80%, but US remains the mainstay for confirming cholelithiasis

Choledocholithiasis

A rapid, noninvasive modality that provides detailed bile duct and pancreatic duct images equal to those of ERCP Sensitivity ≈93% and specificity ≈94%, comparable with those for ERCP Useful for examining nondilated ducts, particularly at the distal portion, which often is not well visualized by US Adjacent structures such as the liver and pancreas can be examined at the same time Recommended for patients with low to moderate clinical probability of choledocholithiasis

CT

Complications of gallstones

Not well suited for detecting uncomplicated stones but excellent for detecting complications such as abscess, perforation of gallbladder or BD, and pancreatitis Spiral CT may prove useful as a noninvasive means of excluding BD stones; some studies suggest improved diagnostic accuracy when CT is combined with an oral cholecystographic contrast agent

  

aPerformed

infrequently. BD, Bile duct.   

65

1038

PART VIII  Biliary Tract

GB

GB

BD

Stone

A

Acoustic shadowing

A

GB BD PD

Stones PV

B

Acoustic shadowing

B

Fig. 65.8  (A) Typical ultrasonographic appearance of cholelithiasis. A gallstone is present within the lumen of the gallbladder (GB), with acoustic shadow behind it. With repositioning of the patient, stones will move, thereby excluding the possibility of a gallbladder polyp. (B) Cholelithiasis in the setting of acute cholecystitis. Multiple gallstones can be seen within the gallbladder lumen, with associated acoustic shadowing. In addition, the gallbladder wall is thickened (arrowheads). (Courtesy Julie Champine, MD, Dallas, TX.)

sonographic Murphy sign is somewhat operator dependent and requires an alert patient. Presence of the sign has a positive predictive value of greater than 90% for detecting acute cholecystitis if gallstones are present.262 US may help localize other abdominal diseases, such as abscesses or pseudocysts, that may be in the differential diagnosis. 

EUS EUS is highly accurate for detecting choledocholithiasis. More invasive and more expensive than standard US, EUS has the advantage of being able to visualize the bile duct from within the GI lumen and is comparable to ERCP in this respect. Intraluminal imaging provides several advantages over transabdominal US, including closer proximity to the bile duct, higher resolution, and lack of interference by bowel gas or abdominal wall layers (Fig. 65.9). In several studies, EUS had a positive predictive value of 99%, negative predictive value of 98%, and accuracy rate of 97% for the diagnosis of bile duct stones compared with ERCP.263,264 If bile duct stones are found on EUS, endoscopic removal of the stones is necessary, and it can be argued that ERCP should be the initial study if choledocholithiasis is

Distal BD Conf

Stone

C Fig. 65.9  EUS with a radial sector scanning endoscope, demonstrating choledocholithiasis. The bile duct (BD) is shown extending to the level of the gallbladder (GB) (top) and distally (A and B). The greatest diameter of the BD is 12 mm (B), and the duct tapers distally to a diameter of 7 mm (C). Within the distal BD, a gallstone is clearly visualized (C). Note the proximity of adjacent structures to the BD and the ease with which these structures are resolved by EUS. Conf, Confluence of portal and splenic veins; PD, pancreatic duct; PV, portal vein.

strongly suspected. Nevertheless, several studies that compared EUS with ERCP have found both techniques to be accurate for confirming or excluding choledocholithiasis, with EUS having advantages in both safety and cost.265-267 EUS has also been found to be superior to MRCP (or simply magnetic resonance cholangiography [MRC]) in detecting the presence or absence of bile duct stones (see later). The major benefit of EUS in patients with a clinical suspicion of

CHAPTER 65  Gallstone Disease

choledocholithiasis is the ability to avoid unnecessary ERCP and sphincterotomy, which is not without risk. Use of EUS to determine if ERCP is indicated may avoid a significant number of ERCPs and result in fewer complications. A systematic review of randomized controlled trials compared EUS-guided ERCP with ERCP alone for detection of bile duct stones.268 Patients randomized to EUS were able to avoid ERCP in 67% of cases and had lower rates of complications and pancreatitis compared with those randomized to ERCP alone (OR, 0.35 and 0.21, respectively). EUS failed to detect bile duct stones in only 2 of 213 patients (0.9%). Therefore, EUS is considered an appropriate modality for excluding bile duct stones, especially if the pretest probability of finding stones is low to intermediate. 

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65

5 min

10 min

15 min

20 min

25 min

30 min

35 min

45 min

60 min

Oral Cholecystography Once the mainstay of imaging studies of the gallbladder, OCG now has limited application as a secondary approach to identifying stones in the gallbladder.254 The only useful clinical indications for OCG are the evaluation of patients in whom medical dissolution of stones or lithotripsy is being considered (see Chapter 66)269 and the evaluation of patients for unsuspected gallbladder disease, such as adenomyomatosis or cholesterolosis, when US has been nondiagnostic (see Chapter 67). 

Cholescintigraphy Cholescintigraphy (hepatobiliary scintigraphy) is a radionuclide imaging test of the gallbladder and biliary tract that is most useful for evaluating patients with suspected acute cholecystitis.270 By demonstrating patency of the cystic duct, cholescintigraphy can exclude acute cholecystitis rapidly (within 90 minutes) in a patient who presents with abdominal pain.271,272 The procedure can be performed on an emergency basis in a nonfasting patient after IV administration of gamma-emitting 99mTc-labeled hydroxyl iminodiacetic acid (HIDA) or diisopropyl iminodiacetic acid (DISIDA), which is taken up rapidly by the liver and secreted into bile.254 As shown in Fig. 65.10, serial scans after injection normally should show radioactivity in the gallbladder, bile duct, and small intestine within 30 to 60 minutes.216 In the past, imaging of jaundiced patients with this technique was limited, but use of DISIDA may allow imaging of the biliary tract in a patient with a serum bilirubin value as high as 20 mg/dL. An abnormal, or “positive,” scan result is defined as nonvisualization of the gallbladder, with preserved excretion into the bile duct or small intestine. The accuracy of the test for detecting acute cholecystitis is 92%, superior to that for US. False-positive results occur primarily in fasting or critically ill patients, in whom gallbladder motility is decreased. The reduction in gallbladder motility leads to greater water resorption, which results in a gelatinous bile. In critically ill patients, cholestasis and hepatocyte dysfunction result in reduced clearance of radionuclide imaging agents. Although nonvisualization of the gallbladder because of cystic duct obstruction is the hallmark of acute cholecystitis, pericholecystic hepatic uptake of radionuclide is a useful secondary sign.273 In some patients (e.g., those with chronic cholecystitis, liver disease, or choledocholithiasis), imaging of the gallbladder by radionuclide scanning is delayed for several hours, and scanning must be repeated in 4 or more hours to confirm absence of acute cholecystitis. This delay in visualization of the gallbladder is problematic in the acutely ill patient but has largely been overcome with the administration of IV morphine sulfate to patients in whom the gallbladder fails to be visualized within 60 minutes. Morphine raises the pressure within the sphincter of Oddi, thereby leading to the preferential flow of bile into the gallbladder if the cystic duct is not obstructed. Another scan is obtained 30 minutes after injection of morphine, and if the gallbladder is

Fig. 65.10  Cholescintigraphy demonstrating an obstructed cystic duct characteristic of acute cholecystitis. The gamma-emitting radioisotope diisopropyl iminodiacetic acid is injected intravenously, rapidly taken up by the liver (at 5 minutes), and excreted into bile (at 20 minutes). Sequential images show the isotope quickly entering the duodenum (at 45 minutes) and passing distally in the small intestine without ever being concentrated in the gallbladder. Failure of the gallbladder to be visualized as a hot spot within 30 to 60 minutes constitutes a positive result and implies obstruction of the cystic duct.

visualized, cystic duct obstruction, and hence acute cholecystitis, is excluded. The gallbladder may not be visualized in approximately half of critically ill patients even after injection of morphine, thereby leading to false-positive cholescintigraphy results. Although primarily a tool for evaluating acutely ill patients with suspected acute cholecystitis, cholescintigraphy after administration of CCK may be useful in identifying patients with chronic acalculous biliary pain who are likely to benefit from empirical cholecystectomy (see Chapter 67). An additional important role for cholescintigraphy is the noninvasive detection of bile leakage from the cystic duct as a complication of cholecystectomy (see Chapter 66).274 

ERCP ERCP is one of the most effective modalities for detecting choledocholithiasis.275 The technique is discussed in more detail in Chapter 70. Stones within the bile duct appear as filling defects and can be detected with a sensitivity of around 95% (Fig. 65.11).276 Care should be taken to avoid inadvertent injection of air into the biliary tract,277 because bubbles may mimic gallstones. The specificity of ERCP for the detection of bile duct stones is approximately 95%. The therapeutic applications of ERCP have revolutionized the treatment of patients with choledocholithiasis278 and other bile duct disorders (see Chapter 70). As the use of EUS and MRC has increased, the role of ERCP in the diagnosis of choledocholithiasis has changed considerably. A National Institutes of Health consensus conference has recommended the use of ERCP only when the clinical probability of choledocholithiasis is high (i.e.,

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PART VIII  Biliary Tract

GB

Stones

BD

Fig. 65.11  ERCP demonstrating choledocholithiasis with dilatation of the bile duct to 15 mm and 3 filling defects representing stones (arrows).

GB

Stone

Fig. 65.13  MRCP demonstrating choledocholithiasis. Within the bile duct (BD) are 2 filling defects representing gallstones. GB, Gallbladder. (Courtesy Charles Owen, III, MD, Dallas, TX.)

MRC is highly useful for imaging the bile duct and detecting gallstones. This modality is especially useful for detecting abnormalities in the most distal extrahepatic portion of the bile duct when the duct is not dilated; this region is often not well visualized by transabdominal US.239 With the advent of laparoscopic cholecystectomy, an easy, quick, and preferably noninvasive method of excluding bile duct stones is needed. MRC permits construction of a 3-dimensional image of the bile duct with a high sensitivity for detecting bile duct stones (Fig. 65.13).266,267 In a systematic review that compared MRC with diagnostic ERCP for detection of choledocholithiasis, MRC had a sensitivity of 93% and a specificity of 94%.268 

CLINICAL DISORDERS Biliary Pain and Chronic Cholecystitis Fig. 65.12  Abdominal CT demonstrating emphysematous cholecystitis with associated cholelithiasis. Pockets of gas (yellow arrow), resulting from a secondary infection with gas-forming organisms, are present within the wall of the gallbladder (GB). (Courtesy Julie Champine, MD, Dallas, TX.)

when the need for therapeutic intervention is likely). For diagnosis of choledocholithiasis alone, EUS and MRC are equal in accuracy to ERCP.279 

CT and MRI In patients with cholelithiasis or choledocholithiasis, CT has been used principally for detecting complications such as pericholecystic fluid in acute cholecystitis, gas in the gallbladder wall (suggesting emphysematous cholecystitis), gallbladder perforation, and abscesses (Fig. 65.12). Helical (or spiral) CT cholangiography (CTC) with use of an oral cholecystographic contrast agent has been studied for the detection of choledocholithiasis.280,281 Although CTC is still inferior to ERCP imaging for detecting bile duct stones, it may reveal other surrounding pathologic abnormalities.282

Biliary pain is the most common presenting symptom of cholelithiasis, and about 75% of patients with symptomatic gallstone disease seek medical attention for episodic abdominal pain. In patients who present with a complication of gallstones, such as acute cholecystitis, a history of recurrent episodes of abdominal pain in the months preceding the complication is often elicited.

Pathogenesis Biliary pain (conventionally referred to as biliary “colic,” a misnomer) is caused by intermittent obstruction of the cystic duct by one or more gallstones. Biliary pain does not require that inflammation of the gallbladder accompany the obstruction. The term “chronic cholecystitis” to describe biliary pain should be avoided because it implies the presence of a chronic inflammatory infiltrate that may or may not be present in a given patient. Indeed, the severity and frequency of biliary pain and the pathologic changes in the gallbladder do not correlate.285 The most common histologic changes observed in patients with biliary pain are mild fibrosis of the gallbladder wall with a chronic inflammatory cell infiltrate and intact mucosa. Recurrent episodes of biliary pain can also be associated with a scarred, shrunken gallbladder and Rokitansky-Aschoff sinuses (intramural diverticula). Bacteria can be cultured from gallbladder bile or gallstones themselves in

CHAPTER 65  Gallstone Disease

about 10% of patients with biliary pain, but bacterial infection is not believed to contribute to the symptoms (see Chapter 67). 

Clinical Features Biliary pain is visceral in nature and thus poorly localized.286 In a typical case, the patient experiences episodes of upper abdominal pain, usually in the epigastrium or RUQ, but sometimes in other abdominal locations. Ingestion of a meal often precipitates pain, but more commonly no inciting event is apparent. The onset of biliary pain is more likely to occur during periods of weight reduction and marked physical inactivity such as prolonged bed rest than at other times. The term “biliary colic,” used in the past, is a misnomer because the pain is steady rather than intermittent, as would be suggested by the word colic. The pain increases gradually over a period of 15 minutes to an hour and then remains at a plateau for an hour or more before slowly resolving. In one third of patients, the onset of pain may be more sudden, and on rare occasions, the pain may cease abruptly. Pain lasting more than 6 hours suggests acute cholecystitis rather than simple biliary pain (see Chapter 11). In order of decreasing frequency, biliary pain is felt maximally in the epigastrium, RUQ, LUQ, and various parts of the precordium or lower abdomen. Therefore, the notion that pain not located in the RUQ is atypical of gallstone disease is incorrect. Radiation of the pain to the scapula, right shoulder, or lower abdomen occurs in half of patients. Diaphoresis and nausea with some vomiting are common, although vomiting is not as protracted as in intestinal obstruction or acute pancreatitis. Like patients with other kinds of visceral pain, the patient with biliary pain is usually restless and active during an episode. Complaints of gas, bloating, flatulence, and dyspepsia, which are common in patients with gallstones, are probably not related to the stones themselves. These nonspecific symptoms are found with similar frequencies in persons without gallstones. Accordingly, patients with gallstones whose only symptoms are dyspepsia and other nonspecific upper GI tract complaints are not candidates for cholecystectomy. Physical findings are usually normal, with only mild to moderate gallbladder tenderness during an attack and perhaps mild residual tenderness lasting several days after an attack. 

Diagnosis In a patient with uncomplicated biliary pain, laboratory parameters are usually normal. Elevations of serum bilirubin, alkaline phosphatase, or amylase levels suggest coexisting choledocholithiasis.. In general, the first, and often the only, imaging study recommended in patients with biliary pain is US of the RUQ. Despite the impressive diagnostic accuracy of US, a clinically important stone is occasionally missed and the correct diagnosis delayed because of the large number of patients who undergo US for any reason.255 Given the relatively benign natural history of biliary pain, patients with suspected gallstones but a negative US result can safely be observed, with further diagnostic testing reserved for those in whom symptoms recur.287 

Differential Diagnosis The differential diagnosis of recurrent episodic upper abdominal symptoms includes reflux esophagitis, peptic ulcer, pancreatitis, renal colic, diverticulitis, carcinoma of the colon, IBS, radiculopathy, and angina pectoris (see Chapter 11). Usually a carefully taken history assists in narrowing the differential diagnosis. In a study of 1008 patients who underwent cholecystectomy for gallstones, clinical features associated with biliary pain (“episodic gallbladder pain”) were episodic pain (usually once a

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month or less), pain lasting 30 minutes to 24 hours, pain during the evening or at night, and the onset of symptoms 1 year or less before presentation.288 Xanthogranulomatous cholecystitis is a rare aggressive variant of chronic cholecystitis characterized by grayish-yellow nodules or streaks, representing lipid-laden macrophages, in the gallbladder wall; it may present as acute jaundice. 

Treatment Patients with recurrent uncomplicated biliary pain and documented gallstones are generally treated with elective laparoscopic cholecystectomy (see Chapter 66). Acute biliary pain improves with administration of meperidine, with or without ketorolac or diclofenac. Aspirin taken prophylactically has been reported to prevent gallstone formation as well as acute attacks of biliary pain in patients with gallstones, but long-term use of other NSAIDs does not prevent gallstone formation.280,281 

Acute Cholecystitis Acute cholecystitis is the most common complication of gallstone disease. Inflammation of the gallbladder wall associated with abdominal pain, RUQ tenderness, fever, and leukocytosis is the hallmark of acute cholecystitis. In approximately 90% of cases, the underlying cause is obstruction of the outlet of the gallbladder by a gallstone in the cystic duct, gallbladder neck, or Hartmann pouch.291 In the remaining 10% of cases, cholecystitis occurs in the absence of gallstones (acalculous cholecystitis [see Chapter 67]). Acute cholecystitis caused by gallstones is a disease of young, otherwise healthy women and generally has a favorable prognosis, whereas acute acalculous cholecystitis occurs more commonly in critically ill patients and is associated with high morbidity and mortality rates.

Pathogenesis Acute cholecystitis generally occurs when a stone becomes embedded in the cystic duct and causes chronic obstruction, rather than transient obstruction as in biliary pain.291 Stasis of bile within the gallbladder lumen results in damage of the gallbladder mucosa, with consequent release of intracellular enzymes and activation of a cascade of inflammatory mediators. In animal studies, if the cystic duct is ligated, the usual result is gradual absorption of the gallbladder contents without the development of inflammation292; the additional instillation of a luminal irritant (e.g., concentrated bile or lysolecithin) or trauma from an indwelling catheter is required to cause acute cholecystitis in an obstructed gallbladder. Phospholipase A is believed to be released by gallstone-induced mucosal trauma and converts lecithin to lysolecithin. Although normally absent from gallbladder bile, lysolecithin is present in the gallbladder contents of patients with acute cholecystitis.293 In animal models, installation of lysolecithin into the gallbladder produces acute cholecystitis associated with increased protein secretion, decreased water absorption, and evidence of WBC invasion associated with elevated production of prostaglandins E and F1α. Administration of indomethacin, a COX inhibitor, has been shown to block this inflammatory response. Studies of human tissue obtained at cholecystectomy have demonstrated enhanced prostaglandin production in the inflamed gallbladder. Additionally, administration of IV indomethacin and oral ibuprofen to patients with acute cholecystitis has been shown to diminish both luminal pressure in the gallbladder and pain.293 Supporting evidence for the role of prostaglandins in the development of acute cholecystitis comes from a prospective study in which patients who presented with biliary pain were randomized to receive diclofenac (a prostaglandin synthetase inhibitor) or placebo.294 Ultimately, acute cholecystitis developed in 9

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PART VIII  Biliary Tract

of 40 patients who received placebo, whereas episodes of biliary pain resolved in all 20 patients who received diclofenac. These data suggest a chain of events in which obstruction of the cystic duct in association with 1 or more intraluminal factors damages the gallbladder mucosa and stimulates prostaglandin synthetase. The resulting fluid secretion and inflammatory changes promote a cycle of further mucosal damage and inflammation.294 Enteric bacteria can be cultured from gallbladder bile in roughly one half of patients with acute cholecystitis.295 Bacteria are not believed to trigger the actual onset of acute cholecystitis, however. 

GB Fluid collection

Pathology If examined in the first few days of an attack of acute cholecystitis, the gallbladder is usually distended and contains a stone embedded in the cystic duct.296 After the gallbladder is opened, inflammatory exudate and, rarely, pus are present. Later in the attack, the bile pigments that are normally present are absorbed and replaced by thin mucoid fluid, pus, or blood. If the attack of acute cholecystitis is left untreated for a long period but the cystic duct remains obstructed, the lumen of the gallbladder may become distended with clear mucoid fluid, a condition known as hydrops of the gallbladder. Histologic changes range from mild acute inflammation with edema to necrosis and perforation of the gallbladder wall. Surprisingly, the severity of histologic changes correlates little with the patient’s symptoms.296 If the gallbladder is resected for acute cholecystitis and no stones are found, the specimen should be carefully examined histologically for evidence of vasculitis or cholesterol emboli, because these systemic disorders may manifest as acalculous cholecystitis (see Chapter 37). 

Clinical Features Approximately 75% of patients with acute cholecystitis report prior attacks of biliary pain (see Table 65.2).297 Often, such a patient is alerted to the possibility that more than simple biliary pain is occurring by the prolonged duration of the pain. If biliary pain has been constant for more than 6 hours, acute cholecystitis should be suspected. In contrast to uncomplicated biliary pain, the physical findings can, in many cases, suggest the diagnosis of acute cholecystitis. Fever is common, but body temperature is usually less than 102°F unless the gallbladder has become gangrenous or has perforated (Fig. 65.14). Mild jaundice is present in 20% of patients with acute cholecystitis and 40% of older adult patients. Serum bilirubin levels are usually less than 4 mg/dL.298 Bilirubin levels above this value suggest the possibility of bile duct stones, which may be found in 50% of jaundiced patients with acute cholecystitis. Another cause of pronounced jaundice in patients with acute cholecystitis is Mirizzi syndrome, which is associated with inflammatory obstruction of the common hepatic duct (see later). The abdominal examination often demonstrates right subcostal tenderness with a palpable gallbladder in a third of patients; a palpable gallbladder is more common in patients having a first attack of acute cholecystitis. Repeated attacks usually result in a scarred, fibrotic gallbladder that is unable to distend. For unclear reasons, the gallbladder is usually palpable lateral to its normal anatomic location. A relatively specific finding of acute cholecystitis is a Murphy sign.297 During palpation in the right subcostal region, pain and inspiratory arrest may occur when the patient takes a deep breath that brings the inflamed gallbladder into contact with the examiner’s hand. The presence of a Murphy sign in the appropriate clinical setting is a reliable predictor of acute cholecystitis, although gallstones should still be confirmed by US. 

Fig. 65.14  US demonstrating a complex fluid collection adjacent to the gallbladder (GB), consistent with gallbladder perforation. (Courtesy Julie Champine, MD, Dallas, TX.)

Natural History The pain of untreated acute cholecystitis generally resolves in 7 to 10 days.299 Not uncommonly, symptoms remit within 48 hours of hospitalization. One study has shown that acute cholecystitis resolves without complications in about 83% of patients but results in gangrenous cholecystitis in 7%, gallbladder empyema in 6%, perforation in 3%, and emphysematous cholecystitis in fewer than 1%.300 

Diagnosis Perhaps because it is so common, acute cholecystitis is often at the top of the differential diagnosis of abdominal symptoms and is actually overdiagnosed when clinical criteria alone are considered. In a prospective series of 100 patients with RUQ pain and tenderness and suspected acute cholecystitis, this diagnosis was correct in only two thirds of cases. The clinician must therefore use laboratory and imaging studies to confirm the presence of acute cholecystitis, exclude complications such as gangrene and perforation, and look for alternative causes of the clinical findings. Table 65.3 shows the most common laboratory findings in acute cholecystitis.299 Leukocytosis with a shift to immature neutrophils is common. Because a diagnosis of bile duct stones with cholangitis is usually in the differential diagnosis, attention should be directed to results of liver biochemical tests.298 Even without detectable bile duct obstruction, acute cholecystitis often causes mild elevations in serum aminotransferase and alkaline phosphatase levels. As noted earlier, the serum bilirubin level may also be mildly elevated (2 to 4 mg/dL), and even serum amylase and lipase values may be elevated nonspecifically. A serum bilirubin value above 4 mg/dL or amylase value above 1000 U/L usually indicates co-existing bile duct obstruction or acute pancreatitis, respectively, and warrants further evaluation. When the level of leukocytosis exceeds 15,000/mm3, particularly in the setting of worsening pain, high fever (temperature >102°F), and chills, suppurative cholecystitis (empyema) or perforation should be suspected, and urgent surgical intervention may be required. Such advanced gallbladder disease may be present even if local and systemic manifestations are unimpressive. US is the single most useful imaging study in acutely ill patients with RUQ pain and tenderness. It accurately establishes the presence or absence of gallstones and serves as an extension of the physical examination. The presence of a sonographic Murphy sign, defined as focal gallbladder tenderness under the transducer, has

CHAPTER 65  Gallstone Disease

a positive predictive value greater than 90% for detecting acute cholecystitis if gallstones are also present, the operator is skillful, and the patient is alert.301 Additionally, US can detect nonspecific findings suggestive of acute cholecystitis, such as pericholecystic fluid and gallbladder wall thickening greater than 4 mm. Both findings lose specificity for acute cholecystitis if the patient has ascites or hypoalbuminemia.255,302 Because the prevalence of gallstones is high in the population, many patients with nonbiliary tract diseases that manifest as acute abdominal pain (e.g., acute pancreatitis and complications of peptic ulcer) may have incidental and clinically irrelevant gallstones. The greatest usefulness of cholescintigraphy in these patients is its ability to exclude acute cholecystitis and allow the clinician to focus on nonbiliary causes of the patient’s acute abdominal pain.248 A normal cholescintigraphy result shows radioactivity in the gallbladder, bile duct, and small intestine within 30 to 60 minutes of injection of the isotope. With rare exceptions, a normal result excludes acute cholecystitis due to gallstones. Several studies have suggested that the sensitivity and specificity of scintigraphy in the setting of acute cholecystitis are approximately 94% each. However, sensitivity and specificity are reduced considerably in patients who have liver disease, are receiving parenteral nutrition, or are fasting. These conditions can lead to a false-positive result, defined as the absence of isotope in the gallbladder in a patient who does not have acute cholecystitis. If a positive result is defined as the absence of isotope in the gallbladder, then a false-negative result is defined as filling of the gallbladder with isotope in the setting of acute cholecystitis, a situation that virtually never occurs. Therefore, scintigraphy should not be used as the initial imaging study in a patient with suspected cholecystitis but rather should be used as a secondary imaging study in patients who already are known to have gallstones and in whom a nonbiliary cause of acute abdominal pain is possible.303 The greatest usefulness of abdominal CT in patients with acute cholecystitis is to detect complications such as emphysematous cholecystitis and perforation of the gallbladder. At the same time, CT can exclude other intra-abdominal processes that may engender a similar clinical picture. For example, abdominal CT is highly sensitive for detecting pneumoperitoneum, acute pancreatitis, pancreatic pseudocysts, hepatic or intra-abdominal abscesses, appendicitis, and obstruction or perforation of a hollow viscus. Abdominal CT usually is not warranted in patients with obvious acute cholecystitis, but if the diagnosis is uncertain or the optimal timing of surgery is in doubt, CT may be invaluable. 

Differential Diagnosis The principal conditions to consider in the differential diagnosis of acute cholecystitis are appendicitis, acute pancreatitis, pyelonephritis or renal calculi, peptic ulcer, acute hepatitis, pneumonia, hepatic abscess or tumor, and gonococcal or chlamydial perihepatitis. These possibilities should be considered before a cholecystectomy is recommended. 

Treatment The patient in whom acute cholecystitis is suspected should be hospitalized. The patient is often hypovolemic from vomiting and poor oral intake, and fluid and electrolytes should be administered intravenously. Oral feeding should be withheld and an NG tube inserted if the patient has a distended abdomen or persistent vomiting. In uncomplicated cases of acute cholecystitis, antibiotics need not be given. Antibiotics are warranted if the patient appears toxic or is suspected of having a complication such as perforation of the gallbladder or emphysematous cholecystitis. Broad-spectrum antibiotic coverage is usually indicated to cover gram-negative

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organisms and anaerobes, with multiple possible regimens. The most commonly used regimens include piperacillin-tazobactam, ceftriaxone plus metronidazole, or levofloxacin plus metronidazole. Definitive therapy of acute cholecystitis consists of cholecystectomy. The safety and effectiveness of a laparoscopic approach in the setting of acute cholecystitis have been demonstrated (see Chapter 66).304 

Choledocholithiasis Choledocholithiasis is defined as the occurrence of stones in the bile ducts. Like stones in the gallbladder, stones in the bile ducts may remain asymptomatic for years, and stones from the bile duct are known to pass silently into the duodenum, perhaps frequently. Unlike stones in the gallbladder, which usually become clinically evident as relatively benign episodes of recurrent biliary pain, stones in the bile duct, when they do cause symptoms, tend to manifest as life-threatening complications such as cholangitis and acute pancreatitis (see Chapter 58). Therefore, discovery of choledocholithiasis generally should be followed by an intervention to remove the stones (see Chapter 70).

Etiology Gallstones may pass from the gallbladder into the bile duct or form de novo in the duct. Generally, all gallstones from one patient, whether from the gallbladder or bile duct, are of one type, either cholesterol or pigment. Cholesterol stones form only in the gallbladder, and any cholesterol stones found in the bile duct must have migrated there from the gallbladder. Black pigment stones, which are associated with old age, hemolysis, alcoholism, and cirrhosis, also form in the gallbladder but only rarely migrate into the bile duct. The majority of pigment stones in the bile duct are the softer brown pigment stones. These stones form de novo in the bile duct as a result of bacterial action on phospholipid and bilirubin in bile (see earlier).305 They are often proximal to a biliary stricture and are frequently associated with cholangitis. Brown pigment stones are found in patients with hepatolithiasis and recurrent pyogenic cholangitis (see Chapter 68).306 Fifteen percent of patients with gallbladder stones also have bile duct stones. Conversely, of patients with ductal stones, 95% also have gallbladder stones.307 In patients who present with choledocholithiasis months or years after a cholecystectomy, determining whether the stones were overlooked at the earlier operation or have subsequently formed may be impossible. In fact, formation of pigment stones in the bile duct is also a late complication of endoscopic sphincterotomy.308 In a study of the long-term consequences of endoscopic sphincterotomy in more than 400 patients, the cumulative frequency of recurrent bile duct stones was 12%; all the recurrent stones were of the brown pigment type, irrespective of the chemical composition of the original gallstones. This observation suggests that sphincterotomy permits chronic bacterial colonization of the bile duct that results in deconjugation of bilirubin and precipitation of pigment stones. Stones in the bile duct usually come to rest at the lower end of the ampulla of Vater. Obstruction of the bile duct raises bile pressure proximally and causes the duct to dilate. The pressure in the bile duct is normally 10 to 15 cm H2O and rises to 25 to 40 cm H2O with complete obstruction. When the pressure exceeds 15 cm H2O, bile flow decreases, and at 30 cm H2O, bile flow stops. The bile duct dilates to the point that dilatation can be detected on either US or abdominal CT in about 75% of cases. In patients who have had recurrent bouts of cholangitis, the bile duct may become fibrotic and unable to dilate. Moreover, dilatation of the duct is sometimes absent in patients with choledocholithiasis because the obstruction is low-grade and intermittent. 

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PART VIII  Biliary Tract

Clinical Features The morbidity of choledocholithiasis stems principally from biliary obstruction, which raises biliary pressure and diminishes bile flow. The rate of onset of obstruction, its extent, and the amount of bacterial contamination of the bile are the major factors that determine resulting symptoms. Acute obstruction usually causes biliary pain and jaundice, whereas obstruction that develops gradually over several months may manifest initially as pruritus or jaundice alone.309 If bacteria proliferate, life-threatening cholangitis may result (see later). Physical findings are usually normal if obstruction of the bile duct is intermittent. Mild to moderate jaundice may be noted when obstruction has been present for several days to a few weeks. Deep jaundice without pain, particularly with a palpable gallbladder (Courvoisier sign), suggests neoplastic obstruction of the bile duct, even when the patient has stones in the gallbladder. With longstanding obstruction, secondary biliary cirrhosis may result, leading to physical findings of chronic liver disease. As shown in Table 65.2, the results of laboratory studies may be the only clue to the presence of choledocholithiasis.310 With bile duct obstruction, serum bilirubin and alkaline phosphatase levels both increase. Bilirubin accumulates in serum because of blocked excretion, whereas alkaline phosphatase levels rise because of increased synthesis of the enzyme by the canalicular epithelium. The rise in the alkaline phosphatase level is more rapid than and precedes the rise in bilirubin level.311 The absolute height of the serum bilirubin level is proportional to the extent of obstruction, but the height of the alkaline phosphatase level bears no relation to either the extent of obstruction or its cause. In cases of choledocholithiasis, the serum bilirubin level is typically in the range of 2 to 5 mg/dL242 and rarely exceeds 12 mg/dL. Transient “spikes” in serum aminotransferase or amylase levels suggest passage of a bile duct stone into the duodenum. The overall sensitivity of liver biochemical testing for detecting choledocholithiasis is reported to be 94%; serum levels of GGTP are elevated most commonly but may not be assessed in clinical practice.311 

Natural History Little information is available on the natural history of asymptomatic bile duct stones. In many patients, such stones remain asymptomatic for months or years, but available evidence suggests the natural history of asymptomatic bile duct stones is less benign than that of asymptomatic gallstones.309,312 

Diagnosis US actually visualizes bile duct stones in only about 50% of cases,259 whereas dilatation of the bile duct to a diameter greater than 6 mm is seen in about 75% of cases. US can confirm, or at least suggest, the presence of bile duct stones but cannot exclude choledocholithiasis definitively. EUS, although clearly more invasive than standard US, has the advantage of visualizing the bile duct more accurately. EUS can exclude or confirm choledocholithiasis with sensitivity and specificity rates of approximately 98% as compared with ERCP.263 ERCP is the standard method for diagnosis and therapy of bile duct stones,313 with sensitivity and specificity rates of about 95%. When the clinical probability of choledocholithiasis is low, however, less invasive studies such as EUS and MRCP should be performed first (see earlier).279 Percutaneous transhepatic cholangiography (THC) is also an accurate test for confirming the presence of choledocholithiasis. The procedure is most readily accomplished when the intrahepatic bile ducts are dilated and is performed primarily when ERCP is unavailable or has been technically unsuccessful.

Laparoscopic US may be used in the surgical suite immediately before mobilization of the gallbladder during cholecystectomy. Laparoscopic US may be as accurate as surgical cholangiography in detecting bile duct stones and may thereby obviate the need for the latter.314 

Differential Diagnosis Symptoms caused by obstruction of the bile duct cannot be distinguished from those caused by obstruction of the cystic duct. Therefore, biliary pain is always in the differential diagnosis in patients with an intact gallbladder. The presence of jaundice or abnormal liver biochemical test results strongly points to the bile duct rather than the gallbladder as the source of the pain. In patients who present with jaundice, malignant obstruction of the bile duct or obstruction from a choledochal cyst may be indistinguishable clinically from choledocholithiasis (see Chapters 62 and 69). AIDS-associated cholangiopathy315 and papillary stenosis should be considered in HIV-positive patients with RUQ pain and abnormal liver biochemical test results (see Chapter 35). 

Treatment Because of its propensity to result in serious complications such as cholangitis and acute pancreatitis, choledocholithiasis warrants treatment in nearly all cases.316 The optimal therapy for a given patient depends on the severity of symptoms, presence of coexisting medical problems, availability of local expertise, and presence or absence of the gallbladder. Bile duct stones discovered at the time of a laparoscopic cholecystectomy present a dilemma to the surgeon. Some surgeons may attempt laparoscopic exploration of the bile duct. In other cases, the operation can be converted to an open cholecystectomy with bile duct exploration, but this approach results in greater morbidity and a more prolonged hospital stay. Alternatively, the laparoscopic cholecystectomy can be carried out as planned, and the patient can return for ERCP with removal of the bile duct stones. Such an approach, if successful, cures the disease but runs the risk of necessitating a third procedure, namely a bile duct exploration, if the stones cannot be removed at ERCP. In general, the greater the expertise of the therapeutic endoscopist, the more inclined the surgeon should be to complete the laparoscopic cholecystectomy and have the bile duct stones removed endoscopically.316 In especially high-risk patients, endoscopic removal of bile duct stones may be performed without cholecystectomy. This approach is particularly appropriate for older adult patients with other severe concurrent illnesses.317 Cholecystectomy is required subsequently for recurrent symptoms in only 10% of patients. Surgical management and endoscopic treatment of gallstones are discussed in detail in Chapters 66 and 70, respectively. 

Cholangitis Of all the common complications of gallstones, the most serious and lethal is acute bacterial cholangitis. Pus under pressure in the bile ducts leads to rapid spread of bacteria via the liver into the blood, with resulting septicemia. Moreover, the diagnosis of cholangitis is often problematic (especially in the critical early phase of the disease) because clinical features that point to the biliary tract as the source of sepsis are often absent.34 Table 65.2 delineates the symptoms, signs, and laboratory findings that can aid in an early diagnosis of cholangitis.

Etiology and Pathophysiology In approximately 85% of cases, cholangitis is caused by a stone embedded in the bile duct, with resulting bile stasis.318 Other causes of bile duct obstruction that may result in cholangitis are neoplasms

CHAPTER 65  Gallstone Disease

(see Chapters 60 and 69), biliary strictures (see Chapters 68 and 70), parasitic infections (see Chapters 68 and 84), and congenital abnormalities of the bile ducts (see Chapter 62). This discussion deals specifically with cholangitis caused by gallstones in the bile duct. Bile duct obstruction is necessary but not sufficient to cause cholangitis. Cholangitis is relatively common in patients with choledocholithiasis and nearly universal in patients with a posttraumatic bile duct stricture but is seen in only 15% of patients with neoplastic obstruction of the bile duct. It is most likely to result when a bile duct that already contains bacteria becomes obstructed, as in most patients with choledocholithiasis and stricture but in few patients with neoplastic obstruction. Malignant obstruction is more often complete than obstruction by a stricture or a bile duct stone and less commonly permits reflux of bacteria from duodenal contents into the bile ducts.319 The bacterial species most commonly cultured from the bile are E. coli, Klebsiella, Pseudomonas, Proteus, and enterococci. Anaerobic species such as Bacteroides fragilis and Clostridium perfringens are found in about 15% of appropriately cultured bile specimens. Anaerobes usually accompany aerobes, especially E. coli. The fever and shaking chills of cholangitis are due to bacteremia from bile duct organisms. The degree of regurgitation of bacteria from bile into hepatic venous blood is directly proportional to the biliary pressure and, hence, the degree of obstruction.303 For this reason, decompression alone often effectively treats the illness. 

Clinical Features The hallmark of cholangitis is Charcot triad, consisting of RUQ pain, jaundice, and fever (see Table 65.2). The full triad is present in only 70% of patients.319 The pain of cholangitis may be surprisingly mild and transient but is often accompanied by chills and rigors. Older adult patients in particular may present solely with mental confusion, lethargy, and delirium. Altered mental status and hypotension in combination with Charcot triad, known commonly as Reynolds pentad, occur in severe suppurative cholangitis. On physical examination, fever is almost universal, occurring in 95% of patients, and usually greater than 102°F. RUQ tenderness is elicited in about 90% of patients, but jaundice is clinically detectable in only 80%. Notably, peritoneal signs are found in only 15% of patients. The combination of hypotension and mental confusion indicates gram-negative septicemia. In overlooked cases of severe cholangitis, intrahepatic abscess may manifest as a late complication (see Chapter 84). Laboratory study results are often helpful in pointing to the biliary tract as the source of sepsis. In particular, the serum bilirubin level exceeds 2 mg/dL in 80% of patients. When the bilirubin level is normal initially, the diagnosis of cholangitis may not be suspected.314 The WBC count is elevated in 80% of patients. In many patients who have a normal WBC count, examination of the peripheral blood smear reveals a dramatic shift to immature neutrophil forms. The serum alkaline phosphatase level is usually elevated, and the serum amylase level may also be elevated if pancreatitis is also present. In the majority of cases, blood culture results are positive for enteric organisms, especially if culture specimens are obtained during chills and fever spikes. The organism found in the blood is invariably the same as that found in the bile. 

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Abdominal CT is an excellent test for excluding complications of gallstones such as acute pancreatitis and abscess, but standard abdominal CT is not capable of excluding bile duct stones. EUS and MRC, as noted earlier, have a much higher accuracy rate than CT for detecting and excluding stones in the bile duct. ERCP is the definitive test for the diagnosis of bile duct stones and cholangitis. Moreover, the ability of ERCP to establish drainage of infected bile under pressure can be lifesaving. If ERCP is unsuccessful, percutaneous THC can be performed (see Chapter 70). 

Treatment In cases of suspected bacterial cholangitis, blood culture specimens should be obtained immediately and therapy started with antibiotics effective against the likely causative organisms.320 In mild cases, initial therapy with a single drug (e.g., cefoxitin 2.0 g IV every 6 to 8 hours) is usually sufficient. In severe cases, more intensive therapy (e.g., gentamicin, ampicillin, and metronidazole or a broad-spectrum agent such as piperacillin-tazobactam 3.375 g IV every 6 hours or, if resistant organisms are suspected, meropenem 1 g IV every 8 hours) is indicated. The patient’s condition should improve within 6 to 12 hours, and in most cases, the infection comes under control within 2 to 3 days, with defervescence, relief of discomfort, and a decline in WBC count. In these cases, definitive therapy can be planned on an elective basis. If, however, after 6 to 12 hours of careful observation, the patient’s clinical status declines, with worsening fever, pain, mental confusion, or hypotension, the bile duct must be decompressed immediately.320 If available, ERCP with stone extraction, or at least decompression of the bile duct with an intrabiliary stent, is the treatment of choice. Controlled studies in which ERCP and decompression of the bile duct were compared with emergency surgery and bile duct exploration have shown dramatically lower morbidity and mortality rates in patients treated endoscopically.316 The surgical treatment and endoscopic management of cholangitis are discussed in detail in Chapters 66 and 70, respectively. 

UNCOMMON COMPLICATIONS Table 65.4 describes the clinical manifestations, diagnosis, and treatment of several uncommon complications of gallstone disease.

Emphysematous Cholecystitis Patients who have emphysematous cholecystitis present with the same clinical manifestations as patients with uncomplicated acute cholecystitis, but in the former, gas-forming organisms have secondarily infected the gallbladder wall. Pockets of gas are evident in the area of the gallbladder fossa on plain abdominal films, US, and abdominal CT (see Fig. 65.13).321 Emphysematous cholecystitis often occurs in diabetic persons or older men who do not have gallstones, in whom atherosclerosis of the cystic artery with resulting ischemia may be the initiating event (see Chapter 67). Emergency antibiotic therapy with anaerobic coverage and early cholecystectomy are warranted because the risk of gallbladder perforation is high. 

Diagnosis

Cholecystoenteric Fistula

The principles of imaging diagnosis of cholangitis are the same as those for choledocholithiasis. Stones in the bile duct are seen ultrasonographically in only about 50% of cases191 but can be inferred by detection of a dilated bile duct in about 75% of cases (see Table 65.3). Normal US findings do not exclude the possibility of choledocholithiasis in a patient in whom the clinical presentation suggests cholangitis.303

A cholecystoenteric fistula occurs when a stone erodes through the gallbladder wall (usually the neck) and into a hollow viscus. The most common entry point into the bowel is the duodenum, followed in frequency by the hepatic flexure of the colon, the stomach, and the jejunum. Symptoms are initially similar to those of acute cholecystitis, although at times the stone may pass into the bowel and may be excreted without causing any symptoms.322 Because the

65

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PART VIII  Biliary Tract

TABLE 65.4  Uncommon Complications of Gallstone Disease Complication

Pathogenesis

Clinical features

Diagnosis/Treatment

Emphysematous cholecystitis

Secondary infection of the gallbladder wall with gas-forming organisms (Clostridium welchii, Escherichia coli, and anaerobic streptococci) More common in older adult diabetic men; can occur without stones (see Chapter 67)

Symptoms and signs similar to those of severe acute cholecystitis

Plain abdominal films may show gas in the gallbladder fossa US and CT are sensitive for confirming gas Treatment is with IV antibiotics, including anaerobic coverage, and early cholecystectomy High morbidity and mortality rates

Cholecystoenteric fistula

Erosion of a (usually large) stone through the gallbladder wall into the adjacent bowel, most often the duodenum, followed in frequency by the hepatic flexure, stomach, and jejunum

Symptoms and signs similar to those of acute cholecystitis, although sometimes a fistula may be clinically silent Stones >25 mm, especially in older adult women, may produce a bowel obstruction, or “gallstone ileus”; the terminal ileum is the most common site of obstruction Gastric outlet obstruction (Bouveret syndrome) may occur rarely

Plain abdominal films may show gas in the biliary tract and/or a small bowel obstruction in gallstone ileus, as well as a stone in the RLQ if the stone is calcified Contrast UGIS may demonstrate the fistula A fistula from a solitary stone that passes may close spontaneously Cholecystectomy and bowel closure are curative Gallstone ileus requires emergency laparotomy; the diagnosis is often delayed, with a resulting mortality rate of ≈20%

Mirizzi syndrome

An impacted stone in the gallbladder neck or cystic duct, with extrinsic compression of the common hepatic duct from accompanying inflammation or fistula

Jaundice and RUQ pain

ERCP demonstrates dilated intrahepatic ducts and extrinsic compression of the common hepatic duct and possible fistula Preoperative diagnosis is important to guide surgery and minimize the risk of BD injury

Porcelain gallbladder

Intramural calcification of the gallbladder wall, usually in association with stones

No symptoms attributable to the calcified wall per se, but carcinoma of the gallbladder is a late complication in ≈20% (see Chapter 69)

Plain abdominal films or CT show intramural calcification of the gallbladder wall Prophylactic cholecystectomy is indicated to prevent carcinoma

  

BD, Bile duct.

  

biliary tract is decompressed, cholangitis is not common, despite gross seeding of the gallbladder and bile ducts with bacteria. The diagnosis of a cholecystoenteric fistula is suspected from imaging evidence of pneumobilia and may be confirmed by barium contrast studies of the upper or lower GI tract; often the precise anatomic location of the fistula is not identified until surgery. If the gallstone exceeds 25 mm in diameter, it may manifest (especially in older adult women) as a small intestinal obstruction (gallstone ileus); the ileocecal area is the most common site of obstruction.323 In such cases, a plain abdominal film may show the pathognomonic features of pneumobilia, a dilated small bowel, and a large gallstone in the right lower quadrant. Unfortunately, the diagnosis of a gallstone ileus is often delayed, with a resulting mortality rate of approximately 20%. Bouveret syndrome is characterized by gastric outlet obstruction resulting from duodenal impaction of a large gallstone that has migrated through a cholecystoduodenal fistula.324 

Mirizzi Syndrome Mirizzi syndrome is a rare complication in which a stone embedded in the neck of the gallbladder or cystic duct extrinsically compresses the common hepatic duct, with resulting jaundice, bile duct obstruction, and in some cases a fistula.325,326 Typically the gallbladder is contracted and contains stones. ERCP usually demonstrates the characteristic extrinsic compression of the common hepatic duct. Treatment is traditionally by an open cholecystectomy, although endoscopic stenting and laparoscopic cholecystectomy have been performed successfully. Preoperative

diagnosis of Mirizzi syndrome is important so that bile duct injury can be avoided (see Chapter 66).327 

Porcelain Gallbladder Strictly speaking, porcelain gallbladder, defined as intramural calcification of the gallbladder wall, is not a complication of gallstones but is mentioned here because of the remarkable tendency of carcinoma to develop as a late complication of gallbladder calcification (specifically, a gallbladder with focal rather than diffuse wall calcification).328 The diagnosis of a porcelain gallbladder can be made with a plain abdominal film or abdominal CT, which shows intramural calcification of the gallbladder wall. In occasional persons, hypersecretion of calcium into bile results in a “milk of calcium” or “limy” bile that can mimic the imaging features of porcelain gallbladder. Prophylactic cholecystectomy, preferably through a laparoscopic approach, is indicated to prevent subsequent development of carcinoma, which may otherwise occur in up to 20% of cases (see Chapter 69).329 Acknowledgment The authors acknowledge the contributions of Drs. Jeffrey D. Browning and Jayaprakash Sreenarasimhaiah to this chapter in previous editions of the book as well as the contributions of colleagues in the gallstone field. This work was supported in part by research grants DK54012, DK73917, DK101793, DK106249, DK114516, and AA025737 (D.Q.-H.W.) from the National Institutes of Health (U.S. Public Health Service). Full references for this chapter can be found on www.expertconsult.com 

.

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Treatment of Gallstone Disease Robert E. Glasgow

CHAPTER OUTLINE MEDICAL TREATMENT����������������������������������������������������1047 Dissolution Therapy������������������������������������������������������1047 Extracorporeal Shock-Wave Lithotripsy������������������������1049 SURGICAL TREATMENT��������������������������������������������������1050 Open Cholecystectomy ������������������������������������������������1050 Laparoscopic Cholecystectomy������������������������������������1051 CHOICE OF TREATMENT��������������������������������������������������1054 INDICATIONS FOR TREATMENT��������������������������������������1055 Asymptomatic Gallstones ��������������������������������������������1055 Biliary Pain and Chronic Cholecystitis ��������������������������1055 Acute Cholecystitis ������������������������������������������������������1055 Gallstone Pancreatitis��������������������������������������������������1057 Special Problems ��������������������������������������������������������1057 CHOLEDOCHOLITHIASIS ������������������������������������������������1059 Choledocholithiasis Known Preoperatively��������������������1059 Choledocholithiasis Identified During Cholecystectomy������1060 Choledocholithiasis Identified After Cholecystectomy������������������������������������������������������1060 BILE DUCT INJURY AND STRICTURE������������������������������1060 POSTCHOLECYSTECTOMY SYNDROME��������������������������1062 Choledocholithiasis������������������������������������������������������1062 Cystic Duct Remnant����������������������������������������������������1062 SOD ����������������������������������������������������������������������������1062 GALLSTONES, CHOLECYSTECTOMY, AND CANCER��������1063 Biliary Tract Cancer������������������������������������������������������1063 Colorectal Cancer��������������������������������������������������������1063

Many options are available for the treatment of patients with symptomatic gallstone disease. Improvements in endoscopic, radiologic, and chemical therapies for gallstones have enhanced the overall management of these patients. Nevertheless, surgery remains the most important therapeutic option. Laparoscopic cholecystectomy is the standard method for the management of patients with biliary pain and complications of gallstone disease, such as acute cholecystitis, gallstone pancreatitis, and choledocholithiasis (see also Chapter 65).

MEDICAL TREATMENT Medical treatment of gallstone disease was first proposed by Schiff in Italy in 1873.1 Dabney of Virginia first reported the effective treatment of gallstones with bile acids in 1876, an observation later confirmed by Rewbridge of Minnesota in 1937.2,3 Despite these initial reports, the use of medical dissolution treatment did not gain acceptance until large clinical series were reported in the 1970s. Contact dissolution of gallstones with solvents and percutaneous cholecystolithotomy techniques also have been reported, but these modalities have not proved superior to oral dissolution, shock-wave lithotripsy, or laparoscopic cholecystectomy and have been abandoned. The mainstay of current nonsurgical treatment

of gallstone disease is oral dissolution with UDCA, with or without extracorporeal shock-wave lithotripsy. Although nonsurgical treatment of gallstones has proved effective in carefully selected patients, only a limited number of patients are candidates for this treatment option. Nonsurgical treatments are effective only in patients with small, radiolucent cholesterol gallstones. Significant admixtures of pigment or calcium salts make stones indissoluble. In addition, long-term success with medical treatment of gallstones occurs only in patients in whom the lithogenic disturbance that led to gallstone formation is transient. For most patients, gallstone formation represents an imbalance in biliary lipid excretion, gallbladder stasis, or infection of the bile (see Chapter 65). In these patients, successful dissolution is followed by recurrence of gallstones in 30% to 50% of patients within 5 years.4-6 Therefore, the proper choice of treatment must take into account the type and severity of symptoms, physical characteristics of the stones, gallbladder function, and characteristics and preference of the patient.

Dissolution Therapy The rationale for oral dissolution therapy is the reversal of the condition that led to formation of cholesterol gallstones, namely, the supersaturation of bile with cholesterol (see Chapter 65). Cholesterol stones dissolve if the surrounding medium can solubilize the cholesterol in the stones. Both chenodeoxycholic acid and UDCA dissolve gallstones by decreasing biliary cholesterol secretion and desaturating bile. These agents encourage the removal of cholesterol from stones via micellar solubilization, formation of a liquid crystalline phase, or both. Chenodeoxycholic acid was the first bile acid used for gallstone dissolution but has been abandoned because of side effects, including diarrhea and increased serum aminotransferase and cholesterol levels. UDCA is well tolerated and is currently used in oral dissolution regimens. In randomized comparisons, UDCA was just as effective as chenodeoxycholic acid alone or in combination with UDCA.6-8 The rate of stone dissolution is a function of (1) thermodynamic forces, including the degree of bile desaturation and concentration of UDCA in bile; (2) kinetic forces, including stirring of bile; and (3) the surface-to-volume ratio of the stones. Oral dissolution targets the thermodynamic forces.9 Because small stones have a smaller surface-to-volume ratio, they respond more quickly and reliably to oral dissolution therapy. The use of oral dissolution therapy does not address the problem of gallbladder stasis.10 Although prokinetic agents, including α-adrenergic antagonists, clarithromycin, and domperidone, have been shown to increase gallbladder motility, their use in preventing and treating gallstones has been shown to be ineffective.11-13

Patient Selection Selection of patients for oral dissolution therapy is a function of the stage of gallstone disease, gallbladder function, and characteristics of the stones. Selection criteria are summarized in Box 66.1. Oral dissolution therapy should be considered for patients with uncomplicated gallstone disease, including those with mild, infrequent biliary pain. Patients with asymptomatic gallstones should not be treated with either dissolution therapy

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or surgery because the natural history of most asymptomatic stones is to remain asymptomatic. Patients with severe or frequent biliary pain and patients with complications of gallstones, including cholecystitis, pancreatitis, and cholangitis, should not be treated with oral dissolution therapy; these patients should be

referred for surgery as soon as possible (see later). In addition, the gallbladder must function, and the cystic duct must be patent to allow unsaturated bile and stones to clear from the gallbladder. The patency of the cystic duct has generally been evaluated by oral cholecystography. More recently, stimulated cholescintigraphy and functional US have been used. These latter modalities assess cystic duct patency as well as gallbladder function. The characteristics of the stones play an important role in determining the efficacy of dissolution treatment. Oral dissolution therapy works only on cholesterol stones. Although verifying the composition of gallstones can be difficult, the appearance of stones on plain films or CT images can be useful. Cholesterol stones are radiolucent on plain films, and they are hypodense or isodense to bile and lack stone calcification on CT images.14 During oral cholecystography, the specific gravity of cholesterol stones is less than or equal to that of contrast-enriched bile, thereby resulting in stone buoyancy. The number of stones does not influence the success of oral dissolution therapy; however, only patients with stones that occupy less than half of the gallbladder volume should be considered for treatment. Although oral dissolution therapy has been effective in stones up to 10 mm in diameter, results are best in stones less than 5 mm in size.15,16 The ideal stones for oral dissolution treatment are shown in Fig. 66.1. 

BOX 66.1 Selection Criteria for Oral Bile Acid Dissolution Therapy STAGE OF GALLSTONE DISEASE Symptomatic (biliary pain) without complications  GALLBLADDER FUNCTION Opacification of gallbladder on oral cholecystography (patent cystic duct) Normal result of stimulated cholescintigraphy (normal gallbladder emptying) Normal result of functional US (normal gallbladder emptying after a test meal)  STONE CHARACTERISTICS Radiolucent Isodense or hypodense to bile and absence of calcification on CT Diameter ≤10 mm ( 4 mm) in the absence of ascites or hypoalbuminemia, (2) sonographic Murphy’s sign (defined as maximum tenderness over the US-localized gallbladder), and (3) pericholecystic fluid collection. A thickened gallbladder wall (Fig. 67.1) is not specific for cholecystitis but in the proper clinical setting is suggestive of gallbladder involvement and should prompt further evaluation. A sonographic Murphy’s sign is operator dependent and requires a cooperative patient but, when present, is a reliable indicator of gallbladder inflammation.51 A pericholecystic fluid collection indicates advanced disease. Sensitivity rates of US for detecting acute acalculous cholecystitis have been reported to range from 67% to 92%, with a specificity of more than 90%.50 Investigators have proposed a US scoring system to improve the diagnostic accuracy of US in critically ill patients.52 Two points are given for distention of the gallbladder or thickening of the gallbladder wall, and one point each is given for “striated” thickening (alternating hypoechoic and hyperechoic layers) of the gallbladder wall, sludge, and pericholecystic fluid. Scores of 6 or higher accurately predict acalculous cholecystitis. One group evaluated the routine use of US for early detection of acalculous cholecystitis in the ICU. In a group of 53

Fig. 67.1  US demonstrating thickening of the gallbladder wall to 17 mm (denoted by asterisks) characteristic of acute acalculous cholecystitis. Point tenderness was noted when the transducer was pressed onto the abdomen over the gallbladder (sonographic Murphy’s sign). The diagnosis was confirmed at surgery. (Courtesy David Hurst, MD, Dallas, TX.)

mechanically ventilated patients, 3 men were diagnosed with acute acalculous cholecystitis by US findings and clinical features; however, gallbladder abnormalities were also detected in 30% of patients without acalculous cholecystitis. US should be performed in patients with a high pretest probability of acute acalculous cholecystitis.53 

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CT CT findings suggestive of cholecystitis are similar to US findings and include gallbladder wall thickening (>4 mm), pericholecystic fluid, subserosal edema (in the absence of ascites), intramural gas, and sloughed gallbladder mucosa. The sensitivity and specificity of these findings for predicting acute acalculous cholecystitis at surgery exceed 95%. CT is also superior to US in detecting disease elsewhere in the abdomen that could be the cause of a patient’s fever or abdominal pain.54 An obvious disadvantage of CT is that it cannot be performed at the bedside, which is necessary in many critically ill patients. Several investigators have emphasized that CT is complementary to US and may detect gallbladder disease in high-risk patients with normal US findings. 

Hepatobiliary scintigraphy Hepatobiliary scintigraphy may be useful for excluding cystic duct obstruction in patients with clinical features suggestive of acute cholecystitis. Under normal conditions, IV-administered radionuclide is taken up by the liver, secreted into bile, concentrated in the gallbladder (where it produces a “hot spot” on a scan), and emptied into the duodenum. A positive scan result for cystic duct obstruction is defined as failure of filling of the gallbladder despite the normal passage of radionuclide into the duodenum. In suspected calculous cholecystitis, the pathogenesis of which involves obstruction of the cystic duct by a stone, filling of the gallbladder on scintigraphy virtually excludes cholecystitis as the cause of the patient’s symptoms.55 Hepatobiliary scintigraphy is less precise in acute acalculous cholecystitis. Gallbladder and cystic wall edema can cause an obstructive picture similar to that of calculous cholecystitis on scintigraphy. Patients with acute acalculous cholecystitis have often fasted for prolonged periods, a state that can result in concentrated, viscous bile that flows poorly through the cystic duct and causes a false-positive hepatobiliary scan result. Most patients with acute acalculous cholecystitis (in contrast to those with calculi) do not have an obstructed cystic duct; hence, hepatobiliary scans can be falsely negative as well.56 The sensitivity of the test may exceed 90%, but the lack of specificity in fasted, critically ill patients limits the usefulness of the test primarily to excluding acute acalculous cholecystitis rather than confirming the diagnosis. A study in which US and cholescintigraphy were performed in critically ill patients found cholescintigraphy to be useful for the early diagnosis of acute acalculous cholecystitis, whereas US alone did not permit an early decision regarding the need for surgery.57 In an effort to improve the accuracy of biliary scintigraphy, investigators have proposed the use of morphine-augmented cholescintigraphy, in which morphine sulfate is administered IV (0.05 to 0.1 mg/kg) to increase resistance to the flow of bile through the sphincter of Oddi and, hence, “force fill” the gallbladder if the cystic duct is patent to reduce the likelihood of a false positive result.58 Although this test may exclude cholecystitis as a cause of sepsis, it is difficult to perform in critically ill patients. 

became the standard surgical approach, but more recently radiographically guided percutaneous cholecystostomy has been used more frequently because patients are often too unstable to tolerate anesthesia and surgery.59,60 If necessary, definitive cholecystectomy can be undertaken after cholecystotomy when the patient is stable. 

Percutaneous Cholecystostomy Several investigators have reported favorable results with the US-guided percutaneous transhepatic placement of a cholecystostomy drainage tube, coupled with IV administration of antibiotics, as definitive therapy in patients in whom surgery poses a high risk.49,61,62 This approach controls acute acalculous cholecystitis in 85% to 90% of patients and has a complication rate of approximately 10%. The short-term mortality rate of patients undergoing cholecystostomy is high but reflects the high mortality of the underlying disease rather than that of the procedure. Most patients with acute acalculous cholecystitis can be treated with percutaneous drainage; if the postdrainage cholangiogram is normal, the catheter can be removed, and subsequent cholecystectomy is unlikely to be necessary.61,62 

Transpapillary or Transmural Endoscopic Cholecystostomy Some critically ill patients with suspected acute acalculous cholecystitis are poor candidates for US-guided percutaneous cholecystostomy, typically because of massive ascites or uncorrectable coagulopathy. Such patients may benefit from an endoscopic approach in which the cystic duct is selectively cannulated during ERCP with an obliquely angled guidewire that tracks along the lateral wall of the bile duct and facilitates cannulation of the cystic duct. If the wire can negotiate the spiral valves within the cystic duct successfully, a pigtail stent is deployed in the gallbladder, and the other end is brought out through a nasobiliary catheter or left to drain internally into the duodenum (a “double-pigtailed” stent).63 The risk of bleeding is low if a sphincterotomy is not performed. Because the gallbladder is in close proximity to the GI tract, EUS-guided transmural placement of a covered, self-expandable, lumen-apposing metal stent is also used as a treatment for acalculous cholecystitis, with reported success rates of 97%.64 This approach is used most often in patients with advanced liver disease and ascites; it may be associated with less pain than a percutaneous procedure. Successful intubation of the gallbladder via ERCP can be achieved in 90% of attempts, and drainage and lavage of the viscous black bile and sludge from the gallbladder result in clinical resolution in most of these critically ill patients. The endoscopic techniques may be more cumbersome and expensive than US placement of a cholecystostomy tube and should be reserved for patients who would not tolerate a percutaneous approach or who have coagulopathy.65 

CHOLESTEROLOSIS

Treatment

Definition

In light of the rapid progression of acute acalculous cholecystitis to gangrene and perforation, early recognition and intervention are required. Supportive medical care should include restoration of hemodynamic stability as well as antibiotic coverage for Gram-negative enteric organisms and anaerobes if biliary tract infection is suspected.

Cholesterolosis is an acquired histologic abnormality of the gallbladder epithelium characterized by excessive accumulation of cholesterol esters and TG within epithelial macrophages (Fig. 67.2).66 Clinicians generally encounter the lesion only as an incidental pathologic finding after surgical resection of the gallbladder, although the diagnosis may be suspected in certain patients before surgery. Cholesterolosis, as well as adenomyomatosis of the gallbladder (see later), has been classified as one of the “hyperplastic cholecystoses,” a term introduced in 1960 to describe several diseases of the gallbladder thought to share the common features

Surgical Cholecystectomy and Cholecystostomy In the past, the definitive therapeutic approach to acute acalculous cholecystitis was emergency laparotomy and cholecystectomy (see Chapter 66). Subsequently, laparoscopic cholecystectomy

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Lipid-laden foamy macrophages

Epithelium

Lamina propria

Muscle layer

Adventitia

Normal gallbladder

Diffuse cholesterolosis

Cholesterol polyp

Fig. 67.2  Schematic representation of a normal gallbladder, diffuse cholesterolosis, and a cholesterol polyp.  Note the distribution of lipid-laden foamy macrophages in cholesterolosis and the cholesterol polyp. The diffuse form of cholesterolosis (center; see also Fig. 67.3) accounts for 80% of cases and generally causes no symptoms. Cholesterol polyps (right), present in 10% of cases of cholesterolosis, are typically small, fragile excrescences that have a tendency to ulcerate or detach spontaneously from the mucosa. Combined diffuse cholesterolosis and cholesterol polyps account for 10% of cases. Although usually asymptomatic, these polyps have been associated with biliary pain and even acute pancreatitis.

of mucosal hyperplasia, hyperconcentration and hyperexcretion of dye on cholecystography, and absence of inflammation.67 The proponents of this concept believed that biliary pain, in the absence of gallstones, could be explained by the presence of one of the hyperplastic cholecystoses. Other investigators, citing the lack of a common etiology and the nonspecificity of the clinical features, have recommended that the term hyperplastic cholecystoses be abandoned. 

Epidemiology Depending on whether gross or microscopic criteria are used for diagnosis, the frequency of cholesterolosis in autopsy specimens has ranged from 5% to 40%. A large autopsy series involving more than 1300 cases in which each gallbladder was examined microscopically found the frequency of cholesterolosis to be 12%.68 When surgically resected gallbladders were examined, the frequency was, not surprisingly, about 50% higher (18%) than that found in autopsy material.69 The incidence of cholesterolosis has not been calculated because its onset is rarely known. The epidemiology of cholesterolosis is analogous to that of cholesterol gallstone disease,70 in that similar groups of persons are predisposed; however, the 2 lesions occur independently and do not necessarily coexist in the same person. Like gallstone disease, cholesterolosis is uncommon in children and shows a marked predilection for women until the age of 60 years. After that, the gender differences are less pronounced. No racial, ethnic, or geographic differences in prevalence have been described, although if the analogy with cholesterol gallstone disease is extended, the prevalence would be expected to be higher in Western than nonWestern societies. Obesity also appears to be a risk factor for cholesterolosis; a frequency of 38% has been observed in gallbladders resected during weight loss surgery.71 

Pathology Cholesterolosis is defined pathologically by the accumulation of lipid (cholesteryl esters and TG) within the gallbladder mucosa. The 4 patterns of lipid deposition are as follows66:   

Diffuse: The lipid is distributed throughout the epithelial lining of the gallbladder and ends abruptly at the cystic duct. This pattern accounts for 80% of all cases. Cholesterol polyps: The excess lipid is confined to one or more areas of the epithelium that eventually form excrescences into the lumen of the gallbladder. Isolated cholesterol polyps in the absence of diffuse cholesterolosis account for about 10% of the total cases. Combined diffuse cholesterolosis and cholesterol polyps: Cholesterol polyps occur on a background of diffuse cholesterolosis. This pattern accounts for about 10% of cases. Focal cholesterolosis: Excess lipid deposition is limited to a small area of the mucosa.

Gross Appearance When the gallbladder is inspected visually at the time of laparotomy or laparoscopy, a diagnosis of cholesterolosis can be made in 20% of the cases on the basis of the gross appearance of the gallbladder mucosa as seen through the translucent serosal surface. When the gallbladder is opened, the mucosa characteristically has pale, yellow linear streaks running longitudinally, giving rise to the term strawberry gallbladder (although the mucosa is usually bile stained rather than red). When cholesterolosis is diagnosed at the time of surgical resection of the gallbladder, gallstones are also present in 50% of cases. If the diagnosis of cholesterolosis is made at autopsy, stones are present in only 10%,68 demonstrating that the 2 disease processes are independent of each other. 

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Fig. 67.3  Histopathology of diffuse cholesterolosis.  Note the hyperplastic, elongated villi, and the foamy macrophages (arrows). (H&E.) (Courtesy Pamela Jensen, MD, Dallas, TX.)

Microscopic Appearance Hyperplasia of the mucosa is invariably present and is described as marked in 50% of cases. Usually, the hyperplasia is of the villous type. The most prominent feature is an abundance of macrophages within the elongated villi. Each macrophage is stuffed with lipid droplets and has a characteristic appearance of a foam cell (Fig. 67.3). In milder cases, the foam cells are limited to the tips of the villi (accounting for the linear streaks seen on gross examination); with more severe involvement, the foam cells may fill entire villi and spill over into the underlying submucosa. Although extracellular deposits of lipid are rare, small yellow particles (lipoidic corpuscles) representing detached masses of foam cells are occasionally seen floating in the bile. 

Pathogenesis The cause of the accumulation of cholesteryl esters and TG in cholesterolosis remains obscure.72 Postulated mechanisms are that the cholesterol is derived from the blood73 or that mechanical factors that impede emptying of the gallbladder lead to local deposition of lipid.74 Data have shown unequivocally that the gallbladder epithelium is capable of absorbing cholesterol from the bile, as might be expected in epithelium that is embryologically and histologically similar to intestinal absorptive cells.75,76 Moreover, the cholesterol in gallbladder bile is already in the ideal physical state for absorption (i.e., a mixed micelle). The question remains as to why, in some patients, resorbed biliary cholesterol is esterified and then stored in foamy macrophages as cholesterolosis.77 Like cholesterol stones, cholesterolosis is frequently, but not always, found in gallbladders exposed to bile that is supersaturated with cholesterol.78 The 2 disorders (cholesterolosis and stone disease), both of which lead to the ectopic accumulation of cholesterol, probably share common pathogenic mechanisms (e.g., the secretion of abnormal bile) but progress independently in a given patient, depending on other factors such as the presence of nucleating proteins in bile and the rate of mucosal esterification of cholesterol.79 Cholesterolosis is not associated with high serum cholesterol levels.70 

Clinical Features Cholesterolosis usually does not cause symptoms, as is evident by how frequently autopsy specimens show the lesion in patients who never had biliary symptoms. On occasion, individual patients

have dull, vague RUQ or epigastric pain that resembles biliary pain and are found subsequently to have cholesterolosis without stones or gallbladder inflammation after cholecystectomy. Of the patients who undergo cholecystectomy for the syndrome of acalculous biliary pain, pain is more likely to resolve in those in whom incidental cholesterolosis is found on pathologic examination of the gallbladder than in those in whom cholesterolosis is not found.9 In a retrospective surgical series of nearly 4000 gallbladders removed by cholecystectomy, 55 cases of acalculous cholesterolosis were identified.80 The investigators found that nearly one half of the patients with cholesterolosis had presented with recurrent pancreatitis of unknown etiology and speculated that small cholesterol polyps had detached from the gallbladder wall and transiently obstructed the sphincter of Oddi, thereby provoking the acute pancreatitis. In 5 years of postoperative follow-up, pancreatitis did not recur. These investigators and others81,82 have suggested that cholesterolosis (or, more specifically, cholesterol polyps) should be considered in the differential diagnosis of idiopathic pancreatitis. A retrospective review of 6868 patients who underwent cholecystectomy, of whom 18% (1053) had cholesterolosis, has challenged this theory: when patients with gallstones were excluded from this population, not a single patient had experienced pancreatitis.83 

Diagnosis Diffuse cholesterolosis (which, as noted earlier, constitutes 80% of cases) is only rarely detectable by either US or oral cholecystography. In the polypoid form, however, polyps of sufficient size have a characteristic appearance on US as single or multiple, nonshadowing, fixed echoes that project into the lumen of the gallbladder.84 Most of the polyps are small (2 to 10 mm). The polyps can be identified accurately as cholesterolosis polyps by EUS, which demonstrates a characteristic aggregation of hyperechoic spots.85 On oral cholecystography, the polyps appear as small, round radiolucencies in the lumen of the opacified gallbladder and are best demonstrated after the gallbladder has emptied partially and abdominal compression has been applied. 

Treatment Because cholesterolosis is only rarely diagnosed before resection of the gallbladder, treatment is usually not a consideration. In the rare case of polypoid cholesterolosis diagnosed on US or cholecystography, the absence of biliary tract symptoms argues against any intervention. If the patient has symptoms consistent with biliary pain or pancreatitis, a cholecystectomy is indicated.80 There is no medical therapy for cholesterolosis. 

ADENOMYOMATOSIS Definition Adenomyomatosis (an unwieldy term that obscures its meaning) of the gallbladder is an acquired, hyperplastic lesion characterized by excessive proliferation of surface epithelium with invaginations into the thickened muscularis or even more deeply.86 The literature on this condition is complicated by the use of a number of different terms to describe the same lesion, the most common of which are adenomyoma (used when the lesion is localized to the gallbladder fundus), Rokitansky-Aschoff sinuses (familiar but anatomically incorrect), and adenomyosis.87 Despite the prefix adeno-, the lesion is generally benign and unrelated to adenomatous epithelia elsewhere in the GI tract. Simple adenomyomatosis is not thought to have the potential for malignant transformation. 

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Epidemiology

Microscopic Appearance

The prevalence of adenomyomatosis of the gallbladder varies greatly according to the criteria used for diagnosis and whether resected gallbladders or autopsy specimens are examined. In a large series of more than 10,000 cholecystectomy specimens, Shepard and associates88 found only 103 cases of adenomyomatosis, for a frequency of about 1%. The lesion is more common in women than men by a 3:1 ratio, and the prevalence rises with age. Neither ethnic nor geographic differences in prevalence have been described. 

Hyperplasia of the muscle layer is invariably present, and the epithelial lining occasionally undergoes intestinal metaplasia. Mild chronic inflammation is often present. 

Pathology A review of the normal histologic architecture of the gallbladder and Rokitansky-Aschoff sinuses is useful for understanding the pathology of adenomyomatosis (Fig. 67.4). Unlike the small intestine, the gallbladder has no muscularis mucosa, and the lamina propria abuts directly on the muscular layer. In childhood, the epithelial layer is cast up into folds and supported by the lamina propria. As the gallbladder ages, the valleys of the epithelial layer may deepen so that they penetrate into the muscular layer and form Rokitansky-Aschoff sinuses. These sinuses are acquired lesions present in about 90% of resected gallbladders. If Rokitansky-Aschoff sinuses are deep and branching and are accompanied by thickening (hypertrophy) of the muscular layer, a diagnosis of adenomyomatosis can be made.86 Rupture of Rokitansky-Aschoff sinuses is thought to underlie the rare entity xanthogranulomatous cholecystitis, in which the gallbladder is involved in an inflammatory process with lipid-laden macrophages (see Chapter 65).

67

Pathogenesis The pathogenesis of adenomyomatosis is unknown. Increased intraluminal pressure in the gallbladder from mechanical obstruction (e.g., an obstructing calculus, kink in the cystic duct, congenital septum) has been postulated to result in cystic dilatation of the Rokitansky-Aschoff sinuses, subsequent hyperplasia of the muscle layer, and adenomyomatosis.86 Like pressurerelated colonic diverticula, Rokitansky-Aschoff sinuses are most likely to be found where the muscle layer is weakest (at the site of a penetrating blood vessel). Nevertheless, evidence of outflow obstruction of the gallbladder is not always found; for example, calculi are present in only about 60% of cases of adenomyomatosis.88 Some investigators have proposed that adenomyomatosis is a consequence of chronic inflammation, but inflammation is not always present, particularly when the lesion is localized to the fundus.89 Finally, several investigators have noted an association between adenomyomatosis and anomalous pancreaticobiliary ductal union (see Chapters 55 and 62). In one study, one half of the patients with adenomyomatosis had pancreaticobiliary malunion (anomalous pancreaticobiliary ductal union),90 and in another study, one third of patients with pancreaticobiliary malunion had adenomyomatosis.91 The pathogenic link between these 2 peculiar entities is unclear. 

Clinical Features

Gross Appearance Adenomyomatosis may involve the entire gallbladder (diffuse or generalized adenomyomatosis) or, more commonly, may be localized to the gallbladder fundus, in which case the lesion is often termed adenomyoma. On rare occasions, the process may be limited to an annular segment of the gallbladder wall (segmental adenomyomatosis) and may give rise to luminal narrowing and a “dumbbell-shaped” gallbladder (Fig. 67.5). In any case, the involved portion of the gallbladder wall is thickened to 10 mm or more, and the muscle layer is 3 to 5 times its normal thickness. On cut sections, cystic dilatations of the Rokitansky-Aschoff sinuses are evident and may be filled with pigmented debris or calculi. 

Adenomyomatosis, like cholesterolosis, usually causes no symptoms and is typically an incidental finding at autopsy or surgical resection. As noted earlier, gallstones are present in more than half of the resected gallbladders that are found to have adenomyomatosis; in these cases, the symptoms can be ascribed to the stones.88 Uncommonly, acalculous adenomyomatosis appears to cause symptoms indistinguishable from the biliary pain of cholelithiasis. On rare occasions, adenocarcinoma of the gallbladder has been found in association with adenomyomatosis (Fig. 67.6)92; however, the malignancy is often far removed from the localized area of adenomyomatosis, and the association has been thought to be coincidental rather than causal. Nevertheless, Lumen

Fig. 67.4  Schematic representation of a normal gallbladder, a Rokitansky-Aschoff sinus, and adenomyomatosis. RokitanskyAschoff sinuses, which are present in about 90% of resected gallbladders, consist of invaginations of the epithelium into the muscle layer to produce tiny intramural diverticula. By themselves, they have no clinical significance. A histologic diagnosis of adenomyomatosis requires that the Rokitansky-Aschoff sinuses be deep, branching, and accompanied by hypertrophy of the muscle layer.

Epithelium

Lumen

Lumen

Lamina propria

Adventitia

Muscle layer

Normal gallbladder

Rokitansky-Aschoff sinus

Adenomyomatosis

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several reports of adenocarcinoma occurring in an area of gallbladder wall involved with adenomyomatosis have created diagnostic uncertainty on US or cholecystography.93 A retrospective review of more than 3000 resected gallbladders revealed a significantly higher frequency (6.4%) of gallbladder cancer in gallbladders with the segmental form of adenomyomatosis than would have been expected by chance alone. The investigators proposed that segmental adenomyomatosis should be considered a potentially premalignant lesion.94 A second review of gallbladder cancers associated with segmental adenomyomatosis revealed a spectrum of cytologic atypia in the specimens ranging from hyperplastic to malignant epithelium, suggestive of neoplastic progression.95 When simple adenomyomatosis of the gallbladder is discovered incidentally, the lesion is likely to be benign. If there is any Lamina propria

suspicion of an associated mass lesion, particularly one greater than 10mm, or if segmental adenomyomatosis is found, however, a thorough radiologic evaluation of the gallbladder is warranted, and cholecystectomy should be considered. 

Diagnosis As noted previously, adenomyomatosis is frequently diagnosed only after resection and direct examination of the gallbladder; however, several specific radiologic and US findings may, if present, allow the diagnosis to be made preoperatively. On oral cholecystography (see Chapter 65), the mural diverticula that constitute Rokitansky-Aschoff sinuses may fill with contrast material and produce characteristic radiopaque dots that parallel the margin of the gallbladder lumen.96 Localized, fundal

Muscle layer

Epithelium

Normal gallbladder

Fundic adenomyomatosis (adenomyoma)

A

Generalized adenomyomatosis

Segmental adenomyomatosis

Fig. 67.5  Schematic representation showing the different patterns of adenomyomatosis.  Most of the cases are localized to the fundus of the gallbladder (in which case the lesion is termed an adenomyoma); generalized and segmental patterns are much less common. An adenomyoma is usually 10 to 20 mm in diameter and may be largely confined to the wall or may project into the lumen to produce a polypoid lesion.

B

Fig. 67.6 A, Gross pathologic appearance of a gallbladder adenomyoma involved by adenocarcinoma. B, Histopathology shows a moderately differentiated adenocarcinoma of the gallbladder undermining the mucosa of the adenomyoma (H&E). (Courtesy Aviva Hopkowitz, MD, Dallas, TX.)  

CHAPTER 67  Acalculous Biliary Pain, Acute Acalculous Cholecystitis, Cholesterolosis, Adenomyomatosis, and Gallbladder Polyps

1073

Treatment In the absence of biliary tract symptoms, adenomyomatosis requires no treatment. If the patient has biliary pain and radiographic or US evidence of adenomyomatosis with calculi, a cholecystectomy is indicated. A more difficult clinical problem arises when a patient is symptomatic and has suspected adenomyomatosis but no stones.93 In such cases, the more extensive or severe the adenomyomatosis appears to be, the more likely that the symptoms are related to the lesion and that the patient will benefit from cholecystectomy. Fear of malignant transformation is not a reason to operate, unless imaging suggests a possible mass or perhaps shows the segmental form of adenomyomatosis. 

GALLBLADDER POLYPS Definition Fig. 67.7  Oral cholecystogram showing segmental adenomyomatosis in a 28-year-old man with postprandial epigastric pain radiating through to the back. The film demonstrates an annular segment of the gallbladder wall (arrowhead ) involved with adenomyomatosis, which has produced a constriction of the lumen. Although no gallstones were present, a cholecystectomy was performed, and the patient’s symptoms were relieved. (Courtesy W. J. Kilman, MD, Dallas, TX.)

adenomyomatosis (adenomyoma) may manifest as a filling defect in the fundus, whereas segmental adenomyomatosis may appear as a circumferential narrowing of the gallbladder lumen (Fig. 67.7). As is the case with cholesterolosis, the radiologic findings in adenomyomatosis are best appreciated when the gallbladder has partially emptied of contrast material and external pressure has been applied during the examination.96 Although US has largely replaced oral cholecystography in the evaluation of the gallbladder, the US findings in adenomyomatosis are less specific. A thickened gallbladder wall (>4 mm) is not specific for adenomyomatosis and can also be seen in many other conditions such as liver disease with ascites.97 Carefully performed studies in which radiologic and US findings of adenomyomatosis were correlated with pathologic findings have shown that diffuse or segmental thickening of the gallbladder wall in association with intramural diverticula (seen as round anechoic foci) accurately predicts adenomyomatosis.98 If the intramural diverticula (dilated Rokitansky-Aschoff sinuses) are filled with sludge or small calculi, the lesions may appear echogenic with acoustic shadowing or a reverberation artifact.99 Contrast-enhanced US has greater sensitivity for characterizing adenomyomatosis.100 Similarly, EUS may demonstrate the characteristic finding of multiple microcysts, corresponding to the proliferated Rokitansky-Aschoff sinuses.85 CT and MRI findings in adenomyomatosis include differential enhancement of gallbladder wall layers,101 detection of Rokitansky-Aschoff sinuses within a thickened gallbladder wall,102 and subserosal fatty proliferation.103 In a study of 20 patients with surgically proved adenomyomatosis who underwent preoperative US, helical CT, and MRI, the diagnostic accuracies of the 3 modalities were 66%, 75%, and 93%, respectively.104 In patients in whom the diagnosis is uncertain, MRI is the most accurate modality for differentiating adenomyomatosis from a malignant gallbladder lesion.105 In one case report, an adenomyoma without histologic evidence of cancer was the cause of a falsepositive finding on 18-fluorodeoxyglucose PET, likely because of the associated inflammatory activity.106 

The term polyp of the gallbladder is used to describe any mucosal projection into the lumen of the gallbladder.107 The vast majority of gallbladder polyps are the result of lipid deposits or inflammation, rather than a neoplasm. Because the nature of a polyp cannot be defined without histologic evaluation, however, clinicians must decide whether concern about malignancy is sufficient to recommend cholecystectomy based on indirect information such as the imaging appearance of the polyp, patient demographics, and symptoms. 

Epidemiology The frequency of gallbladder polyps, defined either pathologically or radiologically,108 ranges from 1% to 4%, but may be as high as 5% to 10% in some populations. Often, a gallbladder polyp is an incidental finding at the time of cholecystectomy. With the increasing use of imaging in clinical practice, incidental gallbladder polyps are detected more frequently than in the past. 

Pathology Polyps of the gallbladder may be classified as shown in Table 67.3 as either non-neoplastic (95% of all gallbladder polyps) or neoplastic.109

Cholesterol Polyps Cholesterol polyps are the most common type of gallbladder polyp. They are variants of cholesterolosis that result from infiltration of the lamina propria with lipid-laden foamy macrophages. The pathogenesis of cholesterol polyps is discussed in the section on cholesterolosis (see earlier). Cholesterol polyps are typically small (12 mm in diameter; lesions 18 mm in size, open rather than laparoscopic cholecystectomy should be considered because invasive cancer is more likely and extended resection may be required

Miscellaneous neoplasms

2 stages, decompensated cirrhosis, liver biochemistries, or symptomatic progression) Improved liver biochemistry

148

UDCA

2001

26

UDCA (20 mg/kg/day) vs. placebo

24 mo

Improved liver biochemistries, reduced histologic and cholangiographic progression

138

UDCA plus Metronidazole

2004

80

UDCA/metronidazole (600-800 mg/day) vs. UDCA/placebo

36 mo

Improved liver biochemistries, Mayo risk score (see Table 68.5), and histology, but not cholangiography

150

UDCA

2005

219

UDCA (17-23 mg/kg/day) vs. placebo

60 mo

No benefit in transplant-free survival, liver biochemistries, or quality of life

351

UDCA

2008

31

UDCA (10 vs. 20 vs. 30 mg/kg/ day)

24 mo

Improved liver biochemistries and Mayo risk score (high dose only)

151

UDCA

2009

150

UDCA (28-30 mg/kg/day) vs. placebo

60 mo

No benefit, increased adverse events

146

Vancomycin or Metronidazole

2013

35

Vancomycin (125 or 250 mg daily) vs. metronidazole (250 vs. 500 mg 3 times daily)

3 mo

Improved liver biochemistries and Mayo risk score with lower dose of metronidazole and with vancomycin

243

nor-UDCA

2017

161

nor-UDCA (500 mg/day, 1000 mg/day, or 1500 mg/day) vs. placebo

12 wk

Reduced alk phos levels (12.3%, to 26.0% reduction compared with 1.2% increase with placebo)

235

  

*Trials with more than 20 subjects. Alk phos, Alkaline phosphatase.   

development of varices in patients receiving high-dose UDCA compared with those receiving placebo.231 Nevertheless, posthoc analyses of these studies have suggested that patients in whom liver biochemical test levels improve may obtain some clinical benefit,163,164 and withdrawal of UDCA has been associated with deterioration in serum biochemical liver test levels and the Mayo risk score (see earlier) in addition to increased pruritus.232 Several newer bile acid‒modulating agents have shown promising initial results in improving liver biochemical test levels. These have included nor-UDCA, a C23 homolog of UDCA with potent choleretic activity233 that, in preclinical studies, showed significant anticholestatic, anti-inflammatory, and antiproliferative properties 234 with less toxicity than UDCA. In a multicenter phase 2 clinical trial in Europe, nor-UDCA improved serum alkaline phosphatase levels regardless of prior UDCA use.235 Other therapies under study include receptor agonist, which regulate bile acid homeostasis and other metabolic processes. The immunologic basis of PSC would appear to make immunosuppressive therapy a reasonable treatment option. Glucocorticoids, administered both orally and via nasobiliary lavage, have not shown a clear benefit in uncontrolled studies.236,237 Oral budesonide has been evaluated in an uncontrolled pilot study in 21 patients with PSC but was not effective and resulted in significant loss of bone mass.237 In a small prospective, controlled trial of methotrexate, no biochemical, histologic, or cholangiographic differences between therapy with placebo were seen after 2 years of treatment.238 A study of tacrolimus demonstrated significant

biochemical improvement after 1 year but no change in cholangiographic or histologic severity.239 Neither infliximab nor etanercept, both of which are TNF-α inhibitors, showed a benefit in patients with PSC.152,240 Antibiotics have been used with no clear benefit but remain under study. In 14 pediatric patients with PSC treated with oral vancomycin, all had improvement in liver biochemical test levels, especially those without cirrhosis.241 The same investigators subsequently found that oral vancomycin improved liver histology and imaging finding, while increasing plasma levels of transforming growth factor-β (TGF-β) and peripheral Tregs, thereby suggesting an immunomodulatory mechanism.242 In adults, oral vancomycin demonstrated a modest reduction in serum alkaline phosphatase levels over 12 weeks of treatment.243 Despite these promising results, the potential harm from indiscriminate alterations in gut flora, as illustrated by the Mdr2-null mouse raised in a germ-free environment, should temper enthusiasm for their widespread use.73 Other approaches under study include antifibrotic medications, but to date none has shown significant benefit. Combination therapy targeting several pathways may be needed for effective therapy in PSC. Historically, combinations of various agents such as azathioprine, glucocorticoids, UDCA, and antibiotics have been studied in a limited fashion.244,245,150 The results of these studies have been mixed, with some showing no benefit and others demonstrating histologic improvement in small numbers of patients. Moreover, combination therapy increases the risk of adverse drug reactions. 

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PART VIII  Biliary Tract

Medical Treatment of Complications An important component in the medical care of patients with PSC is the management of complications of the disease, including pruritus, nutritional deficiencies, and bacterial cholangitis. Pruritus should be managed as in other cholestatic conditions (see Chapter 91), including counseling on the exacerbating effects of heat and other stimuli on pruritus. Anion-exchange resins such as cholestyramine, colestipol hydrochloride, or colesevelam are considered first-line therapy, although compliance is a problem due to their relative unpalatability, constipating effects, and interference with the absorption of other medications. Rifampin may be an effective and safe alternative for patients who do not respond to conservative measures and resins.246 Opiate antagonists such as naloxone and naltrexone have also been shown to be effective for cholestatic pruritus, although self-limited episodes of opioid withdrawal-like symptoms may occur.174,175,247,248 Selective serotonin reuptake inhibitors (SSRIs) have shown limited efficacy.249 Patients who are unresponsive to these measures and who do not obtain relief from endoscopic or percutaneous drainage (see later) may need to be considered for plasmapheresis or nasobiliary drainage. LT was considered for intractable pruritus in the past but is unlikely to be a viable option unless a suitable living donor is available. Patients with PSC should be screened for nutritional deficiencies by measurement of fat-soluble vitamin levels and the INR. In most patients, vitamin supplements are given orally, but a parenteral route may be necessary in patients with severe intestinal fat malabsorption. Along with vitamin D deficiency, osteopenia is frequent in patients with PSC, and the severity is unrelated to the severity of liver disease.250 Therefore patients with PSC should be screened at diagnosis and every 2 to 3 years for mineral bone deficiency. If osteopenia is detected, vitamin D (1000 IU/day) and calcium (1 to 1.5 g/day) repletion should be started, whereas bisphosphonate therapy should be considered in those with osteoporosis.125 Prolongation of the INR is more likely to be the result of advanced liver disease than of vitamin K deficiency, although a trial of oral vitamin K is warranted in patients with coagulopathy (see Chapter 94). Bacterial cholangitis is a frequent complication of PSC and occurs in approximately 10% of patients annually. In addition to the risk of spontaneous bacterial cholangitis, patients with PSC are at high risk of cholangitis following biliary instrumentation and should receive antibiotic prophylaxis following any biliary procedure, usually with a 5- to 7-day course of a fluoroquinolone, cephalosporin, or a beta-lactamase inhibitor. There are no established criteria for the diagnosis of bacterial cholangitis in PSC; established criteria such as the Tokyo Guidelines for acute cholangitis (see Chapter 65) rely on abnormal liver biochemical test levels and are not applicable in PSC. Bacterial cholangitis in patients with PSC can be indolent and the illness should be suspected in the presence of fever, leukocytosis, RUQ pain, or a worsening of liver biochemical test levels. Although some patients have recurring bouts of bacterial cholangitis that can be debilitating, bacterial cholangitis did not increase the risk of waitlist mortality in a multicenter study of patient with PSC listed for LT.251 Patients with recurring cholangitis may benefit from long-term suppressive antibiotic prophylaxis with rotating courses of amoxicillin-clavulanic acid, ciprofloxacin, and/or trimethoprim/sulfamethoxazole every 3 to 4 weeks. 

Endoscopic Management In select patients, endoscopic therapy for PSC carries the potential to relieve jaundice, pruritus, and abdominal pain; improve biochemical cholestasis; decrease the frequency of episodes of bacterial cholangitis; and improve bile flow. In theory, improved long-term biliary patency could slow the progression of the

disease and prevent or delay biliary cirrhosis, but studies of endoscopic intervention in patients with PSC have been small, retrospective, and uncontrolled. Therefore routine endoscopic therapy in PSC is not recommended. Patients who are most likely to benefit from endoscopic intervention are those with a known or suspected dominant stricture, defined as a stenotic area with diameter less than or equal to 1.5 mm in the bile duct or less than or equal to 1 mm in the hepatic duct,252 particularly if they present with worsening jaundice or pruritus, cholangitis, or abdominal pain. Dominant strictures are associated with reduced transplant-free survival253 and multiple studies have reported significant improvements in clinical, biochemical, and cholangiographic end points in patients with a dominant stricture treated with endoscopic therapy,254-258 usually balloon dilation with or without temporary stent placement. Sphincterotomy is controversial because it can result in further sclerosis of the distal biliary tract and increase the risk of bacterial cholangitis. Despite an increased risk of periprocedural bleeding, especially in cirrhotic patients, sphincterotomy may protect against post-ERCP pancreatitis in those who are likely to undergo multiple ERCPs with complex cannulation. Choledocholithiasis should be considered in patients with worsening cholestasis. In as many as 30% of the cases, small stones may be missed by ERCP and regarded as wall irregularities, consistent with PSC.259 Use of direct cholangioscopy enables the detection of these stones and the use of lithotripsy, if needed. Direct visualization with cholangioscopy is also useful for the evaluation of dominant strictures and allows targeted biopsies, which improve overall diagnostic accuracy compared with ERCP.260 Placement of a biliary stent after balloon dilation appears to increase the risk of complications compared with balloon dilation alone.261,154 Professional society guidelines recommend avoiding routine placement of a stent for dominant biliary strictures in PSC, although short-term stenting (20 per high-powered field) are identified in pinch biopsies obtained from the major papilla or bile duct.157,326,327 The treatment of IgG4-sclerosing cholangitis is similar to that of autoimmune pancreatitis and includes glucocorticoids, to which more than 95% will respond.321 However, relapse is frequent and often requires long-term maintenance therapy with azathioprine or other immunosuppressant. Development of cirrhosis or cholangiocarcinoma is rare, and the long-term prognosis is excellent. 

Recurrent Pyogenic Cholangitis Recurrent pyogenic cholangitis (RPC) is a form of SSC that was first described by Digby in 1930 and defined by Cook and colleagues as a syndrome characterized by recurrent bacterial cholangitis, intrahepatic pigment stones, and biliary strictures, possibly leading to chronic liver disease and cholangiocarcinoma.328,329 RPC has also been called “oriental cholangiohepatitis,” “Hong Kong disease,” “biliary obstruction syndrome of the Chinese,” and hepatolithiasis. Although the prevalence has been decreasing, RPC remains most common in Southeast Asia and can also be found in immigrants to Western countries. Men and women are affected equally, and rural residence and lower socioeconomic status appear to be risk factors,330,331 suggesting that the changing epidemiology may be related to the adoption of a Western-style diet with a higher protein content; improved hygiene, and reduction in disease burden related to Clonorchis sinensis and Ascaris lumbricoides, infections often cited as contributors to RPC (see Chapter 84). Infection with C. sinensis, Opisthorchis species, and A. lumbricoides is endemic in the same geographic region where RPC is prevalent, suggesting an important role of these infections. However, patients with RPC do not appear to have an increased frequency of these infections compared with the general population, and approximately one half of patients with RPC demonstrate no evidence of infection.332-334 Furthermore, some parts of Asia with a high prevalence of RPC have low or undetectable rates of infection with C. sinensis.335 Bacterial infections have also been proposed as a cause of RPC, and portal bacteremia, possibly related to GI infection and bacterial translocation, has been associated with low socioeconomic status and malnutrition.331 Diets low in saturated fat have been implicated due to the potential to reduce gallbladder contractility and promote stone formation.

Clinical Features and Diagnosis Patients with RPC often present with symptoms of acute bacterial cholangitis, including fever, RUQ pain, and jaundice, also referred to as Charcot triad (see Chapter 65).336 Patients may also present with abdominal pain or pancreatitis. Imaging findings in patients with RPC are characteristic, with the majority of patients (75% to 80%) having intrahepatic stones, with predominant involvement of the left hepatic duct (Fig. 68.6). Dilatation of the bile ducts is found almost universally. The central bile ducts are dilated disproportionately, with abrupt tapering and attenuation of more peripheral bile ducts within

CHAPTER 68  Primary and Secondary Sclerosing Cholangitis

1095

eggs or— intact worms. Peripheral eosinophilia may be present in cases of parasitic infection and may be associated with elevated serum IgE levels.340 

Treatment

Fig. 68.6  CT in a patient with a history of recurrent pyogenic cholangitis. Note the severe right-sided intrahepatic biliary dilatation with obvious intraductal calculi (arrow).

the liver. The presence of bile duct calculi is usually associated with intrahepatic bile duct dilatation and downstream strictures.337 Direct cholangiography, whether performed by the percutaneous or endoscopic route, allows localization of intrahepatic stones and strictures and placement of drains or extraction of stones. In a comparison with direct cholangiography, MRCP identified all dilated bile ducts and 98% of focal duct strictures and intraductal stones; however, only 44% to 47% of segmental bile duct abnormalities were identified by direct cholangiography. Therefore MRCP is the preferred diagnostic test.338 In 82 patients in whom cholangiocarcinoma was associated with RPC, cholangiocarcinoma tended to be located in atrophic segments associated with biliary calculi and was often accompanied by portal vein occlusion or narrowing.339 Patients who present with an initial episode of cholangitis associated with intrahepatic stones and strictures should undergo evaluation for infection with Clonorchis and Opisthorchis species, particularly if the patient comes from or has traveled to an endemic area. The diagnosis of a parasitic infection is made by the identification of eggs in fecal specimens; concentrated stool may be required. Eggs are present in stool after 4 weeks of infection.337 Duodenal or biliary fluid may also demonstrate

Antibiotic therapy should be initiated promptly, once cultures of blood and bile (if accessible) have been obtained. In those with parasitic infection, treatment with an antihelminthic agent is indicated in patients with evidence of active parasitic infection (see also Chapter 84). In patients with evidence of cholangitis and dilated intra- and extra-hepatic bile ducts, ERCP is the preferred interventional procedure. ERCP with sphincterotomy, with or without placement of a nasobiliary drain or percutaneous biliary drainage, may be required to remove bile duct stones and traverse strictures (see Chapter 70). Several studies have reviewed the success of various nonoperative interventions for the initial management of patients with RPC presenting acutely. Sperling and colleagues336 compared outcomes in 41 patients with RPC based on whether they underwent therapeutic ERCP, hepatobiliary surgery, or no intervention. Symptoms recurred in 62% of patients who underwent only diagnostic ERCP but half as often in those treated with therapeutic ERCP or surgery. Therapeutic ERCP was particularly effective in patients with disease involving the extrahepatic bile ducts and was comparable in efficacy to surgery. Patients with disease involving both the right and left hepatic duct branches tend to undergo more imaging studies, percutaneous cholangiograms, and endoscopic or surgical procedures.341 Hepaticojejunostomy has been a commonly used surgical procedure for the treatment of intrahepatic stones in patients with RPC.342 Laparoscopic biliary bypass surgery has been proposed as a technically feasible and effective option for patients with RPC.343,344 

Prognosis and Complications The natural history of RPC has not been well documented. Recurrent cholangitis is common recurring in 25% at 3 years and 37% at 5 years.345 Secondary biliary cirrhosis may develop and require LT. Cholangiocarcinoma is associated with RPC with a cumulative frequency of 3% to 9% (see Chapter 69).346 Acknowledgments The authors acknowledge the contributions of Drs. Andrew S. Ross and Kris V. Kowdley to this chapter in previous editions of the book. Full references for this chapter can be found on www.expertconsult.com 

.

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120. Brandt D, MacCarty R, Charboneau J, et al. Gallbladder disease in patients with primary sclerosing cholangitis. AJR Am J Roentgenol 1988;150:571–4. 121. Said K, Glaumann H, Bergquist A. Gallbladder disease in patients with primary sclerosing cholangitis. J Hepatol 2008;48:598–605. 122. Schimanski U, Stiehl A, Stremmel W, et al. Low prevalence of alterations in the pancreatic duct system in patients with primary sclerosing cholangitis. Endoscopy 1996;28:346–9. 123. Braden B, Faust D, Ignee A, et al. Clinical relevance of perihepatic lymphadenopathy in acute and chronic liver disease. J Clin Gastroenterol 2008;42:931–6. 124. Johnson KJ, Olliff JF, Olliff SP. The presence and significance of lymphadenopathy detected by CT in primary sclerosing cholangitis. Br J Radiol 1998;71:1279–82. 125. Chapman R, Fevery J, Kalloo A, et al. Diagnosis and management of primary sclerosing cholangitis. Hepatology 2010;51:660–78. 126. Lindor KD, Kowdley KV, Harrison ME. ACG Clinical Guideline: primary sclerosing cholangitis. Am J Gastroenterol 2015;110:646–59. 127. Schramm C, Eaton J, Ringe KI, et al. Recommendations on the use of magnetic resonance imaging in PSC-A position statement from the International PSC Study Group. Hepatology 2017;66:1675–88. 128. Eaton JE, Dzyubak B, Venkatesh SK, et al. Performance of magnetic resonance elastography in primary sclerosing cholangitis. J Gastroenterol Hepatol 2016;31:1184–90. 129. Corpechot C, Gaouar F, El Naggar A, et al. Baseline values and changes in liver stiffness measured by transient elastography are associated with severity of fibrosis and outcomes of patients with primary sclerosing cholangitis. Gastroenterology 2014;146:970–9. 130. Lefkowitch J. Primary sclerosing cholangitis. Arch Intern Med 1982;142:1157–60. 131. Ludwig J. Surgical pathology of the syndrome of primary sclerosing cholangitis. Am J Surg Pathol 1989;13:43–9. 132. Katabi N, Albores-Saavedra J. The extrahepatic bile duct lesions in end-stage primary sclerosing cholangitis. Am J Surg Pathol 2003;27:349–55. 133. Harrison R, Hubscher S. The spectrum of bile duct lesions in endstage primary sclerosing cholangitis. Histopathology 1991;19:321–7. 134. Wiesner R, LaRusso N, Ludwig J, et al. Comparison of the clinicopathologic features of primary sclerosing cholangitis and primary biliary cirrhosis. Gastroenterology 1985;88:108–14. 135. Gregorio G, Portmann B, Karani J, et al. Autoimmune hepatitis/ sclerosing cholangitis overlap syndrome in childhood: a 16-year prospective study. Hepatology 2001;33:544–53. 136. Gross Jr JB, Ludwig J, Wiesner R, et al. Abnormalities in tests of copper metabolism in primary sclerosing cholangitis. Gastroenterology 1985;89:272–8. 137. Ludwig J, Barham SS, LaRusso NF, et al. Morphologic features of chronic hepatitis associated with primary sclerosing cholangitis and chronic ulcerative colitis. Hepatology 1981;1:632–40. 138. Mitchell SA, Bansi DS, Hunt N, et al. A preliminary trial of highdose ursodeoxycholic acid in primary sclerosing cholangitis. Gastroenterology 2001;121:900–7. 139. Muir A, Goodman Z, Levy C, et al. Efficacy and safety of simtuzumab for the treatment of primary sclerosing cholangitis: results of a phase 2b, dose-ranging, randomized, placebo-controlled trial. J Hepatol 2017;66. S73-S73. 140. de Vries EM, de Krijger M, Farkkila M, et al. Validation of the prognostic value of histologic scoring systems in primary sclerosing cholangitis: an international cohort study. Hepatology 2017;65:907–19. 141. de Vries EM, Verheij J, Hubscher SG, et al. Applicability and prognostic value of histologic scoring systems in primary sclerosing cholangitis. J Hepatol 2015;63:1212–9. 142. Nakanuma Y, Zen Y, Harada K, et al. Application of a new histological staging and grading system for primary biliary cirrhosis to liver biopsy specimens: interobserver agreement. Pathol Int 2010;60:167–74. 143. Angulo P, Larson D, Therneau T, et al. Time course of histological progression in primary sclerosing cholangitis. Am J Gastroenterol 1999;94:3310–3. 144. Angulo P, Batts KP, Jorgensen RA, et al. Oral budesonide in the treatment of primary sclerosing cholangitis. Am J Gastroenterol 2000;95:2333–7.

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145. Sterling RK, Salvatori JJ, Luketic VA, et al. A prospective, randomized-controlled pilot study of ursodeoxycholic acid combined with mycophenolate mofetil in the treatment of primary sclerosing cholangitis. Aliment Pharmacol Ther 2004;20:943–9. 146. Lindor KD, Kowdley KV, Luketic VA, et al. High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis. Hepatology 2009;50:808–14. 147. LaRusso NF, Wiesner RH, Ludwig J, et al. Prospective trial of penicillamine in primary sclerosing cholangitis. Gastroenterology 1988;95:1036–42. 148. Lindor KD. Ursodiol for primary sclerosing cholangitis. Mayo primary sclerosing cholangitis-ursodeoxycholic acid study group. N Engl J Med 1997;336:691–5. 149. van Hoogstraten HJ, Wolfhagen FH, van de Meeberg PC, et al. Ursodeoxycholic acid therapy for primary sclerosing cholangitis: results of a 2-year randomized controlled trial to evaluate single versus multiple daily doses. J Hepatol 1998;29:417–23. 150. Farkkila M, Karvonen AL, Nurmi H, et al. Metronidazole and ursodeoxycholic acid for primary sclerosing cholangitis: a randomized placebo-controlled trial. Hepatology 2004;40:1379–86. 151. Cullen SN, Rust C, Fleming K, et al. High dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis is safe and effective. J Hepatol 2008;48:792–800. 152. Hommes DW, Erkelens W, Ponsioen C, et al. A double-blind, placebo-controlled, randomized study of infliximab in primary sclerosing cholangitis. J Clin Gastroenterol 2008;42:522–6. 153. Said K, Glaumann H, Bergquist A. Gallbladder disease in patients with primary sclerosing cholangitis. J Hepatol 2008;48:598–605. 154. Ponsioen CY, Arnelo U, Bergquist A, et al. No superiority of stents vs balloon dilatation for dominant strictures in patients with primary sclerosing cholangitis. Gastroenterology 2018;155:752–9. 155. Dave M, Elmunzer BJ, Dwamena BA, et al. Primary sclerosing cholangitis: meta-analysis of diagnostic performance of MR cholangiopancreatography. Radiology 2010;256:387–96. 156. European Association for the Study of the Liver. EASL clinical practice guidelines: the diagnosis and management of patients with primary biliary cholangitis. J Hepatol 2017;67:145–72. 157. Bjornsson E, Chari S, Smyrk T, et al. Immunoglobulin G4 associated cholangitis: description of an emerging clinical entity based on review of the literature. Hepatology 2007;45:1547–54. 158. Alexopoulou E, Xenophontos PE, Economopoulos N, et al. Investigative MRI cholangiopancreatography for primary sclerosing cholangitis-type lesions in children with IBD. J Pediatr Gastroenterol Nutr 2012;55:308–13. 159. Ponsioen C, Vrouenraets S, Prawirodirdjo W, et al. Natural history of primary sclerosing cholangitis and prognostic value of cholangiography in a Dutch population. Gut 2002;51:562–6. 160. Al Mamari S, Djordjevic J, Halliday JS, et al. Improvement of serum alkaline phosphatase to 2 cm or multifocal disease).69  Locoregional Therapies In patients with advanced, unresectable intrahepatic cholangiocarcinoma, locoregional therapies represent an alternative

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TABLE 69.2  TNM and AJCC/UICC Staging Systems for Intrahepatic Cholangiocarcinoma TNM Stage

Criteria

Tx

Primary tumor cannot be assessed

T0

No evidence of primary tumor

Tis

Carcinoma in situ (intraductal tumor)

T1a

Solitary tumor ≤5 cm without vascular invasion

T1b

Solitary tumor >5 cm without vascular invasion

T2

Solitary tumor with vascular invasion OR multiple tumors, with or without vascular invasion

T3

Tumor perforating the visceral peritoneum

T4

Tumor involving the local extrahepatic structures by direct invasion

Nx

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastases

N1

Regional lymph node metastases present

M0

No distant metastases

M1 AJCC/UICC Stage

Distant metastases Tumor

Node

Metastasis

0

Tis

N0

M0

IA

T1a

N0

M0

IB

T1b

N0

M0

II

T2

N0

M0

IIIA

T3

N0

M0

IIIB

T4 Any T

N0 N1

M0 M0

IV

Any T

Any N

M1

AJCC, American Joint Committee on Cancer; UICC, Union for International Cancer Control

TABLE 69.3  MSKCC Staging System for Perihilar Cholangiocarcinoma Stage

Criteria

T1

Tumor involving biliary confluence ± unilateral extension to secondary radicles

T2

Tumor involving biliary confluence ± unilateral extension to secondary radicles AND Ipsilateral portal vein involvement ± ipsilateral hepatic lobe atrophy

T3

Tumor involving biliary confluence + bilateral extension to secondary radicles OR Unilateral extension to secondary radicles + contralateral portal vein involvement OR Main or bilateral portal vein involvement

MSKCC, Memorial Sloan Kettering Cancer Center

treatment option. Transarterial chemoembolization (TACE) is associated with a median overall survival of 12 to 15 months in patients with advanced intrahepatic cholangiocarcinoma.70 The safety and effectiveness of transarterial radioembolization using yttrium-90 microspheres are comparable to those of TACE.71 

Perihilar and Distal Cholangiocarcinoma Surgical resection is also the treatment of choice for perihilar and distal cholangiocarcinomas in the absence of PSC (Box 69.2). Perihilar cholangiocarcinomas are resected by lobar or extended lobar hepatic and biliary duct resection with regional lymphadenectomy and Roux-en-Y hepaticojejunostomy. Occasionally, resectability can be achieved by preoperative portal vein embolization,

TABLE 69.4  Mayo Clinic Staging System for Perihilar Cholangiocarcinoma Stage

Criteria

I

Unicentric mass ≤3 cm ECOG performance status 0 Serum CA 19-9 level (U/mL) 1 cm) Chronic Salmonella Typhi or Paratyphi carrier status First-degree relative with gallbladder cancer IBD Intrahepatic biliary dysplasia Lynch syndrome Pancreaticobiliary malunion Porcelain gallbladder PSC Segmental adenomyomatosis in patients ≥60 years of age *Methylcholanthrene, O-aminoazotoluene, nitrosamines, possibly others.

1105

cholelithiasis.94,95 Gallbladder carcinoma actually develops in only 1% to 3% of patients with cholelithiasis, and 20% of patients with gallbladder carcinoma do not have evidence of cholelithiasis. Therefore, a prophylactic cholecystectomy in an asymptomatic patient with gallstones to prevent gallbladder carcinoma cannot be recommended. A positive correlation between the risk of gallbladder carcinoma and the size and number of gallstones has been reported but likely reflects the duration of cholelithiasis.96 No differences in the risk of gallbladder carcinoma have been observed with different types of gallstones. Porcelain gallbladder (extensive calcification of the gallbladder wall) is a classic, albeit controversial, risk factor for gallbladder carcinoma.97 Although an increased risk of gallbladder carcinoma has been reported in patients with a porcelain gallbladder, the risk may be limited to patients with selective mucosal calcification (types II and III porcelain gallbladder) rather than those with diffuse mucosal calcification (type I).98 Adenomatous polyps of the gallbladder constitute another risk factor for gallbladder carcinoma (see Chapter 67). The risk correlates positively with the size, type, and growth rate of the polyps. Patients with adenomatous polyps that are greater than 1 cm in size, sessile, and associated with gallstones, exhibit a rapid increase in size, demonstrate arterial flow on Doppler US, or are symptomatic are at increased risk of malignant transformation and warrant prophylactic cholecystectomy.97,99 Pancreaticobiliary malunion, or anomalous union of the pancreaticobiliary ductal system (AUPBD), has been associated with the development of gallbladder carcinoma (see Chapter 55).100 In this congenital defect, the pancreatic and bile ducts unite outside the duodenal wall in a long common channel. The anomaly is most prevalent in Asia, particularly Japan, and leads to cholestasis and reflux of pancreatic secretions into the gallbladder, with resulting chronic inflammation of the mucosa. The frequency of biliary tract cancer, especially gallbladder carcinoma, is high in patients with AUPBD, with some series reporting a frequency of approximately 50%.100 However, the frequency can vary from 10% to 38%, depending on the presence or absence of associated bile duct dilatation.101 Patients with an associated choledochal cyst have a lower frequency of gallbladder carcinoma than those without a choledochal cyst.101 Patients with AUPBD are usually 10 years younger at the time of diagnosis of gallbladder carcinoma and have a lower frequency of cholelithiasis than those without AUPBD.101 On the basis of the significantly increased risk of gallbladder carcinoma, several Japanese hepatobiliary oncology associations have recommended prophylactic cholecystectomy in patients with AUPBD.97,101 PSC has been associated with gallbladder carcinoma, and studies have reported that adenocarcinoma of the gallbladder develops in up to 20% of patients with PSC and that 40% to 60% of gallbladder masses in patients with PSC are malignant.102 Therefore, patients with PSC and a gallbladder mass of any size should undergo cholecystectomy or be monitored closely for gallbladder carcinoma (see Chapters 67 and 68). Adenomyomatosis of the gallbladder is characterized by microscopic invaginations (Rokitansky-Aschoff sinuses) of the mucosa with cyst formation in the muscularis propria (see Chapter 67). A large Japanese study showed an increased frequency of gallbladder carcinoma in patients 60 years of age or older with segmental adenomyomatosis of the gallbladder.103 In general, however, adenomyomatosis is viewed as a benign condition. Other conditions associated with gallbladder carcinoma include IBD, intrahepatic biliary dysplasia, and cholangiocarcinoma.102 Chronic carriers of Salmonella Typhi or Paratyphi have been shown to be at increased risk for the development of gallbladder carcinoma.104 Other bacteria such as Escherichia coli and Hp have also been associated with gallbladder carcinoma, but the data are not conclusive. First-degree relatives of patients with gallbladder carcinoma have a relative risk of 13.9 for developing this malignancy.105 Exposure to aflatoxin, a known liver carcinogen, has been linked to gallbladder carcinoma.106,108 Patients who

69

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have higher plasma levels of aflatoxin adducts have an odds ratio for gallbladder carcinoma development of 7.61 compared with patients who have lower levels.107,108 Other carcinogens, including methylcholanthrene, O-aminoazotoluene, and nitrosamines, have been identified in animal models of gallbladder carcinoma. Other potential carcinogens include mustard oil, products of free radical oxidation, and secondary bile acids. Obesity has been suggested to be a risk factor for gallbladder carcinoma, especially in women,109 but the independence of obesity from cholelithiasis as a risk factor has not been shown. 

gallbladder carcinomas.116,117 PIK3CA mutations lead to activation of the PI3K pathway–AKT pathway, which mediates oncogenesis in a spectrum of malignancies. Other genetic aberrations encountered in gallbladder carcinoma include CDKN2A/B loss (5.9% to 19%) and mutations in KRAS (4% to 13%), as well as in ARID1A (13%) and NRAS (6.3%).116 

Pathology From 80% to 95% of gallbladder carcinomas are adenocarcinomas; the majority of these are moderately to well differentiated.110 Adenocarcinomas are further divided into papillary, tubular, and nodular variants, with the papillary adenocarcinomas being the least aggressive form.111 Less common types, in order of frequency, include undifferentiated or anaplastic carcinoma, squamous cell carcinoma, and adenosquamous carcinoma. Rare types include carcinoids, small cell carcinomas, malignant melanomas, lymphomas, and sarcomas.111 Sixty percent of gallbladder carcinomas are located in the gallbladder fundus, 30% are found in the body, and 10% are found in the gallbladder neck.110 Analogous to cholangiocarcinoma, the papillary form of gallbladder carcinoma has a lower potential for invasion and metastatic spread to lymph nodes.111 Gallbladder carcinoma spreads via direct invasion, lymphatic or hematogenous metastasis, perineural invasion, and intraperitoneal or intraductal invasion. Lymphatic tumor cell spread is determined by the physiologic gallbladder lymphatic plexus, including the first-level lymph nodes along the biliary tract (cystic duct, bile duct, and hepatic duct), followed by pancreaticoduodenal lymph nodes, as well as lymph nodes along the common hepatic artery and celiac axis. Lymph node metastases are described in 54% to 64% of patients and correlate with the depth of invasion. Gallbladder carcinoma has a predisposition to involve the liver bed because of venous drainage, predominantly into hepatic segments IVb and V (see Chapter 71), and the anatomic proximity that allows direct hepatic invasion. Perineural spread is observed in 24% and intraductal spread in 19% of cases.

Pathogenesis Gallbladder carcinoma can develop from foci of mucosal dysplasia or carcinoma in situ that progress to adenocarcinoma or from an adenoma-carcinoma sequence similar to that seen with colon cancer (see Chapter 127).112-114 Foci of dysplasia and carcinoma in situ are frequently found adjacent to gallbladder carcinoma in surgically resected gallbladder specimens and are thought to be precursors of invasive adenocarcinoma.88 The time of progression of dysplasia to carcinoma is estimated to be 10 to 15 years.113 The major pathogenic factor is inflammation. Whole-exome and targeted gene sequencing studies have helped define the mutational landscape of gallbladder carcinoma. These analyses indicate that gallbladder carcinomas are genetically distinct from cholangiocarcinomas.115,116 In one cohort, whole-exome and ultradeep sequencing identified mutations in the ErbB family of proteins in 35.8% of cases.115 Moreover, cases with ErbB pathway mutations had a worse outcome. Similarly, molecular characterization of biliary tract cancer including gallbladder carcinoma identified frequent activation of the epidermal growth factor receptor (EGFR) family of genes (EGFR, ERBB2, ERBB3) in gallbladder carcinoma, as well as somatic telomerase reverse transcriptase (TERT) promoter mutations.26 Mutations in the tumor suppressor gene TP53 have been reported in 47.1% to 59% of gallbladder carcinomas in different series.115,116 Activating mutations of PIK3CA have been reported in 5.95 to 12.5% of

A

B

C Fig. 69.6  Imaging of gallbladder carcinoma. A, Axial CT view of the abdomen. Cholelithiasis is seen inferior to the gallbladder mass (arrow). B, Coronal view of the same patient. C, US in the same patient showing a large mass (arrow) originating from the gallbladder wall and protruding into the lumen.

CHAPTER 69  Tumors of the Bile Ducts, Gallbladder, and Ampulla

Clinical Features and Diagnosis

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are 85% and 80%, respectively; early cancers, especially sessile polyps, can be missed. Typical imaging presentations of gallbladder carcinoma include focal or diffuse mural thickening of the gallbladder, an intraluminal mass greater than 2 cm in size that originates in the gallbladder wall, and a subhepatic mass that replaces or obscures the gallbladder and often invades adjacent organs (Fig. 69.6). Findings indicative of the malignant nature of a gallbladder lesion include irregular, asymmetrical mural thickening greater than 1 cm in depth and a nodular or smooth intraluminal mass greater than 1 cm in size, with fixation to the gallbladder wall, that is not displaced by the patient’s movements and has no acoustic shadow. In indeterminate cases, Doppler US can be attempted to differentiate a malignant from a benign gallbladder lesion on the basis of the pattern of the color signal, blood flow velocity, and resistive index (a measure of resistance to arterial blood flow).121 MRI and CT can be helpful in the diagnosis if the US findings are indeterminate. Helical CT has an 83% to 86% accuracy in assessing the local extent, with better performance in T2 and higher stages (see later), and is, thus, helpful in preoperative planning.122,123 The role of PET in gallbladder carcinoma is evolving and not routine.124 The sensitivity of PET for detecting gallbladder carcinoma is only 75% to 78%.125,126 Its main impact is in the detection of distant metastases that result in a change in management.44 

In 47% to 78% of patients, gallbladder carcinoma is found incidentally during cholecystectomy for presumed benign disease, reflecting the initial clinically silent nature of this malignancy.118 Incidentally diagnosed gallbladder carcinomas generally are lower in stage than symptomatic carcinomas at the time of diagnosis and are associated with better median survival rates.118 Common clinical presentations include biliary or abdominal pain and jaundice secondary to direct invasion of the biliary ducts or metastasis to the hepatoduodenal ligament. Weight loss, abdominal distention, or other symptoms resulting from compression or invasion of adjacent organs indicate more advanced disease. CEA and CA 19-9 are the most commonly used tumor markers for gallbladder carcinoma.119 At a cutoff at 4.0 ng/mL, an elevated serum CEA level has a sensitivity and specificity of 50% and 93%. The sensitivity and specificity of an elevated serum CA 19-9 level at a cutoff of 20 U/mL are 79% and 79%.119,120 These tests aid in diagnosis but should not be relied on because levels can be elevated in inflammatory conditions and other GI and gynecologic malignancies; moreover, a subset of the population does not produce CEA. Abdominal US is often one of the first imaging studies performed in a patient who presents with the aforementioned symptoms. The sensitivity and accuracy of US for gallbladder carcinoma TABLE 69.7  TNM and AJCC/UICC Staging Systems for Gallbladder Carcinoma TNM Stage

Criteria

Tx

Primary tumor cannot be assessed

T0

No evidence of primary tumor

Tis

Carcinoma in situ

T1a

Tumor invades lamina propria

T1b

Tumor invades muscularis propria

T2a

Tumor invades perimuscular connective tissue on the peritoneal side, without involvement of serosa

T2b

Tumor invades perimuscular connective tissue on the hepatic side, without direct extension into the liver

T3

Tumor perforates the serosa AND/OR Tumor directly invades the liver AND/OR Tumor invades one other adjacent organ (i.e., stomach, duodenum, colon, pancreas, omentum, extrahepatic bile ducts)

T4

Tumor invades the portal vein or hepatic artery OR Tumor invades ≥2 extrahepatic organs or structures

Nx

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastases

N1

Regional lymph node metastases (≤3 lymph nodes)

N2

Regional lymph node metastases (≥4 lymph nodes)

M0

No distant metastases

M1 AJCC/UICC Stage

Distant metastases Tumor

Node

Metastasis

0

Tis

N0

M0

I

T1

N0

M0

IIA

T2a

N0

M0

IIB

T2b

N0

M0

IIIA

T3

N0

M0

IIIB

T1-3

N1

M0

IVA

T4

N0-1

M0

IVB

Any T Any T

N2 Any N

M0 M1

AJCC, American Joint Committee on Cancer; UICC, Union for International Cancer Control

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Staging Staging systems for gallbladder carcinoma include the NevinMoran classification system and the Japanese Biliary Surgical Society staging system. The most commonly used staging system is the TNM system described by the AJCC and UICC (Table 69.7). The TNM-based staging system correlates with survival. Reported 5-year survival rates for patients with stages 0, I, II, III A, III B, IV A, and IV B gallbladder carcinoma are 80%, 50%, 28%, 8%, 7%, 4%, and 2%, respectively. In the 2018 version of the AJCC/UICC staging system, stage T2 was separated into T2a (tumor location on the peritoneal side of gallbladder) and T2b (tumor location on the hepatic side of the gallbladder).57 In comparing different prognostic and therapeutic studies, it is important to account for differences in the version of the applied staging system. 

Treatment Surgery is the only potentially curative therapeutic option for gallbladder carcinoma.127 Only 15% to 47% of patients are candidates for surgical resection at the time of diagnosis because the stage of the disease is advanced in most cases. Contraindications to resection include multiple hepatic or distant metastases, gross vascular invasion or encasement of major vessels, malignant ascites, and poor functional status.110 Direct invasion of the colon, duodenum, or liver is not considered an absolute contraindication to surgical resection. The goal of surgical treatment is an R0 resection, defined as negative margins and nodal dissection one level past microscopically involved lymph nodes. R0 resection in gallbladder carcinoma has been shown to correlate with survival and with significantly increased 5-year survival rates118,128; however, R0 resection is achieved in only 36% to 49% of patients undergoing surgical exploration or re-exploration.118,128 Surgical procedures with curative intent include (1) simple cholecystectomy; (2) extended or radical cholecystectomy with additional resection of greater than 2 cm of the gallbladder bed plus lymphadenectomy of the hepatoduodenal ligament behind the second part of the duodenum, head of the pancreas, and celiac axis; (3) extended cholecystectomy with hepatic, segmental, or lobar resection; (4) extended cholecystectomy with extensive para-aortic lymph node resection; and (5) extended cholecystectomy with bile duct resection or pancreaticoduodenectomy. The surgical approach is dictated by the extent of tumor. Less than 10% of patients with gallbladder carcinoma are diagnosed with Tis and T1a tumors. At these stages, gallbladder carcinomas can be treated with simple cholecystectomy, with 5-year survival rates of 85% to 100%. A few reports have also favored simple cholecystectomy for stage 1b gallbladder carcinoma and have reported similar survival rates after either simple or radical cholecystectomy.129,130 Up to 15% of patients with stage 1b gallbladder carcinoma, however, are positive for lymph node metastases, compared with 2.5% of patients with stage 1a gallbladder carcinoma.131 Also, higher recurrence rates have been observed after simple (vs. radical) cholecystectomy; therefore, radical cholecystectomy is recommended for stage 1b gallbladder carcinoma.131–134 Invasion of the muscularis propria, as in stage T2 tumors, requires radical cholecystectomy, resulting in 5-year survival rates of 59% to 90%, compared with 17% to 40% with simple cholecystectomy.135–137 It is important to note that the risk of tumor invasion and mode of cancer spread in T2 gallbladder carcinoma is influenced by whether the tumor is located on the hepatic or peritoneal side of the gallbladder. Patients with T2 gallbladder carcinoma with tumors on the hepatic side have higher rates of vascular invasion, neural invasion, and nodal metastasis than those with tumors on the peritoneal side (51% versus 19%, 33% versus 8%, and 40% versus 17%, respectively).138 Therefore, the updated AJCC/UICC staging system has divided T2 gallbladder

carcinoma into T2a and T2b, on the basis of tumor location on the peritoneal or hepatic side of the gallbladder, respectively.57 The surgical approach to stage T3 and T4 tumors (tumors invading beyond the serosa) is controversial. Some studies have shown no 5-year survival benefit after radical cholecystectomy for stage T3 and T4 tumors, but other studies have reported 5-year survival rates of 15% to 63% and 7% to 25%, respectively.139 Because of the poor prognosis of gallbladder carcinoma and the possibility of a survival benefit, as well as prolongation of survival until recurrence, a radical surgical approach to these advancedstage gallbladder carcinomas is recommended by many centers. When gallbladder carcinoma is diagnosed during laparoscopy, the procedure should be converted to an open procedure, and the laparoscopic port sites should be resected because tumor may recur at these sites secondary to iatrogenic dissemination.140 Further surgical management then depends on the tumor stage, as outlined earlier and in Fig. 69.7. When gallbladder carcinoma is diagnosed postoperatively, further management depends on the tumor stage and the presence or absence of tumor at the margins of the surgical specimen. The likelihood of finding residual disease at reexploration has been reported to be 50%, 61%, 85%, and 100% for stages T1, T2, T3, and T4 tumors, respectively, in the initial specimen.118 Neoadjuvant or adjuvant therapies do not provide a survival benefit and are not recommended.65,118 The standard of care for patients with unresectable gallbladder carcinoma is chemotherapy with gemcitabine combined with cisplatin. This recommendation is based largely on the ABC-02 trial (see earlier), which included 149 patients with gallbladder carcinoma and showed an improvement in overall survival of 3.6 months, similar to Diagnosis of gallbladder cancer

Staging

T2, T3, T4

T1

T1a

T1b

Re-exploration

Resectable

No further treatment if margins are negative

M1

Radical cholecystectomy

Unresectable

Palliative treatment

Fig. 69.7  Algorithm for the management of gallbladder carcinoma discovered intra- or postoperatively at laparoscopic cholecystectomy. In cases in which pathologic examination of the cholecystectomy specimen identifies a stage T1a tumor with negative surgical margins, no further treatment is indicated. If the tumor is found to be a stage T1b tumor or the margins of resection are positive for malignant tissue, re-exploration for further resection is indicated. Similarly, patients with gallbladder carcinoma found to be stage T2, T3, or T4 should undergo surgical re-exploration. If reexploration reveals resectable gallbladder carcinoma, radical cholecystectomy should be performed. If the tumor is deemed unresectable, palliative management is indicated. When postoperative staging reveals metastatic spread, palliative management is indicated. M, metastasis stage; T, tumor stage. (Modified from Misra S, Chaturvedi A, Misra NC, Sharma ID. Carcinoma of the gallbladder. Lancet Oncol 2003;4:167-76.)

CHAPTER 69  Tumors of the Bile Ducts, Gallbladder, and Ampulla

that for cholangiocarcinoma.78 Other chemotherapeutic agents and gemcitabine-based combination therapies (with oxaliplatin, 5-fluorouracil [5-FU], or capecitabine) and targeted agents (cetuximab, erlotinib, or bevacizumab) have been assessed in smaller studies but have failed to show outcomes superior to those for the combination of gemcitabine and cisplatin, which, therefore, remains first-line treatment for unresectable gallbladder carcinoma. In general, gallbladder carcinoma is considered radioresistant.79 

AMPULLARY CARCINOMA Carcinomas of the ampulla of Vater belong to the family of periampullary carcinomas. This family includes carcinomas of the duodenum, ampulla of Vater, distal bile duct, and pancreas (see Chapter 60). Ampullary carcinomas are the second most common form of periampullary carcinoma (after pancreatic head cancer). The distinction between the different forms is important because ampullary carcinomas are often diagnosed earlier than the others and, therefore, at a resectable stage, thereby resulting in a better prognosis.141

Epidemiology Ampullary carcinomas are rare, accounting for fewer than 1% of all GI cancers and 4% to 8% of periampullary carcinomas. The annual incidence has been estimated to be 0.6 per 100,000 population.141,142 Peak incidence is in the 7th decade of life. There is a slight male predominance, with a male-to-female ratio of 1.48:1.143 Racial heterogeneity has been observed; the vast majority of patients are Caucasian, followed by patients of Hispanic and Asian descent. African Americans have the lowest incidence rates in the USA.141 The incidence of ampullary carcinoma has increased by 0.9% annually in the USA since the 1970s.143 

Etiology Although the etiology of ampullary carcinomas is unknown in the majority of cases, several conditions have been associated with this malignancy, mostly in case reports or small series. Familial adenomatous polyposis (FAP) is an important risk factor for the development of ampullary carcinomas, (see Chapter 126).144 Periampullary carcinoma is the second most common cause of death (after colon cancer) in patients with FAP. Usually, periampullary carcinoma arises later than colorectal carcinoma in this patient group but earlier in comparison with sporadic ampullary carcinomas.144 Screening for upper GI neoplasms (polyps or carcinoma) at regular intervals of 6 months to 4 years, depending on the degree of duodenal polyposis, is, therefore, recommended in patients with FAP.144 Similarly, increased rates of ampullary carcinoma have been described in patients with Gardner syndrome, a variant of FAP (see Chapter 126).145 Lynch syndrome (hereditary nonpolyposis colorectal cancer) does not appear to predispose to ampullary carcinoma (see Chapter 127).146 Other genetic diseases reported to predispose to the development of ampullary carcinoma include neurofibromatosis type 1 and Muir-Torre syndrome.147,148 As in cholangiocarcinoma, chronic liver fluke infection has been reported to be a risk factor for ampullary carcinoma (see Chapter 84).142 

Pathology The ampulla of Vater is an anatomically complex area that consists of the papilla, common pancreaticobiliary channel, distal bile duct, and distal main pancreatic duct. Macroscopically, ampullary carcinomas are classified into the following 3 types: (1) intramural protruding (intra-ampullary), (2) extramural protruding (periampullary), and (3) ulcerating ampullary.142 The ulcerating type is usually diagnosed at an advanced stage and has the highest rate of lymph node metastasis. Consistent with its anatomic heterogeneity, the ampulla includes several different histologic cell types, such

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as epithelia of the common pancreaticobiliary channel, bile duct, pancreatic duct, or duodenal mucosa, Brunner glands, and aberrant pancreatic acini in the wall of the bile duct. The most common site of cellular atypia is found in the area of the common pancreaticobiliary channel, followed by the pancreatic duct, duodenal epithelium, and Brunner glands.149 Seventy-five percent of all ampullary neoplasms are adenocarcinomas, 20% are benign adenomas, and 5% are neuroendocrine tumors.150 Adenocarcinomas account for 90% of ampullary malignancies; the rest include unusual types, such as mucinous, signet-ring cell, and undifferentiated carcinomas.150 Histopathologically, 90% of ampullary adenocarcinomas can be classified into pancreaticobiliary or intestinal types.151,152 Histomolecular phenotyping of ampullary carcinomas based on histologic subtype and immunohistochemical expression of caudal-type homeodomain transcription factor 2 (CDX2) and Mucin 1 (MUC1) staining may have prognostic value. In 2 different series, patients with a pancreaticobiliary histomolecular phenotype (CDX2 negative, MUC1 positive) had worse outcomes than patients with an intestinal phenotype (CDX2 positive, MUC1 negative)153,155; however, a subsequent study did not identify prognostic differences between the 2 subtypes.156 

Pathogenesis The majority of ampullary carcinomas follow an adenoma-carcinoma sequence. In 30% to 91% of ampullary carcinomas, residual adenomatous tissue is found.142 Although precursor lesions can develop from intestinal as well as pancreaticobiliary-type tissue, carcinomas of the intestinal type typically develop from adenomas, whereas pancreaticobiliary and ulcerating carcinomas often lack a precursor lesion.142 The intestinal and pancreaticobiliary types have distinct molecular alterations. KRAS alterations are more frequent in pancreaticobiliary type, whereas adenomatous polyposis coli (gene alterations are a more frequent occurrence in the intestinal type.157 Other genetic aberrations include TP53 mutations, ERBB2 amplification, and CDKN2A loss.157 Based on in-depth genomic analyses of ampullary carcinomas, the frequency of driver gene mutations differs between the intestinal and pancreatobiliary types, although there is significant overlap for common mutations, including KRAS, TP53, SMAD4, and CTNNB1.158 Notably, ELF3 has been identified as a novel mutated driver tumor suppressor gene in ampullary carcinoma. Inactivating mutations of ELF3, a member of the ETS transcription factor family that encodes an E26 transformation-specific transcription factor, are present in 10% to 12% of ampullary carcinomas.29,158 ELF3 inactivation promotes motility and invasion of epithelial cells.158 

Clinical Features and Diagnosis Like the other periampullary and biliary malignancies, ampullary carcinomas present initially with obstructive jaundice in 70% to 82% of cases. Pancreaticobiliary ampullary carcinomas in particular have been reported to present initially with obstructive jaundice.151 Because of their anatomic location, cholestasis develops at an earlier stage than do other periampullary and biliary malignancies, and the resectability rate is, therefore, higher at the time of diagnosis. Anicteric patients may present with bacterial cholangitis. Rare patients have “silver stools” as a result of the combination of acholic stools that result from bile duct obstruction and bleeding of the tumor. When obstructive cholangitis is suspected, further diagnostic evaluation is similar to that for other biliary malignancies. Immunohistochemical analysis has shown high expression of CEA and CA 19-9 in the tumor.159 Elevated serum concentrations of CEA and CA 19-9 have been detected in 11% to 29% and 41% to 63%, respectively, of patients with ampullary carcinomas. Elevations of these serum tumor markers have been associated with tumor recurrence and lower rates of disease-free survival in univariate but not multivariate analyses.159,160

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Usually, ampullary carcinomas are diagnosed by endoscopy on the basis of their macroscopic appearance and findings on biopsy specimens (Fig. 69.8). Subsequent diagnostic tests are directed toward an assessment of resectability and detection of metastases. As for other biliary and periampullary carcinomas, imaging techniques such as CT and MRI are commonly used in this setting.161 On MRI with MRCP, ampullary carcinoma is usually seen as a discrete, hypodense mass on T2-weighted images. Occasionally, the tumor can present as irregular thickening around the bile duct or bulging into the duodenum. Frequently, dilatation of both the bile and pancreatic ducts (“double-duct sign”) or only the bile duct is seen; dilatation of the pancreatic duct alone is rarely seen.161 Addition of diffusion-weighted imaging to conventional MR imaging enhances detection of ampullary carcinoma.162 Often, EUS is used in the preoperative evaluation. Its accuracy for detecting invasion of adjacent organs is 80% to 90%, and its sensitivity and specificity for detecting vascular invasion are 73% and 90%, respectively.163,164 The role of PET in ampullary neoplasms has not been well studied. 

Staging Ampullary carcinomas are classified according to the AJCC/ UICC TNM classification (Table 69.8).57 Five-year survival rates have been reported to be 49%, 40%, 44%, 33%, 26%, 16%, and 4% for stages 0, I A, I B, II A, II B, III, and IV, respectively. The T stage was shown to be predictive of survival in a univariate analysis but not in a multivariate analysis.151,165 The risk of lymph

Fig. 69.8  Endoscopic appearance of ampullary carcinoma. A catheter was placed in the ampulla of Vater for biliary drainage after a sphincterotomy was performed. TABLE 69.8  TNM and AJCC/UICC Staging Systems for Ampullary Carcinoma TNM Stage

Criteria

Tx

Primary tumor cannot be assessed

T0

No evidence of primary tumor

Tis

Carcinoma in situ

T1a

Tumor limited to ampulla of Vater or sphincter of Oddi

T1b

Tumor invades beyond the sphincter of Oddi and/or into the duodenal submucosa

T2

Tumor invades into the duodenal muscularis propria

T3a

Tumor invades pancreas (≤0.5 cm)

T3b

Tumor extends >5 cm into the pancreas OR Tumor extends into the peripancreatic soft tissue without involvement of the celiac axis or superior mesenteric artery OR Tumor invades the duodenal serosa without involvement of the celiac axis or superior mesenteric artery

T4

Tumor involves the celiac axis, superior mesenteric artery, and/or the common hepatic artery

Nx

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastases

N1

Regional lymph node metastases (≤3 lymph nodes)

N2

Regional lymph node metastases (≥4 lymph nodes)

M0

No distant metastases

M1 AJCC/UICC Stage

Distant metastases Tumor

Node

Metastasis

0

Tis

N0

M0

IA

T1a

N0

M0

IB

T1b-2

N0

M0

IIA

T3a

N0

M0

IIB

T3b

N0

M0

IIIA

T1-3

N1

M0

IIIB

T4 Any T

Any N N2

M0 M0

IV

Any T

Any N

M1

AJCC, American Joint Committee on Cancer; UICC, Union for International Cancer Control

CHAPTER 69  Tumors of the Bile Ducts, Gallbladder, and Ampulla

node metastases, however, has been reported to increase with increasing T stage. Overall, 42% to 60% of patients are found to have lymph node metastases at the time of surgery.166,167 Nodal involvement is a negative predictor of overall survival, with 9% to 47% 5-year survival rates for node-positive compared with 59% to 63% for node-negative disease.159,168 Other independent predictors of survival by multivariate analysis are lymphovascular invasion, perineural invasion, advanced stage, and pancreaticobiliary type of tumor.151,159,169 

Treatment Surgical resection is the only curative treatment for ampullary carcinomas. In contrast to the other biliary malignancies, however, 77% to 93% of ampullary carcinomas are resectable at the time of diagnosis.166,170 The standard surgical approach is pancreaticoduodenectomy. Outcomes are good in the absence of lymph node metastases, with 5-year survival rates of 59% to 78%.171–173 In the presence of lymph node-positive disease, the prognosis worsens significantly, with 5-year survival rates of 16% to 25%.171–173 Extracapsular lymph node involvement results in further worsening of the prognosis, with a 5-year survival rate of only 9%. Node microinvolvement has been reported to be an adverse prognostic factor, and immunohistochemical analysis of resected nodes has been recommended.174 Limited surgical or endoscopic papillectomy has been reported but is not recommended, because recurrence rates are higher than with pancreaticoduodenectomy.1 A retrospective analysis of patients who received preoperative chemotherapy with or without radiotherapy did not show a mortality benefit nor an improvement in 5-year overall survival.175 Therefore, further studies are needed to evaluate the role of neoadjuvant therapy in ampullary carcinoma. Two large randomized controlled trials have evaluated the benefit of adjuvant chemotherapy and chemoradiation therapy. The Johns Hopkins–Mayo Clinic collaborative study showed a significant improvement in outcome in lymph node-positive patients with adjuvant 5-FU-based chemoradiation, with an increase in the 5-year survival rate from 6% to 28%.173 Similarly, the European Study Group for Pancreatic Cancer-3 periampullary cancer trial reported a median survival of 58 months in patients who received adjuvant 5-FU plus folinic acid and 71 months in patients who received gemcitabine, compared with 41 months in those who did not receive adjuvant chemotherapy; the benefit of adjuvant chemotherapy reached statistical significance after correction for independent prognostic factors.176 Subsequent meta-analyses have reported conflicting results, with one demonstrating a significant reduction in the risk of death (hazard ratio 0.75) in patients receiving adjuvant chemoradiotherapy177 and the other showing no survival benefit for adjuvant therapy.178 Nevertheless, adjuvant chemotherapy or chemoradiation may have a role in a subset of patients with ampullary carcinoma, in particular those with lymph node–positive disease. The benefit of chemotherapy or radiation therapy for patients with unresectable ampullary carcinoma has not been evaluated in large, randomized controlled trials. Treatment trials have included patients with various types of periampullary cancers, including 20 patients with ampullary carcinoma in the ABC-02 trial described earlier.78 In the absence of randomized controlled trials of sufficient numbers of patients with unresectable ampullary carcinoma, the roles of chemotherapy and radiation therapy are not defined. Palliative treatment should be directed at alleviating tumorassociated complications, with the goal of optimizing the patient’s quality of life. Obstructive cholestasis is a major cause of morbidity and can usually be treated palliatively either by endoscopic or percutaneous placement of a biliary stent or by a surgical bypass similar to that carried out for other biliary or periampullary malignancies. 

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BOX 69.4 Tumors of the Biliary Tract Other than Adenocarcinoma GALLBLADDER Benign Adenoma Granular cell tumor Mesenchymal tumor (lipoma, leiomyoma, hemangioma, lymphangioma) Paraganglioma Malignant Adenosquamous carcinoma Neuroendocrine tumor (carcinoid) Small cell carcinoma Spindle cell sarcomatoid carcinoma Others (angiosarcoma, carcinosarcoma, Kaposi sarcoma, leiomyosarcoma, malignant fibrous histiocytoma, melanoma, metastatic tumors, non-Hodgkin lymphoma, rhabdomyosarcoma) Tumor-Like Lesions Adenomyoma/adenomyomatosis Cholesterol polyp Heterotopia (gastric, pancreatic, liver, adrenal, thyroid) Inflammatory polyp BILE DUCTS Benign Adenofibroma Adenoma Adenomyoma Ciliated hepatic foregut cyst Cystadenoma and cystadenocarcinoma Granular cell tumor Hamartoma Neuroma Serous cystadenoma Solitary or multiple cysts Malignant Embryonal (botryoid) rhabdosarcoma Leukemia Lymphoma Melanoma Metastatic tumor Neuroendocrine tumor (carcinoid) Paraganglioma Precursor Lesions Dysplasia (intraepithelial neoplasia/atypical hyperplasia) Intraductal papillary mucinous tumor of the bile duct (biliary ­papillomatosis)

OTHER TUMORS OF THE BILIARY TRACT Other neoplastic diseases may involve the biliary tract (Box 69.4). Their inclusion in the differential diagnosis of biliary tumors is essential because management differs depending on the tumor type. Tumors of neuroectodermal origin, such as carcinoids (see Chapter 34) and paragangliomas, are rare and typically nonfunctioning.179 They are most commonly located in the ampulla of Vater. Occasionally, carcinoids develop in the extrahepatic biliary tract, predominantly in the bile duct. Patients are usually female and young. Primary carcinoids of the biliary tract constitute less than 1% of all GI carcinoids and usually are not associated with the carcinoid syndrome.180,181 Approximately one third of patients have metastases at diagnosis. The treatment of choice is surgical resection, and the prognosis is generally good.182–184 Patients with

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PART VIII  Biliary Tract

paragangliomas often present with GI bleeding; only 25% present with jaundice. Their malignant potential has been estimated to be 33%, and some investigators recommend pancreaticoduodenectomy as the treatment of choice.185 Granular cell tumors, which are of neuronal derivation, are extremely rare; only a few cases have been described. Usually, they are located in the extrahepatic biliary tract, particularly at the junction of the cystic duct and the bile duct.186 Occasionally, they can cause biliary obstruction, as occurs when they are located in the hepatic hilum.186 Because of their benign character, resection is usually curative.187 Rarely, neuromas of the extrahepatic biliary tract develop after cholecystectomy.188 Mesenchymal tumors, such as lipomas, leiomyomas, hemangiomas, and lymphangiomas, have been described in the gallbladder. In general, mesenchymal tumors are extremely rare and restricted to case reports. Lymphangiomas are often asymptomatic and detected incidentally; however, they can increase in size and result in abdominal pain or jaundice. US, CT, and MRI with MRCP aid in the preoperative diagnosis. Usually, lymphangiomas manifest as a multilocular, fluid-filled, cystic mass with thin walls and septa and show enhanced signal density with administration of a contrast agent.189 Most of the reported cases have been treated successfully with surgical resection, including cholecystectomy, if the tumor is located within the gallbladder, or endoscopic resection if the tumor is in the area of the ampulla of Vater.190–193 Hamartomas have also been reported in the area of the ampulla of Vater and have been resected successfully by endoscopy.194 Heterotopia of the gallbladder may be caused by gastric, pancreatic, hepatic, adrenal, or thyroid tissue. Clinical complications such as hemorrhage are extremely rare.195,196 Benign bile duct lesions include adenomas, cystadenomas, adenofibromas, cysts, and granular cell tumors. Adenomyomas are found more commonly in the ampulla of Vater. Cystadenomas are more common in women and manifest primarily with abdominal pain. They are found predominantly in the intrahepatic biliary tract and are characterized on US by papillary extrusions of the wall and septa. They are considered premalignant because of their potential to transform into cystadenocarcinomas; therefore, the treatment of choice is complete resection.197–199 Malignant tumors of the biliary tract other than cholangiocarcinoma include cystadenocarcinomas, lymphomas, and malignant melanomas. These malignancies arise primarily in the extrahepatic bile ducts. Cystadenocarcinomas can be distinguished morphologically from cholangiocarcinomas by their cystic character.200 They are rarely located in the gallbladder.201 Symptoms are nonspecific, and CT and MRI can be helpful in making the diagnosis. The treatment of choice is surgical resection.201 Malignant melanoma of the biliary tract is uncommon and should prompt investigation for a cutaneous melanoma, because cases of metastatic spread to the bile ducts have been

described.202,203 Lymphomas can occasionally involve the extrahepatic biliary tract and are often mistaken for cholangiocarcinoma.204,205 In general, biliary lymphomas are very rare and account for less than 1% of lymphomas.205,206 Few reports exist of follicular lymphomas originating in the extrahepatic biliary tract and gallbladder. Often, these tumors are diagnosed after resection. Embryonal rhabdomyosarcoma of the biliary tract is extremely rare in adults but is the most common malignant tumor at this anatomic location in children.207 Frequently, it is misdiagnosed preoperatively as a choledochal cyst.208 Complete surgical resection is rarely possible, and a multidisciplinary approach to treatment is recommended. The prognosis of biliary rhabdosarcomas is good, with reported 5-year survival rates of up to 78%.209 Precursor lesions for cholangiocarcinoma include high-grade dysplasia and intraductal papillary mucinous tumor of the bile duct (IPNB). High-grade dysplasia of the bile ducts may be a harbinger of cholangiocarcinoma, particularly in patients with PSC.210–213 Patients with high-grade dysplasia are more likely to have FISH polysomy compared with those with low-grade dysplasia or no dysplasia.211 A metaplasia-dysplasia-carcinoma sequence has been described in PSC-associated cholangiocarcinoma212; however, the management of PSC patients with high-grade dysplasia remains a challenge. A conservative approach, which includes observation and intensive surveillance with serial MRCPs and/or ERCPs, is typically used in the USA. In countries with favorable organ allocation, LT has been proposed as the treatment of choice for highgrade dysplasia arising in the setting of PSC.210 IPNB encompasses intraductal papillary cholangiocarcinoma and precursor lesions such as biliary papillomatosis and biliary intraductal papillary mucinous neoplasm.214 Biliary papillomatosis, a rare disease with high malignant potential, is characterized by numerous papillary adenomas in the biliary tract.215 The clinical presentation of IPNB includes recurrent abdominal pain, jaundice, and acute cholangitis. Because IPNB is a diffuse/multifocal entity, MRCP or ERCP is used to delineate its extent within the biliary tract.216 Patients with IPNB should be considered for surgical resection due to the high malignant potential of these lesions.217 Acknowledgment This work was supported by grants from the NIH DK59427 (G.J.G.) and K08CA236874 (S.H.R.). Support was also provided to Dr. Rizvi by a Pilot & Feasibility Award by the Center for Cell Signaling in Gastroenterology (P30DK084567), and an AGA Research Scholar Award. Full references for this chapter can be found on www.expertconsult.com.

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Endoscopic and Radiologic Treatment of Biliary Disease Theodore W. James, Todd H. Baron

CHAPTER OUTLINE IMAGING OF THE BILIARY TRACT ����������������������������������1113 Transabdominal US������������������������������������������������������1113 MRCP and Multidetector CT Cholangiography��������������1113 Diagnostic EUS������������������������������������������������������������1114 ERCP����������������������������������������������������������������������������1115 EUS-Guided Biliary Drainage����������������������������������������1115 ENDOSCOPIC TREATMENT����������������������������������������������1116 Bile Duct Stones����������������������������������������������������������1116 Bile Leaks��������������������������������������������������������������������1117 PSC������������������������������������������������������������������������������1117 Benign Biliary Strictures ����������������������������������������������1117 Indeterminate Biliary Strictures������������������������������������1118 Malignant Biliary Strictures������������������������������������������1118 SOD ����������������������������������������������������������������������������1121 Surgically Altered Anatomy������������������������������������������1121 Adverse Events������������������������������������������������������������1122 PERCUTANEOUS TRANSHEPATIC CHOLANGIOGRAPHY������1122 Technique��������������������������������������������������������������������1122 Postoperative Biliary Strictures������������������������������������1123 PSC������������������������������������������������������������������������������1124 Bile Leaks��������������������������������������������������������������������1124 Bile Duct Injury������������������������������������������������������������1125 Bile Duct Stones����������������������������������������������������������1125 Malignant Biliary Obstruction����������������������������������������1125 PERCUTANEOUS CHOLECYSTOSTOMY TUBE PLACEMENT����������������������������������������������������������1125 COMBINED PERCUTANEOUS AND ENDOSCOPIC APPROACHES ����������������������������������������������������������������1126

IMAGING OF THE BILIARY TRACT Imaging of the biliary tract is of utmost importance in planning the management approach to patients with biliary disorders, regardless of whether an endoscopic or percutaneous approach is taken, and is discussed briefly in this context.

Transabdominal US Noninvasive imaging of the biliary tract frequently begins with transabdominal US, which provides a global picture of the liver and is nearly universally available. There is no radiation exposure, and contrast agents are not required. Intrahepatic ductal dilatation can be visualized easily, and the size of the bile duct can be documented. US also provides imaging of the gallbladder and detects gallstones (see Chapter 65). For detection of choledocholithiasis, US has a high specificity, but the sensitivity does not exceed 68% and is often lower than 50%.1-3 The sensitivity decreases if the stones are small and the bile ducts are not dilated. US is highly accurate (78% to 98%) for detecting extrahepatic biliary obstruction; however, the pretest probability of choledocholithiasis greatly affects the utility of the test.4 When used in conjunction with clinical and laboratory evaluation, US allows differentiation between liver parenchymal disease and extrahepatic biliary obstruction with a reasonable sensitivity and high specificity (see Chapter 21). US is less accurate, however, at defining the level and cause of obstruction, with accuracy rates ranging from 27% to 95% and 23% to 88%, respectively.2 In addition, US is limited in the ability to distinguish malignant from benign causes of obstruction. These limitations may be pronounced in obese patients due to the increased distance the ultrasound wave must travel, thereby reducing the resolution and depth of the image. Advances in US have included 3- and 4-dimensional imaging,5 use of contrast agents,6 and elastography (see Chapter 74). 

MRCP and Multidetector CT Cholangiography Endoscopic therapy and radiologic treatment of biliary disease have evolved in separate but parallel manners. Endoscopic therapy is performed using ERCP and EUS-guided techniques. ERCP is performed primarily by endoscopists trained in a gastroenterology fellowship program, but in some centers it is performed by surgeons. ERCP is one of the most technically demanding endoscopic procedures, and for the successful management of complex cases the learning curve is steep. EUS-guided therapies are done almost exclusively by gastroenterology-trained endoscopists and have seen an expansion in utility as new indications for their use have been demonstrated. Radiologic therapy of the biliary tract is performed via a percutaneous approach by interventional radiologists. The 3 approaches should be seen as complementary rather than competitive. The decision to proceed with an endoscopic or radiologic approach is often based on local expertise; other considerations include physician referral patterns, the location of a lesion within the biliary tract, failure of one method, and altered anatomy as a result of prior surgery.

MRCP is an MRI study (and thus noninvasive) that is dependent on the high T2-signal characteristics of bile, which produce a high-intensity bright signal on the resulting image. Solid material such as choledocholithiasis will appear as well-defined, dark filling defects within the bile duct. MRI does not require administration of oral or IV contrast material. For the detection of choledocholithiasis, MRCP has a sensitivity ranging from 81% to 100%, a specificity ranging from 96% to 100%, and high overall diagnostic accuracy (Fig. 70.1).7-9 False-positive results may arise from pneumobilia. In addition, MRCP is highly accurate in demonstrating the presence of benign and malignant strictures10,11 and allows a thorough evaluation of the intrahepatic bile ducts. In patients suspected of having biliary complications after LT (see Chapter 97), IV administration of mangafodipir trisodium (Teslascan, Amersham Health, Princeton, NJ) may be used. This agent is excreted primarily in the bile and may improve imaging sensitivity for post–liver transplant biliary leaks and strictures.12 In addition, MRI can be performed with an IV contrast agent, such as gadodiamide (Omniscan, GE Healthcare, UK)

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or gadopentetate dimeglumine (Magnevist, Bayer Healthcare, Leverkusen, Germany or MultiHance, Bracco, Princeton, NJ), to detect and characterize mass lesions in the liver, porta hepatis, or pancreas. Contraindications to MRI include a cardiac pacemaker, an automatic implantable cardioverter defibrillator, and some types of cerebral aneurysm clips. A particular concern about gadolinium-based IV contrast agents is that they may precipitate nephrogenic systemic fibrosis, a rare scleroderma-like disease manifested by hardening of the skin and fibrotic changes that affect multiple organs. The cause remains unclear, but reports suggest that patients with preexisting kidney disease (renal failure) are at greatest risk.13,14 Avoiding gadolinium and using lower doses in patients with renal insufficiency reduce the risk.15 Multidetector CT cholangiography (MDCT) with multiplanar reformation is a CT-based imaging study. MDCT combines rapid-volume acquisition and thin-slice imaging. Water is used as an oral contrast agent for the biliary tract, and IV iodinated contrast is also administered. Images acquired in the axial plane can be reconstructed sagittally or coronally and reformatted 3 dimensionally. The IV contrast dye is not excreted in bile but enhances adjacent surrounding visceral structures such as the liver, pancreas, and other soft tissues. Bile ducts thus appear as low-attenuation structures that are best visualized if dilated. Following surgical resection of malignant tumors involving the liver and bile ducts, MDCT is preferred over MRCP due to a high spatial resolution and ability to demonstrate small anastomotic tumor recurrences.16 The sensitivity and specificity of MDCT for bile duct strictures are 85.7% and 100%, respectively.17 MDCT also has a high sensitivity and specificity for the detection of bile duct stones, although diagnostic accuracy decreases considerably when calculi are small or similar in intensity to bile.18 MDCT has the disadvantage of exposing the patient to the potentially harmful effects of ionizing radiation and contrast injection.

Diagnostic EUS Diagnostic EUS uses an echoendoscope which has an ultrasound transducer located at its tip and emits high-frequency acoustic

Fig. 70.1  Choledocholithiasis on MRCP and ERCP. A, MRCP showing a filling defect in distal bile duct (arrow). B, Corresponding ERCP with the same filling defect.

Fig. 70.2  EUS image demonstrating choledocholithiasis. Note a single stone in the middle third of the bile duct. Stones have a hyperechoic interface with the EUS transducer and postacoustic shadowing.

waves to the surrounding tissues. Either a radial scanning EUS or a linear array EUS is used depending on the images desired and the potential for needle aspiration and biopsy. EUS examination of the biliary tract can be performed by a transgastric or transduodenal approach. Aside from extrapancreaticobiliary structures, the transgastric approach provides images of the pancreatic neck, body, and tail, as well as the gallbladder and left intrahepatic ducts, whereas the transduodenal approach allows imaging of the pancreatic head, gallbladder, ampulla, and bile duct. On EUS, choledocholithiasis demonstrates hyperechoic foci with acoustic shadowing (Fig. 70.2). EUS has a sensitivity and specificity of 95% and 97%, respectively, for the detection of choledocholithiasis19,20 and is highly accurate for determining the cause of extrahepatic biliary obstruction, with a sensitivity of 97% and a specificity of 88%. EUS has the ability to distinguish different causes of malignant obstruction. In particular, EUS is more sensitive (93% to 100%) than CT (5% to 77%), transabdominal US (50% to 67%), MRI (50% to 67%), and ERCP (90%)

CHAPTER 70  Endoscopic and Radiologic Treatment of Biliary Disease

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A

B Fig. 70.3  Fluoroscopic images of EUS-guided choledochoduodenostomy (CD) in a patient with malignant biliary obstruction due to metastatic melanoma. A, Radiographic image showing contrast material injection into the biliary tract through a 19-gauge needle. A stricture is seen in the distal bile duct. B, Radiographic image showing lumen-apposing metal CD stent in place. A 10-mm by 6-cm fully covered metal stent was placed through the CD stent into the bile duct, and a 7-Fr plastic stent was placed within the fully covered metal stent.

for the detection of pancreatic tumors (see Chapters 60 and 61). EUS is less invasive than ERCP and has no associated radiation or contrast exposure. EUS combined with FNA permits tissue diagnosis of masses and lymph nodes. EUS may be preferred over MRCP in some patients, particularly those with contraindications to MRI, and morbid obesity. MRCP may be favored over EUS in patients with altered surgical anatomy, particularly Roux-en-Y and Billroth II anatomy where the endoscope cannot be advanced to the area of interest to provide images. In patients with symptomatic cholelithiasis and an intermediate probability of choledocholithiasis, both EUS and MRCP are acceptable preoperative imaging modalities.21 

ERCP ERCP has evolved from a purely diagnostic to an almost exclusively therapeutic procedure. ERCP is commonly performed using moderate sedation,22 although in most centers in the USA it is carried out with anesthesia support, especially in more severely ill patients and in cases anticipated to be complex. Patients who receive propofol-based anesthesia for ERCP may have a faster recovery time than those who receive other forms of general anesthesia.23 ERCP is performed with a side-viewing duodenoscope that allows identification of the major papilla. The bile duct is cannulated under endoscopic and fluoroscopic guidance. A variety of catheters, guidewires, and stents are available to allow therapeutic interventions to be performed. Diagnostic ERCP is now considered obsolete and reserved for facilitating manometry in patients with suspected SOD (see Chapter 63) and in those with a possible diagnosis of PSC when other imaging techniques are nondiagnostic (see Chapter 68).24-26

EUS-Guided Biliary Drainage In tertiary centers EUS-guided biliary drainage (EUS-BD) has increasingly become an alternative method of biliary decompression in patients who fail standard ERCP or in whom ERCP is not possible,27-30 as may occur because of surgically altered anatomy, gastric outlet obstruction, periampullary diverticulum, or inability to advance a guidewire beyond the biliary obstruction.31,32

Although percutaneous transhepatic biliary drainage has conventionally been performed in cases of failed ERCP, it is associated with high morbidity and reduced quality of life (see later).33 The most common approaches to EUS-BD are a transgastric approach to the intrahepatic biliary system and a transduodenal approach to the extrahepatic biliary system. The therapeutic procedures include EUS-guided choledochoduodenostomy (EUS-CD), EUS-guided cholecystoduodenostomy, EUS-guided hepaticoenterostomy (EUS-HE), and EUS-guided rendezvous (EUS-RV) and require technical proficiency in both EUS and ERCP. EUS-CD consists of transduodenal puncture of the extrahepatic bile duct with an FNA needle under EUS guidance, followed by advancement of a guidewire into the biliary tract, dilation of the tract, and placement of a stent with the proximal portion in the first part of the duodenum.34,35 Various biliary access and fistula dilation methods have been described, and the choice of each depends on institutional and endoscopist preferences. One meta-analysis of EUS-CD found a technical success rate of 94% and an early adverse event (AE) (complication) rate of 19%.36 Self-expandable metal stents are typically preferred over plastic stents because of prevention of bile leaks and increased durability and patency. EUS-guided cholecystoduodenostomy is used for both primary gallbladder drainage in patients unfit to undergo cholecystectomy and secondary gallbladder drainage to allow removal of a previously placed, temporary percutaneous cholecystostomy tube (Video 70.1). The procedure consists of FNA puncture of the gallbladder neck through the wall of the duodenum followed by guidewire placement into the gallbladder. Typically, lumenapposing metal stents are used to create an anastomosis between the organs, with a decreased risk for stent migration (Fig. 70.3). A plastic pig tail stent is often placed within the metal stent to prevent stent occlusion.37 EUS-HE consists of transgastric or transjejunal (in the case of surgically altered anatomy) FNA puncture of a branch of the left intrahepatic bile duct followed by advancement of a guidewire into the biliary system and stent placement (Fig. 70.4).38 Color Doppler is used to detect interposing vessels so that these may be avoided, and biliary puncture is confirmed by aspirating bile and/or injection of contrast to perform cholangiography. EUS-HE can be used

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B Fig. 70.4  Fluoroscopic images of EUS-guided hepaticogastrostomy (HG) in a patient who had undergone surgical hepaticojejunostomy after a bile duct injury during laparoscopic cholecystectomy. A, Radiographic image showing injection of contrast material into the biliary tract through a 19-gauge needle. An obstructing stone is seen proximal to the hepaticojejunostomy. B, Radiographic image showing the HG stent in place. Through the HG stent, a 7-Fr plastic stent was placed into the right biliary system across the bifurcation after balloon dilation.

as definitive therapy, as in palliation of malignant biliary obstruction, for preoperative decompression, or as a portal for downstream therapy, including antegrade stent placement.39,40 EUS-RV is used in cases of failed ERCP as a means to aid cannulation and/or guidewire placement on a repeat attempt at ERCP. The procedure consists of EUS-guided puncture of the biliary system from either the stomach or duodenum followed by a cholangiogram and guidewire placement into the biliary system.41 The guidewire is advanced beyond the ampulla and into the duodenum. Following fluoroscopic confirmation of guidewire placement, the echoendoscope and needle are removed, while the guidewire position is maintained. One of 2 approaches can next be performed. In the first, a duodenoscope is inserted alongside the guidewire and advanced to the ampulla, where the guidewire is found and used to assist in cannulation. Alternatively, the distal end of the guidewire can be grasped using a forceps or snare and withdrawn through the mouth, either through the accessory channel or along with the endoscope; a duodenoscope can then be back-loaded over the guidewire and advanced to the ampulla. By either method, the ultimate aim is to endoscopically provide relief of obstruction.42-44 The technique is most useful for enabling biliary cannulation and stone removal in patients with a large periampullary diverticulum. The choice of EUS-BD modality depends on both patient and provider characteristics and is often determined by the preference of the endoscopist. It has been proposed that EUS-RV should be initially attempted if the ampulla is accessible, followed by EUS-CD or EUS-HE as a salvage procedure if the guidewire cannot be advanced to the desired location.45 EUS-CD or EUS-HE may be attempted initially if the ampulla is inaccessible. Both strategies appear to be equally effective and safe in patients with failed ERCP.46 A growing body of evidence suggests that EUS-BD may be equivalent to ERCP as a primary therapy for malignant biliary obstruction when performed by an endoscopist with experience in both modalities.47,48 

ENDOSCOPIC TREATMENT Bile Duct Stones ERCP is usually performed in patients with known choledocholithiasis or in those with at least a moderate clinical suspicion of choledocholithiasis (see Chapter 65).49 In patients with gallbladder stones and a low clinical suspicion of choledocholithiasis,

a noninvasive imaging study (MRCP, MDCT) or EUS is preferred to minimize the potential for complications of ERCP.7 In patients with a low clinical suspicion of choledocholithiasis in whom cholecystectomy is planned, intraoperative cholangiography can be performed, and, if stones are identified, laparoscopic exploration and stone removal can be undertaken. ERCP can then be reserved for patients in whom the stones are not extracted.8 The standard method for stone removal is endoscopic biliary sphincterotomy to allow enlargement of the papilla and subsequent extraction of stones with a balloon or basket (Fig. 70.5). With this approach, more than 80% of all stones can be removed successfully.50 Larger stones may require additional removal techniques (discussed later). Precut sphincterotomy, whereby an incision is made on the papilla prior to cannulation and/or wire guidance, may be used in cases in which cannulation by conventional means has failed and is not associated with an increased risk of AEs when performed by a skilled endoscopist.51 An alternative to biliary sphincterotomy is balloon dilation of the papilla (balloon sphincteroplasty), which can be performed using small-diameter balloons (4 to 8 mm).52 The technique was introduced as a way to preserve sphincter of Oddi function, especially in young patients. The stones are removed using balloon or basket techniques. Most of the literature on balloon sphincteroplasty comes from outside the USA. Two meta-analyses of randomized trials of balloon sphincteroplasty versus sphincterotomy have shown that the rates of pancreatitis and need for mechanical lithotripsy are significantly higher, but the risk of bleeding is significantly lower, with balloon sphincteroplasty than with sphincterotomy.53,54 In the USA, the only randomized trial that compared balloon sphincteroplasty and sphincterotomy was closed prematurely because of 2 deaths in young patients from post-ERCP pancreatitis after sphincteroplasty.55 Sphincteroplasty still remains, however, an alternative approach in patients with coagulopathy,53 persons with underlying cirrhosis (particularly Child-Pugh class C53 [see Chapters 74 and 92]), and those with altered anatomy (e.g., Billroth II gastrojejunostomy [see Chapter 53]), in which sphincterotomy is technically difficult.53 Measures to reduce the risk of pancreatitis such as prophylactic placement of a pancreatic stent and administration of rectal indomethacin should be used in such cases.56,57 Removal of large bile duct stones (defined arbitrarily as ≥1.5 cm in diameter) may require techniques in addition to those

CHAPTER 70  Endoscopic and Radiologic Treatment of Biliary Disease

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B Fig. 70.5  Endoscopic images during removal of a bile duct stone. A, A bulging papilla consistent with an impacted stone is seen. B, After endoscopic sphincterotomy, the stone is extracted.

described earlier to be removed successfully. One such technique is lithotripsy. One form of lithotripsy is mechanical lithotripsy, in which the stone is captured in a specialized large basket and crushed (Fig. 70.6).58 The fragments are removed using standard extraction techniques. Another form of lithotripsy is intraductal lithotripsy, which is performed by fragmenting stones under direct cholangioscopic visualization using a laser or electrohydraulic catheter.59 Direct visualization is necessary to ensure the lithotripsy device is directed at the stone and not the bile duct wall. The combination of biliary sphincterotomy and largediameter (12 to 20 mm) balloon dilation has been used to remove large stones and decrease the need for mechanical lithotripsy (Video 70.2). This large-diameter dilation method appears to be safe and not associated with an increased risk of post-ERCP pancreatitis.60 If large stones cannot be removed, a biliary stent is placed to relieve the obstruction (Video 70.3).61 Additional procedures can then be undertaken electively to remove residual stones.

Bile Leaks As discussed previously, bile leaks arise as a result of postsurgical complications and trauma. Laparoscopic cholecystectomy carries an incidence rate of bile duct injury from 0.06% to 0.3%.62 Most commonly, postcholecystectomy leaks arise from either the cystic duct or duct of Luschka (see Chapter 62). These smaller leaks can usually be managed with biliary sphincterotomy alone, placement of a plastic biliary stent (7 to 10 Fr), or both.63 This approach diverts bile away from the leak into the duodenum and negates the effect of the otherwise high-pressure biliary sphincter. More complex leaks usually require placement of one or more large-caliber plastic biliary stents in combination with biliary sphincterotomy (Fig. 70.7).64 The use of a removable, covered self-expanding metal stent (SEMS) for treatment of refractory leaks has also shown clinical utility.65,66 

PSC Patients with PSC may benefit from endoscopic intervention to treat a dominant stricture or biliary lithiasis (see Chapter 68).67 Patients with a dominant bile duct stricture usually present with

progressive biliary obstruction; however, considerable overlap exists between the symptoms of cholangiocarcinoma and those of a benign dominant stricture.68 For this reason, cholangiocarcinoma must always be considered in patients with PSC. Routine brush cytology has a low sensitivity in these patients, but fluorescence in situ hybridization has been shown to have a high sensitivity for the detection of cholangiocarcinoma (see Chapter 69)69; however, the specificity is low in the absence of a dominant stricture.70 Choledochoscopy (cholangioscopy) may improve the detection of malignancy in these patients.71 Probe-based confocal laser endomicroscopy has been used in the diagnosis of indeterminate biliary strictures.72 This technology requires injection of fluorescein contrast and use of a specialized probe that allows real-time visualization of cellularity. Criteria for interpretation have been proposed for the use of probe-based confocal laser endomicroscopy; however, more data are needed before this technique can be recommended routinely.73 Endoscopic treatment of a dominant stricture involves balloon dilation, often in combination with short-term (50% direct)

1000 U/L) includes viral hepatitis (A to E), toxininduced liver injury, DILI, ischemic hepatitis, and less commonly, autoimmune hepatitis, acute Budd-Chiari syndrome, ALF caused by Wilson disease, and acute obstruction of the biliary tract. The ratio of AST to ALT in serum is helpful in a few specific circumstances—perhaps most importantly in the recognition of alcohol-associated liver disease. If the AST level is less than 300 U/L, a ratio of AST to ALT of more than 2 suggests alcoholassociated liver disease, and a ratio of more than 3 is highly suggestive of alcohol-associated liver disease.19 The ratio results from a deficiency of pyridoxal 5′-phosphate in patients with alcoholassociated liver disease; ALT synthesis in the liver requires pyridoxal phosphate more than AST synthesis does.20 When a patient with chronic alcohol-associated liver disease sustains a superimposed liver injury, particularly acetaminophen hepatotoxicity, the aminotransferase levels can be strikingly elevated, yet the AST/ ALT ratio is maintained. Elevated AST and ALT levels may also be seen in muscle disorders. The degree of elevation is typically less than 300 U/L, but in rare cases, such as rhabdomyolysis, levels typically observed

CHAPTER 73  Liver Chemistry and Function Tests

BOX 73.1 Causes of Elevated Serum Aminotransferase Levelsa CHRONIC, MILD ELEVATIONS, ALT > AST ( AST (>1000 U/L OR > 20-25 × NORMAL) Hepatic Acute bile duct obstruction Acute Budd-Chiari syndrome Acute viral hepatitis Autoimmune hepatitis Drugs and toxins Hepatic artery ligation Ischemic hepatitis Wilson disease SEVERE, ACUTE ELEVATIONS, AST > ALT (>1000 U/L OR >20-25 × NORMAL) Hepatic Medications or toxins in a patient with underlying alcohol-associated liver injury Nonhepatic Acute rhabdomyolysis Chronic, mild elevations, AST > ALT (20 such tests are described in the literature).

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Hyaluronic acid is a glucosaminoglycan produced in mesenchymal cells and widely distributed in the extracellular space. Typically degraded by hepatic sinusoidal cells, serum levels of hyaluronic acid are elevated in patients with cirrhosis as a result of sinusoidal capillarization (see Chapter 92). A fasting hyaluronic acid level greater than 100 mg/L had a sensitivity of 83% and specificity of 78% for the detection of cirrhosis in patients with a variety of chronic liver diseases.45 Hyaluronic acid has been shown to be useful for identifying advanced fibrosis in patients with chronic hepatitis C, chronic hepatitis B, alcohol-associated liver disease, and NASH.46 Preoperative serum hyaluronic acid levels also have been shown to correlate with the development of hepatic dysfunction after hepatectomy.47 FibroTest (marketed as FibroSure in the USA) is the best evaluated of the multiparameter blood tests. The test incorporates haptoglobin, bilirubin, GGTP, apolipoprotein A-1, and α2-macroglobulin and has been found to have high positive and negative predictive values for diagnosing advanced fibrosis in patients with chronic hepatitis C (see Chapter 80). One study showed that use of a higher index cutoff led to a sensitivity of 90%, specificity of 36%, positive predictive value of 88%, and negative predictive value of 40% for the diagnosis of bridging fibrosis in patients with chronic hepatitis C.48 The test has similar performance characteristics in patients with chronic hepatitis B and alcohol-associated liver disease and has been shown to predict advanced fibrosis in patients taking methotrexate for psoriasis.49 The newer FIBROSpect II assay (subsequently FIBROSpect HCV and FIBROSpect NASH) incorporates hyaluronic acid, tissue inhibitor of metalloproteinase 1, and α2-macroglobulin. In a group of patients with chronic hepatitis C, FIBROSpect II had a sensitivity of 72% and a specificity of 74% for identifying advanced fibrosis.50 Vibration-controlled transient elastography, marketed as FibroScan, as well as acoustic radiation force impulse elastography, uses US waves to measure hepatic stiffness noninvasively (see Chapter 74). Central to the development of this technique were the principles that fibrosis leads to increased stiffness of hepatic tissue and that a shear wave will propagate faster through stiff material than through elastic material.51 The US transducer emits a low-frequency (50 Hz) shear wave, and the amount of time required for the wave to go through a set “window” of tissue is measured.52 The window of tissue is 1 cm by 4 cm—100 times the area of an average liver biopsy specimen. A meta-analysis showed that transient elastography performed best at differentiating cirrhosis from absence of cirrhosis but was less accurate for the estimation of lesser degrees of fibrosis.53 Transient elastography has been shown to be accurate for identifying advanced fibrosis in patients with chronic hepatitis C, PBC, hemochromatosis, NAFLD, and recurrent chronic hepatitis after LT54-57 and was approved by the FDA in 2013 for use in patients with liver disease. Magnetic resonance elastography (MRE) is another noninvasive technique that has been approved by the FDA. The shear elasticity of the liver is measured after low-frequency (65 Hz) waves are transmitted into the right lobe of the liver. In one study,58 MRE was found to be superior to transient elastography for staging liver fibrosis in patients with a variety of chronic liver diseases, but it is more expensive. 

QUANTITATIVE LIVER FUNCTION TESTS Quantitative function tests have been developed in the hope of evaluating the excretory or detoxification capacity of the liver more specifically than the serum bilirubin level. Although these tests lead to improved sensitivity, their lack of specificity and often cumbersome methodology have limited their widespread acceptance, except in research settings.

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Indocyanine Green Clearance Indocyanine green (ICG) is a nontoxic dye that is cleared exclusively by the liver; 97% of an administered dose (0.5 mg/kg given as an IV bolus) is excreted unchanged into bile. ICG can be measured directly by spectrophotometry. Noninvasive methods (dichromatic earlobe densitometry and fingertip optical sensors) generate data that appear to correlate well with levels determined by blood sampling. Possible uses of ICG include the assessment of hepatic dysfunction, measurement of hepatic blood flow, and prediction of clinical outcomes in patients with liver disease. Unfortunately, measurement of ICG has proved to be insensitive for detecting hepatic dysfunction and is inaccurate for measuring blood flow in patients with cirrhosis because of decreased ICG extraction by the diseased liver. Although ICG measurement has shown some promise for predicting outcomes in certain clinical situations such as burn patients, it has not been used widely outside of research protocols.59 

Galactose Elimination Capacity The galactose elimination capacity (GEC) has been studied as a measure of functional hepatic mass. Galactose is given as a single IV bolus (0.5 g/kg), and blood samples are collected. Patients with cirrhosis and chronic hepatitis have reduced galactose clearance from serum as compared with healthy controls. In a study of 781 patients with newly diagnosed cirrhosis and a decreased GEC, the GEC was a strong predictor of short- and long-term all-cause and cirrhosis-related mortality.60 

Caffeine Clearance Caffeine clearance tests quantify functional hepatic capacity by ass­ essing the activity of cytochrome P450 1A2, N-acetyltransferase, and xanthine oxidase. Caffeine is given orally (200 to 366 mg), and levels are measured in blood, urine, saliva, breath, or scalp hair. The alternative (nonblood measurement) methods correlate well with the plasma clearance method. Tobacco use increases caffeine clearance, and drug interactions can affect results. Increasing age correlates with decreased caffeine clearance. Overnight salivary caffeine clearance has been shown to correlate with ICG measurements and galactose clearance as well as with results of the aminopyrine breath test (see later).61 

Lidocaine Metabolite Formation Lidocaine is metabolized to its major metabolite monoethyl­ glycinexylidide (MEGX) by the hepatic cytochrome P450 system.62 Serum samples are taken 15, 30, and 60 minutes after IV administration of lidocaine (1 mg/kg). Neither MEGX formation nor galactose elimination was found to be superior to the Child-Turcotte-Pugh (CTP) (see Chapter 92) or MELD score (see Chapter 97) in predicting prognosis in patients with cirrhosis secondary to viral hepatitis (see later).63 Other studies have suggested that a decline in MEGX concentration correlates well with histologic worsening in patients with chronic liver disease.64 

Aminopyrine Breath Test The 15C and 14C aminopyrine breath tests (ABTs) measure hepatic mixed-function oxidase mass. The radioactive methyl groups of aminopyrine undergo demethylation and eventual conversion to labeled CO2, which is then exhaled and can be measured. After an overnight fast, a known dose of 15C aminopyrine (1 to 2 μCi) is administered orally, and breath samples are taken every 30 minutes for 4 hours; some investigators check a single sample at either 1 or 2 hours. Healthy

subjects excrete 6.6% ± 1.3% of the administered dose in the breath in 2 hours; patients with hepatocellular injury excrete considerably less. The degree of decrease in excretion of aminopyrine overlaps considerably in patients with all types of severe liver disease, including cirrhosis, chronic hepatitis, alcohol-associated liver disease, and HCC.65 Although data have been conflicting regarding the ability of this test to predict survival in patients with chronic liver disease, a study in 2012 of 50 patients showed that the ABT accurately predicted the risk of disease progression in patients with HCV-related chronic hepatitis.66

BILE ACIDS Bile acids are synthesized from cholesterol in hepatocytes, conjugated to glycine or taurine, and secreted into bile (see Chapter 64). After passage into the small intestine, most bile acids are actively reabsorbed. The liver efficiently extracts bile acids from the portal blood. In healthy persons, all bile acids in serum emanate from the reabsorption of bile acids in the small intestine. Maintenance of normal serum bile acid concentrations depends on hepatic blood flow, hepatic uptake, secretion of bile acids, and intestinal transit. Serum bile acids are sensitive but nonspecific indicators of hepatic dysfunction and allow some quantification of functional hepatic reserve. Serum bile acid levels correlate moderately well with the results of ABTs in patients with chronic hepatitis.67 Unfortunately, the correlation between serum bile acid levels and the histologic severity of chronic hepatitis and alcohol-associated liver disease is poor.68 Serum bile acid levels are elevated in patients with cholestatic liver diseases but normal in patients with Gilbert syndrome and Dubin-Johnson syndrome and can be used to make the distinction. Although decreased serum bile acid levels are highly specific indicators of liver dysfunction, they are not as sensitive as initially hoped. 

SPECIFIC APPLICATIONS OF LIVER BIOCHEMICAL TESTING Liver biochemical tests have been used to monitor for and assess the severity of DILI, assess operative risk, identify candidates for LT, and direct donor organ allocation.

DILI Most drugs that are hepatotoxic cause idiosyncratic liver injury, defined as injury that is unpredictable, occurs at therapeutic drug levels, and is infrequent (see Chapter 88). The estimated frequency of idiosyncratic DILI for any particular medication ranges from 1 in 1000 to 1 in 100,000. These reactions are marked by a variable latency period ranging from 5 to 90 days, or even longer.69 Other drugs produce dose-dependent toxicity. These injuries are predictable, have a high incidence, and generally have a well-understood mechanism. Acetaminophen is the classic example of a drug that causes dose-dependent liver injury. The dose of acetaminophen exceeds 15 g, almost 4 times the recommended daily dose, in 80% of cases. Acetaminophen doses within the therapeutic range (≤4 g/day) can be sufficient to cause liver injury in susceptible persons, such as those who use ethanol chronically. The King’s College criteria identify patients with a poor prognosis from acetaminophen-induced liver injury: those with an arterial pH below 7.3 or those with an INR above 6.5, serum creatinine level above 3.4 g/dL, and stage 3 to 4 hepatic encephalopathy (see Chapters 88 and 95).70 Most occurrences of DILI are mild and respond promptly to drug withdrawal with complete resolution. Isolated elevation of the serum aminotransferase levels, even to values greater than 3 times the upper limit of normal, is associated with a favorable

CHAPTER 73  Liver Chemistry and Function Tests

outcome. When aminotransferase elevations are associated with clinical jaundice (so-called Hy’s Law, after the late Dr. Hyman Zimmerman), the risk of mortality is increased to as high as 10% (see Chapter 88).71 

Surgical Candidacy and Organ Allocation Patients with acute and chronic liver disease are potentially at increased risk of morbidity and mortality if they undergo surgery. The risk depends on the etiology of the liver disease, severity of the liver disease, and planned operation.72 Although routine preoperative liver biochemical testing is not recommended in otherwise healthy people, the identification of unexpected elevated liver enzyme levels should prompt a postponement of surgery until the cause of the abnormalities has been identified. A retrospective analysis found that patients with acute viral hepatitis who undergo laparotomy had an operative mortality rate of approximately 9.5%.72 Elective surgery should be postponed in patients with acute hepatitis. The surgical risk in patients with chronic hepatitis correlates with the severity of histologic inflammation in the liver. Those with only portal inflammation and interface hepatitis have low operative risk, whereas those with panlobular hepatitis have an increased risk. The etiology of chronic hepatitis does not influence outcome. Examination of histology is also critical in assessing the surgical risk in patients with alcohol-associated liver disease. Hepatic steatosis alone is associated with a low operative risk, whereas alcoholic hepatitis is associated with a mortality rate as high as 55% in patients undergoing portosystemic shunt surgery, for example. A period of abstinence of 3 to 6 months before elective surgery is recommended in these patients. Few data exist for surgical risk in patients with NAFLD, but the mortality rate appears to correlate with the severity of steatosis in patients undergoing liver resection. Steatohepatitis may carry a higher risk than that for steatosis. An estimated 10% of patients with advanced liver disease undergo surgery in the last 2 years of their lives. Cirrhosis is associated with increased operative risk, particularly with certain types of surgery, including hepatic resection, other abdominal operations, and cardiothoracic surgery. The data evaluating the surgical

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risk in these patients were derived retrospectively but point consistently toward the usefulness of the CTP scoring system for predicting perioperative mortality. Two studies performed more than 10 years apart examined mortality after abdominal surgery in cirrhotic patients and reported nearly identical rates of mortality for patients with Child-Pugh class A, B, and C cirrhosis: 10%, 30% to 31%, and 76% to 82%, respectively73,74; however, lower mortality rates have since been reported with greater use of laparoscopic surgery at an expert center.75 In general, surgery may be undertaken in patients with Child-Pugh class A cirrhosis, whereas the medical condition of patients with Child-Pugh class B cirrhosis should be optimized prior to planned surgery. The mortality rate in patients with Child-Pugh class C cirrhosis is prohibitive, and surgery should be avoided. The MELD score was created originally to predict survival in patients with cirrhosis and portal hypertension undergoing placement of a TIPS.76 The score has subsequently been validated as an accurate predictor of survival in patients with advanced liver disease. The MELD score incorporates 3 objective variables into a mathematical formula: 9.57 × loge(creatinine) + 3.78 × loge(total bilirubin) + 11.2 × loge(INR) + 6.43. The working range is 6 to 40, and the score has been shown to correlate with mortality in patients undergoing surgery other than LT, including hepatic resection, other abdominal procedures, and cardiac surgery.77-79 The MELD score is used most often for prioritizing the allocation of donor organs for LT.80 After implementation of the MELD score for prioritizing organ allocation, the number of deaths among patients on the wait list decreased (see Chapter 97). In 2016, the serum sodium was added to the MELD score equation for the purpose of organ allocation: MELD + 1.32 × (137 − Na) − [0.033 × MELD × (137 − Na)]. It was shown that doing so increases the predictive accuracy for determining death on the transplant waiting list.81 Furthermore, investigators showed that implementation of the MELD-Na score would prevent 7% of waiting-list deaths.82 The use of the MELD-Na score in assessing surgical risk (other than LT) has not been studied. Full references for this chapter can be found on www.expertconsult.com.

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REFERENCES

1. Lester R, Schmid R. Bilirubin metabolism. N Engl J Med 1964;270:779–86. 2. Levi A, Gatmaitan Z, Arias I. Two hepatic cytoplasmic protein fractions, Y and Z, and their possible role in the hepatic uptake of bilirubin sulfobromophthalein, and other anions. J Clin Invest 1969;48:2156–67. 3. Bosma P, Seppen J, Goldhoorn B, et al. Bilirubin UDP-glucuronosyltransferase 1 is the only relevant bilirubin glucuronidating isoform in man. J Biol Chem 1994;269:17960–4. 4. Gatmaitan Z, Arias I. ATP-dependent transport systems in the canalicular membrane of the hepatocyte. Physiol Rev 1995;75:261–75. 5. Poland R, Odell G. Physiologic jaundice: the enterohepatic circulation of bilirubin. N Engl J Med 1971;284:1–6. 6. van den Bergh A, Muller P. Uber eine direkte und eine indirekte Diazoreaktion auf Bilirubin. Biochem Z 1916;77:90. 7. Zieve L, Hill E, Hanson M, et al. Normal and abnormal variations and clinical significance of the one-minute and total serum bilirubin determinations. J Lab Clin Med 1951;38:446–69. 8. Bloomer J, Berk P, Howe R, et al. Interpretation of plasma bilirubin levels based on studies with radioactive bilirubin. J Am Med Assoc 1971;218:216–20. 9. van Hoogstraten HJ, Hansen BE, van Buuren HR, et al. Prognostic factors and long-term effects of ursodeoxycholic acid on liver biochemical parameters in patients with primary biliary cirrhosis. Dutch Multi-Centre PBC Study Group. J Hepatol 1999;31:256–62. 10. van de Steeg E, Stranecky V, Hartmannova H, et al. Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver. J Clin Invest 2012;122:519–28. 11. Karmen A, Wroblewski F, Ladue J. Transaminase activity in human blood. JCI 1955;34:126–31. 12. Kallai L, Hahn A, Roeder V, et al. Correlation between histological findings and transaminase values in chronic diseases of the liver. Acta Med Scand 1964;175:49–56. 13. Piton A, Poynard T, Imbert-Bismut F, et al. Factors associated with serum alanine transaminase activity in healthy subjects: consequences for the definition of normal values, for selection of blood donors, and for patients with chronic hepatitis C. Hepatology 1998;27:1213–9. 14. Prati D, Taioli E, Zanella A, et al. Updated definitions of healthy ranges for serum alanine aminotransferase levels. Ann Intern Med 2002;137:1–10. 15. Kim H, Nam C, Jee S, et al. Normal serum aminotransferase concentration and risk of mortality from liver diseases: prospective cohort study. BMJ 2004;328:983. 16. Kaplan M. Alanine aminotransferase levels: what’s normal? Ann Intern Med 2002;137:49–51. 17. Kunde S, Lazenby A, Clements R, et al. Spectrum of NAFLD and diagnostic implications of the proposed new normal range for serum ALT in obese women. Hepatology 2005;42:650–6. 18. Dong MH, Bettencourt R, Brenner DA, et al. Serum levels of alanine aminotransferase decrease with age in longitudinal analysis. Clin Gastroenterol Hepatol 2012;10:285–90. 19. Cohen J, Kaplan M. The SGOT/SGPT ratio: an indicator of alcoholic liver disease. Dig Dis Sci 1979;24:835–8. 20. Diehl A, Boitnott J, Van Duyn M, et al. Relationship between pyridoxal 5’-phosphate deficiency and aminotransferase levels in alcoholic hepatitis. Gastroenterology 1984;86:632–6. 21. Nathwani R, Pais S, Reynolds T, et al. Serum alanine aminotransferase in skeletal muscle diseases. Hepatology 2005;41:380–2. 22. Sheth S, Flamm S, Gordon F, et al. AST/ALT ratio predicts cirrhosis in patients with chronic hepatitis C virus infection. Am J Gastroenterol 1998;93:44–8. 23. Giannini E, Botta F, Fasoli A, et al. Progressive liver functional impairment is associated with an increase in AST/ALT ratio. Dig Dis Sci 1999;44:1249–53. 24. Sainsbury A, Sanders DS, Ford AC. Meta-analysis: coeliac disease and hypertransaminasaemia. Aliment Pharmacol Ther 2011;34:33–40. 25. Kaplan M. Alkaline phosphatase. Gastroenterology 1972;62:452–68. 26. Kaplan M. Serum alkaline phosphatase: another piece is added to the puzzle. Hepatology 1986;6:526. 27. Bamford K, Harris H, Luffman J, et al. Serum-alkaline phosphatase and the ABO blood groups. Lancet 1965;1:530–1. 28. Wolf P. Clinical significance of an increased or decreased serum alkaline phosphatase level. Arch Pathol Lab Med 1978;102:497–501.

29. Rutenberg A, Goldbarg J, Pineda G, et al. Serum γ-glutamyl transpeptidase activity in hepatobiliary pancreatic disease. Gastroenterology 1963;45:43. 30. Rosalki S, Tarlow D, Rau D. Plasma gamma-glutamyl transpeptidase elevation in patients receiving enzyme-inducing drugs. Lancet 1971;2:376–7. 31. Bani-Sadr F, Miailhes P, Rosenthal E, et al. Risk factors for grade 3 or 4 gamma- glutamyl transferase elevation in HIV/hepatitis C viruscoinfected patients. AIDS 2008;22:1234–6. 32. Hadzagic-Catibusic F, Hasanbegovic E, Melunovic M, et al. Effects of carbamazepine and valproate on serum aspartate aminotransferase, alanine aminotransferase and gamma-glutamyltransferase in children. Med Arch 2017;71:239–42. 33. Moussavian S, Becker R, Piepmeyer J, et al. Serum gamma-glutamyl transpeptidase and chronic alcoholism: influence of alcohol ingestion and liver disease. Dig Dis Sci 1985;30:211–4. 34. Hu G, Tuomilehto J, Pukkala E, et al. Joint effects of coffee consumption and serum gamma-glutamyltransferase on the risk of liver cancer. Hepatology 2008;48:7–9. 35. Yang M, Chen T, Wang S, et al. Biochemical predictors for absence of common bile duct stones in patients undergoing laparoscopic cholecystectomy. Surg Endosc 2008;22:1620–4. 36. Pinkham CA, Krause KJ. Liver function tests and mortality in a cohort of life insurance applicants. J Insur Med 2009;41:170–7. 37. Kaplan M, Rogers L. Separation of serum alkaline phosphatase isoenzymes by polyacrylamide gel electrophoresis. Lancet 1968;2: 1029–31. 38. Rothschild M, Oratz M, Zimmon D, et al. Albumin synthesis in cirrhotic subjects studied with carbonate 14C. J Clin Invest 1969;48:344–50. 39. Rothschild M, Oratz M, Schreiber S. Serum albumin. Hepatology 1988;8:385–401. 40. van Zantsen S, Depla A, Dekker P, et al. The clinical importance of routine measurement of liver enzymes, total protein, and albumin in a general medicine outpatient clinic: a prospective study. N Engl J Med 1992;40:53–61. 41. Trotter JF, Brimhall B, Arjal R. Specific laboratory methodologies achieve higher Model for End-stage Liver Disease (MELD) scores for patients listed liver transplantation. Liver Transpl 2004;10:995– 1000. 42. Bellest L, Eschwege V, Poupon R, et al. A modified international normalized ratio as an effective way of prothrombin time standardization in hepatology. Hepatology 2007;46:528–34. 43. Tripodi A, Chantarangkul V, Prirnignani M, et al. The international normalized ratio calibrated for cirrhosis normalizes prothrombin time results for Model for End-stage Liver Disease calculation. Hepatology 2007;46:520–7. 44. Martinez SM, Crespo G, Navasa M, et al. Noninvasive assessment of liver fibrosis. Hepatology 2011;53:325–35. 45. Plevris J, Kaydon G, Simpson K, et al. Serum hyaluronan: a non-invasive test for diagnosing liver cirrhosis. Eur J Gastroenterol Hepatol 2000;12:1121–7. 46. Kaneda H, Hashimoto E, Yatsuji S, et al. Hyaluronic acid levels can predict severe fibrosis and platelet counts can predict cirrhosis in patients with nonalcoholic fatty liver disease. J Gastroenterol Hepatol 2006;21:1459–65. 47. Mizguchi T, Katsuramaki T, Nobuoka T, et al. Serum hyaluronate level for predicting subclinical liver dysfunction after hepatectomy. World J Surg 2004;28:971–6. 48. Poynard T, McHutchison J, Manns M, et al. Biochemical surrogate markers of liver fibrosis and activity in a randomized trial of peginterferon alpha-2b and ribavirin. Hepatology 2003;38: 481–92. 49. Berends M, Snoek J, de Jong E, et al. Biochemical and biophysical assessment of MTX- induced liver fibrosis in psoriasis patients. Liver Int 2007;27:639–45. 50. Zaman A, Rosen H, Ingram K, et al. Assessment of FIBROSpect II to detect hepatic fibrosis in chronic hepatitis C patients. Am J Med 2007;280:e9–14. 51. Sandrin L, Fourquet B, Hasquenoph J, et al. Transient elastography: a new noninvasive method for assessment of hepatic fibrosis. Ultrasound Med Biol 2003;29:1705–13. 52. Nguyen-Khac E, Capron D. Noninvasive diagnosis of liver fibrosis by ultrasonic transient elastography (Fibroscan). Eur J Gastroenterol Hepatol 2006;18:1321–5.

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53. Friedrich-Rust M, Martens S, Sarrazin C, et al. Performance of transient elastography for the staging of liver fibrosis: a meta-analysis. Gastroenterology 2008;134:960–74. 54. Yoneda M, Mawatari H, Fujita K, et al. Noninvasive assessment of liver fibrosis by measurement of stiffness in patients with nonalcoholic fatty liver disease (NAFLD). Dig Liver Dis 2008;40:371–8. 55. Adhoute X, Foucher J, Laharie D, et al. Diagnosis of liver fibrosis using FibroScan and other noninvasive methods in patients with hemochromatosis: a prospective study. Gastroenterol Clin Biol 2008;32:180–7. 56. Rigamonti C, Donato M, Fraquelli M, et al. Transient elastography predicts fibrosis progression in patients with recurrent hepatitis C after liver transplantation. Gut 2008;576:821–7. 57. Gomez-Dominguez E, Mendoza J, Garcia-Buey L, et al. Transient elastography to assess hepatic fibrosis in primary biliary cirrhosis. Aliment Pharmacol Ther 2008;27:441–7. 58. Huwart L, Sempoux C, Vicaut E, et al. Magnetic resonance elastography for the noninvasive staging of liver fibrosis. Gastroenterology 2008;135:32–40. 59. Steinvall I, Fredrikson M, Bak Z, et al. Incidence of early burninduced effects on liver function as reflected by the plasma disappearance rate of indocyanine green: a prospective descriptive cohort study. Burns 2012;38:214–24. 60. Jepsen P, Vilstrup H, Ott P, et al. The galactose elimination capacity and mortality in 781 Danish patients with newly-diagnosed liver cirrhosis: a cohort study. BMC Gastroenterol 2009;9:50. 61. Jost G, Wahllander A, von Mandach U, et al. Overnight salivary caffeine clearance: a liver function test suitable for routine use. Hepatology 1987;7:338–44. 62. Oellerich M, Armstrong V. The MEGX test: a tool for the realtime assessment of hepatic function. Ther Drug Monit 2001;23: 81–92. 63. Addario L, Scaglione G, Tritto G, et al. Prognostic value of quantitative liver function tests in viral cirrhosis: a prospective study. Eur J Gastroenterol Hepatol 2006;18:713–20. 64. Shiffman M, Luketic V, Sanyal A, et al. Hepatic lidocaine metabolism and liver histology in patients with chronic hepatitis and cirrhosis. Hepatology 1994;19:933–40. 65. Carlisle R, Galambos J, Warren W. The relationship between conventional liver tests, quantitative function tests, and histopathology in cirrhosis. Dig Dis Sci 1979;24:358–62. 66. Rocco A, de Nucci G, Valente G, et al. 13C-aminopyrine breath test accurately predicts long-term outcome of chronic hepatitis C. J Hepatol 2012;56:782–7. 67. Monroe P, Baker A, Schneider J, et al. The aminopyrine breath test and serum bile acids reflect histologic severity in chronic hepatitis. Hepatology 1982;2:317–22.

68. Einarsson K, Angelin B, Bjorkhem I, et al. The diagnostic value of fasting individual serum bile acids in anicteric alcoholic liver disease: relation to liver morphology. Hepatology 1985;5:108–11. 69. Lee W. Drug-induced hepatotoxicity. N Engl J Med 2003;349:474–85. 70. O’Grady J, Alexander G, Hayllar K, et al. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology 1989;97:439–45. 71. Maddrey W. Drug-induced hepatotoxicity. J Clin Gastroenterol 2005;39:S83–9. 72. Northup PG, Friedman LS, Kamath PS. AGA Clinical Practice Update on surgical risk assessment and perioperative management in cirrhosis: expert review. Clin Gastroenterol Hepatol 2019;17:595-606. 73. Powell-Jackson P, Greenway B, William R. Adverse effects of laparotomy in patients with unsuspected liver disease. Br J Surg 1982;69:449–51. 74. Garrison R, Cryer H, Howard D, et al. Clarification of risk factors for abdominal operations in patients with hepatic cirrhosis. Ann Surg 1984;199:648–55. 75. Mansour A, Watson W, Shayani V, et al. Abdominal operation in patients with cirrhosis: still a major surgical challenge. Surgery 1997;122:730–6. 76. Telem DA, Schiano T, Goldstone R, et al. Factors that predict outcome of abdominal operations in patients with advanced cirrhosis. Clin Gastroenterol Hepatol 2010;8:451–7. 77. Kamath P, Kim W. The model for end-stage liver disease (MELD). Hepatology 2007;45:797–805. 78. Teh S, Christein J, Donohue J, et al. Hepatic resection of hepatocellular carcinoma in patients with cirrhosis: model for End-stage Liver Disease (MELD) score predicts perioperative mortality. J Gastrointest Surg 2005;9:1207–15. 79. Seaman A, Barnes D, Zein N, et al. Predicting outcome after cardiac surgery in patients with cirrhosis: a comparison of Child-Pugh and MELD score. Clin Gastroenterol Hepatol 2004;2:719–23. 80. Northup PG, Wanamaker RC, Lee VD, et al. Model for End-stage Liver Disease (MELD) predicts non-transplant surgical mortality in patients with cirrhosis. Ann Surg 2005;242:244–51. 81. Wiesner R, Edwards E, Freeman R, et al. Model for end-stage liver disease (MELD) and allocation of donor livers. Gastroenterology 2003;124:91–6. 82. Biggins SW, Kim WR, Terrault NA, et al. Evidence-based incorporation of serum sodium concentration into MELD. Gastroenterology 2006;130:1652–60. 83. Kim WR, Biggins SW, Kremers WK, et al. Hyponatremia and mortality among patients on the liver transplant waiting list. N Engl J Med 2008;359:1018–26.

74

Overview of Cirrhosis Patrick S. Kamath, Vijay H. Shah

CHAPTER OUTLINE PATHOGENESIS��������������������������������������������������������������1164 DIAGNOSIS����������������������������������������������������������������������1164 NATURAL HISTORY ��������������������������������������������������������1167 PROGNOSIS��������������������������������������������������������������������1167 TREATMENT��������������������������������������������������������������������1169 Reversal of Fibrosis������������������������������������������������������1170 ACUTE-ON-CHRONIC LIVER FAILURE ����������������������������1170 Definition ��������������������������������������������������������������������1170 Epidemiology ��������������������������������������������������������������1170 Pathophysiology ����������������������������������������������������������1171 Clinical Features and Prognosis������������������������������������1171 Treatment��������������������������������������������������������������������1171

Cirrhosis, a final pathway for a wide variety of chronic liver diseases (Box 74.1), is a pathologic entity defined as diffuse hepatic fibrosis with the replacement of the normal liver architecture by nodules. The rate of progression of chronic liver disease to cirrhosis may be quite variable, from weeks in patients with complete biliary obstruction to decades in patients with chronic hepatitis C. Cirrhosis is one of the leading causes of mortality in the USA and particularly afflicts persons in the most productive years of their lives. Acute-on-chronic liver failure (ACLF) is also discussed in this chapter, and the protean complications of cirrhosis (Box 74.2) are discussed in other chapters (see Chapters 21, 92, 93, 94, and 96).

PATHOGENESIS The liver cell type most implicated in the pathogenesis of liver fibrosis is the hepatic stellate cell. In normal liver, the hepatic stellate cell is viewed as a pericyte that lies abluminal to the sinusoidal endothelial cell in the space of Disse1 (see Chapter 71). On activation, a hepatic stellate cell transforms into a myofibroblast (Fig. 74.1).2 Activation is characterized by increases in the expression of smooth muscle actin, motility, and contractility. Most importantly for the development of liver fibrosis, the stellate cell begins to generate various forms of matrix, which lead to liver fibrosis.2 Fibronectin is the earliest form of matrix produced by stellate cells, which ultimately produce other forms of matrix, including collagen type 1.3 Matrix deposition in turn leads to further hepatic stellate cell activation and changes in the hepatic angioarchitecture.3 The canonical pathways that are most implicated in activation of the hepatic stellate cell include kinase activation pathways mediated through platelet-derived growth factor, transforming growth factor-β, and integrin signaling pathways. In addition to the hepatic stellate cell, other cells, including the portal fibroblast,4 may ultimately culminate in the myofibroblast phenotype that deposits collagen matrix. The portal fibroblast resides closer than hepatic stellate cells to the portal tract and is implicated in the liver fibrosis that develops in response to portal-based cholestatic injury, as in PBC and PSC.4 It is hypothesized that epithelial cell injury in the periportal region leads to

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transformation of portal fibroblasts into myofibroblasts. Other studies suggest that hepatic stellate cells may be responsible for fibrosis even in biliary forms of liver injury.1 Cell types other than myofibroblasts are also important in the fibrosis process. For example, epithelial cell injury is the initiating step in most forms of liver injury that leads to fibrosis. Injury to epithelial cells, either through apoptosis, inflammation, or sterile necrosis, culminates in the recruitment and activation of hepatic stellate cells.5 The macrophage is also important in fibrosis owing to release of inflammatory cytokines, which in turn lead to transactivation of hepatic stellate cells into myofibroblasts. Macrophages are a complex target because some subclasses promote fibrosis whereas others are required for fibrosis resolution.2 Studies have also indicated an important role for the sinusoidal endothelial cell in fibrosis development. Sinusoidal endothelial cells act through autocrine and paracrine signaling pathways to participate in angiogenesis. Angiogenesis may lead to fibrosis through paracrine release of hepatic stellate cell activating molecules from angiogenic sinusoidal endothelial cells. Therefore, multiple cell types in the liver participate in fibrogenesis, although the hepatic stellate cell is most directly implicated in this process because of its abundant capacity to produce matrix. 

DIAGNOSIS Although cirrhosis is strictly speaking a histologic diagnosis (Fig. 74.2), a combination of clinical, laboratory, and imaging features can help confirm a diagnosis of cirrhosis. Several physical findings suggestive of cirrhosis result in part from alterations in the metabolism of estrogen by the cirrhotic liver. An intense red coloration of the thenar and hypothenar eminences suggests palmar erythema. Terry’s nails are characterized by proximal nail bed pallor, which can also involve the entire nail plate, with predominant involvement of the thumb and index finger. Clubbing of the fingernails may result from the presence of arteriovenous shunts in the lung as a result of portal hypertension. Gynecomastia is the enlargement of the male breast with palpable tissue. Spider telangiectasias (or angiomata) are dilated arterioles characterized by a prominent central arteriole with radiating vessels. Compression of the central arteriole with a pinhead results in blanching followed by reformation of the “spider” after release of pressure on the arteriole. In general, more than 2 to 3 spider telangiectasias are considered abnormal. Dilated abdominal veins (caput medusae) with flow away from the umbilicus, toward the inferior vena cava in the infraumbilical area and toward the superior vena cava in the supraumbilical area, suggest intrahepatic portal hypertension. On the other hand, dilatation of veins in the flank with blood draining toward the superior vena cava suggests inferior vena caval obstruction. Parotid enlargement is also a feature of cirrhosis, especially alcohol-associated cirrhosis. Patients with a history of chronic liver disease with gastroesophageal varices, ascites, or hepatic encephalopathy are likely to have cirrhosis, and liver biopsy is not essential in such cases for confirming cirrhosis. In patients with a diagnosis of chronic liver disease without these complications, physical findings of an enlarged left hepatic lobe with splenomegaly, along with the cutaneous stigmata of liver disease described earlier, suggest cirrhosis, especially in the setting of thrombocytopenia and impaired

CHAPTER 74  Overview of Cirrhosis

BOX 74.1 Causes of Cirrhosis

BOX 74.2 Principal Complications of Cirrhosis

VIRAL HBV HCV HDV

PORTAL HYPERTENSION Ascites Variceal bleeding

AUTOIMMUNE Autoimmune hepatitis PBC PSC TOXIC Alcohol Arsenic METABOLIC α1 Antitrypsin deficiency Galactosemia Glycogen storage disease Hemochromatosis NAFLD and NASH Wilson disease BILIARY Atresia Stone Tumor VASCULAR Budd-Chiari syndrome Cardiac fibrosis GENETIC CF Lysosomal acid lipase deficiency IATROGENIC Biliary injury Drugs: high-dose vitamin A, methotrexate

hepatic synthetic function (e.g., hypoalbuminemia, prolongation of the prothrombin time). If physical and laboratory findings are not suggestive of cirrhosis, imaging studies can help make a diagnosis of cirrhosis. A small nodular liver with splenomegaly and intra-abdominal collaterals and the presence of ascites on abdominal US (or other cross-sectional imaging study) suggests cirrhosis (Fig. 74.3). A number of commercially available tools combine hematologic parameters, liver biochemical tests, and serologic markers to determine the degree of hepatic fibrosis.6 In general, these tools are useful for discriminating early from late stages of fibrosis but not between individual stages of fibrosis (see Chapters 73 and 80). Where available, vibration-controlled transient elastography (or fibroelastography), acoustic radiation force impulse (ARFI) elastography (another form of US elastography),6 or magnetic resonance elastography (MRE) can help confirm a diagnosis of cirrhosis. On transient elastography, a liver stiffness measurement (measured in kilopascals) of greater than 14 kPa suggests cirrhosis, with values greater than 21 kPa associated with portal hypertension and its complications,7 and posthepatectomy complications.3 Moreover, esophageal varices are unlikely if the hepatic stiffness is less than 19.5 kPa.4 ARFI imaging values greater than 2.6 m/sec suggest cirrhosis; moreover, ARFI imaging is more easily performed than transient elastography.6 On MRE, liver stiffness values greater than 5.9 kPa suggest cirrhosis, and a liver biopsy is typically not required to confirm the diagnosis. Increasing spleen stiffness on US elastography or MRE is associated with the onset

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MALIGNANCY Cholangiocarcinoma HCC BACTERIAL INFECTIONS Bacteremia CDI Cellulitis Pneumonia SBP Urinary tract infection CARDIOPULMONARY DISORDERS Cardiomyopathy Hepatic hydrothorax Hepatopulmonary syndrome Portopulmonary hypertension GI DISORDERS GI bleeding Nonvariceal Variceal Protein-losing enteropathy Venous thrombosis RENAL DISORDERS Hepatorenal syndrome Other causes of acute kidney injury METABOLIC DISORDERS Adrenal insufficiency Hypogonadism Malnutrition Osteoporosis NEUROPSYCHIATRIC DISORDERS Depression Hepatic encephalopathy HEMATOLOGIC DISORDERS Anemia Hypercoagulability Hypersplenism Impaired coagulation UNCLEAR ETIOLOGY Erectile dysfunction Fatigue Muscle cramps

of portal hypertension.8 It is important to emphasize that liver stiffness is overestimated in the postprandial state and in the presence of hepatic inflammation, cholestasis, and right-sided heart failure. Liver biopsy has long been the gold standard for diagnosing cirrhosis but is associated with costs and procedure-related risks, albeit infrequently (see Chapter 21). The major concerns regarding the use of a liver biopsy to diagnose cirrhosis includes sampling error and interobserver disagreement in the estimation of the extent of fibrosis. The ideal combination of clinical findings and routine laboratory tests to determine whether a patient has cirrhosis without the need for a liver biopsy has been addressed in a systematic fashion.9 The most commonly used scoring systems are outlined in Table 74.1. Others are also used in practice, in some cases for assessment of fibrosis in a specific liver disease such as

74

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PART IX  Liver Fibrogenesis Epithelial cell (hepatocyte, cholangiocyte)

Matrix

Fibrosis Resolution

Proteases

n

tio

va

ti ac

De Activation

Kupffer cell

Apoptosis

Sen

esce

Hepatic stellate cell or portal fibroblast Myofibroblast

Endothelial cell

A

B

C

D

nce

Fig. 74.1  Schematic overview of the pathogenesis of fibrosis and reversal of fibrosis in cirrhosis.  Epithelial cell injury in combination with release of cytokines by Kupffer cells and release of paracrine molecules by sinusoidal endothelial cells leads to activation of hepatic stellate cells (or portal fibroblasts) into myofibroblasts. Reversal of fibrosis results from deactivation, apoptosis, or senescence of myofibroblasts. Release of matrix proteases can also lead to resolution of fibrosis (see text for details).

Fig. 74.2  Histologic stages of hepatic fibrosis.  A, A normal portal tract containing a portal vein branch, hepatic artery branch, and interlobular bile duct. The acinar parenchyma shows mild steatosis but no fibrosis. This is stage 0 fibrosis. (H & E.) B, A Masson trichrome stain highlights in blue a normal (minimal) amount of collagen in a portal tract in stage 0. C, In stage 1 (of 4), there is a significant increase in collagen (fibrosis) in the portal tract. (H & E.) D, The fibrosis in stage 1 is highlighted in blue by a Masson trichrome stain. The fibrosis expands the portal tract but does not involve the surrounding periportal acinar parenchyma. E, Periportal fibrosis characterizes stage 2. Expansion of the portal tract by fibrosis in blue is seen. The collagen is not confined to the portal tract but also extends to involve the surrounding periportal acinar parenchyma (arrows). (Masson trichrome stain.) F, In stage 3, bridging fibrosis is seen. Multiple portal tracts demonstrate increased fibrosis in blue and connect with one another, forming fibrous bridges (arrows). (Masson trichrome stain.) G, In cirrhosis (stage 4), the normal liver architecture is completely distorted and replaced by regenerative nodules that are separated by fibrous septa in blue. (Masson trichrome stain.) (Images courtesy Taofic Mounajjed, MD, Rochester, Minn.)

CHAPTER 74  Overview of Cirrhosis

1167

74

E

F

G Fig. 74.2—Cont’d

chronic hepatitis C, and have varying performance characteristics (see Chapters 73 and 80). A serum AST/platelet ratio index (APRI) of greater than 2 suggests cirrhosis, as does a Bonacini cirrhosis discriminant score of 7 or greater. A Bonacini score of less than 3 or a Lok index of less than 0.2 argues against a diagnosis of cirrhosis. Ascites and a platelet count of less than 160,000/mm3 render the diagnosis of cirrhosis more likely, whereas the absence of hepatomegaly of a firm liver and a platelet count of 160,000/mm3 or greater make cirrhosis unlikely. Transient elastography is superior to tests like APRI in the diagnosis of cirrhosis in patients with hepatitis C, hepatitis B, NAFLD, and alcohol-associated liver disease. 

NATURAL HISTORY Cirrhosis has traditionally been classified as compensated or decompensated. The development of complications of variceal hemorrhage, ascites, encephalopathy, jaundice, or HCC characterizes decompensated cirrhosis. In compensated cirrhosis, these complications are absent. Four clinical stages of cirrhosis have been proposed: stages 1 and 2 represent compensated cirrhosis, and stages 3 and 4 represent decompensated cirrhosis. Stage 1 cirrhosis is characterized by absence of both ascites and varices; stage 2 cirrhosis is characterized by the presence of varices without bleeding and the absence of ascites; stage 3 cirrhosis is characterized by ascites with or without esophageal varices; and stage 4 cirrhosis is characterized by variceal bleeding with or without ascites. In the future, staging of cirrhosis may consider not only

clinical and histologic parameters, but also hemodynamic and biological data.10 Most deaths in patients with cirrhosis occur as a result of hepatic decompensation leading to hepatic and extrahepatic organ failure; however, in the compensated stages, the most common cause of death is cardiovascular disease, followed by stroke, malignancy, and renal disease.11 Complications of portal hypertension, HCC, and sepsis12 are the usual causes of mortality in patients with decompensated cirrhosis. Infection is now recognized as a distinct stage in the natural history of cirrhosis and associated with poor survival even after clearance of the infection.5 An alternative pathway to multiple organ failure and death, ACLF, has been recognized in patients with cirrhosis (see later). 

PROGNOSIS Chronic liver disease is the 12th leading disease cause of death in the USA. Among persons 45 to 64 years of age, cirrhosis is the third leading cause of death. As compared with the general population, persons with compensated cirrhosis have a 5-fold increased risk of death, whereas patients with decompensated cirrhosis have a 10-fold increased risk. The median survival in patients with compensated cirrhosis is 9 to 12 years, compared with 2 years in those with decompensated cirrhosis. In a nationwide Danish population study, the overall survival probability in patients with cirrhosis was 66% at 1 year, 38% at 5 years, and 22% at 10 years.13 The majority of deaths were related to cirrhosis. Most deaths among patients with compensated

1168

PART IX  Liver

*

A

B

C

E

D

F

Fig. 74.3  Imaging in cirrhosis.  A, A transverse US image of the right lobe of liver demonstrates the characteristic heterogeneous liver parenchyma with surface nodularity (arrows). B, Axial contrast-enhanced CT image shows a nodular left lobe of the liver (white arrow). Note the gastric and esophageal varices (black arrow) and splenomegaly (asterisk). C, Images from T2-weighted and D, contrast-enhanced T1-weighted MRIs show hypointense siderotic nodules (white arrows) and an enlarged left lobe and splenomegaly. E, Contrast-enhanced MRI shows a heterogeneous liver with an enlarged left lobe. F, A stiffness map from magnetic resonance elastography shows increased stiffness of the liver (dotted outline), with a mean stiffness value of 9.2 kPa. The normal liver stiffness value is less than 2.93 kPa. (F, From Yin M, Talwalker JA, Glaser KJ, et al. Assessment of hepatic fibrosis with magnetic resonance elastography. Clin Gastroenterol Hepatol 2007; 5:1207-13. Other images courtesy Sudhakar Venkatesh, MD, Rochester, Minn.)

CHAPTER 74  Overview of Cirrhosis

1169

TABLE 74.1  Commonly Used Scores for Predicting Cirrhosis

74

APRI* (AST/upper limit of normal AST) × (100/platelet count [×103/mm3]) Bonacini Cirrhosis Discriminant Score (CDS)† Platelet score + ALT/AST ratio score + INR score Score Platelets (×103/mm3)

ALT/AST ratio

INR

0

>340

>1.7

1.4

3

160-219

70)

  

*For all the assays, results in homozygotes and heterozygotes may overlap.

holo-ceruloplasmin and typically overestimate the true amount of functional ceruloplasmin in plasma. The oxidase assay, although technically less convenient for laboratories that perform automated testing, provides a more reliable measure of ceruloplasmin for diagnosis because the assay measures enzymatically active, copper-containing ceruloplasmin. This method permits an accurate estimate of non-ceruloplasmin-bound copper41 and can also indicate possible early copper deficiency in treated patients.42 Serum ceruloplasmin measurement by itself is not an adequate diagnostic test for Wilson disease. A low serum level of ceruloplasmin is not unique to Wilson disease; synthesis of ceruloplasmin may be reduced in other types of chronic liver disease, intestinal malabsorption, nephrotic syndrome, and malnutrition. Furthermore, a subnormal ceruloplasmin concentration is found in at least 10% of heterozygotes for Wilson disease. Nevertheless, an impressively low ceruloplasmin concentration (1.6 μmol/day), although typical, is not sufficiently sensitive. A patient with a basal 24-hour urinary copper excretion of greater than 40 μg/day (>0.6 μmol/day) requires further investigation for Wilson disease.52 Heterozygotes usually have a normal basal 24-hour urinary copper excretion, although the value may be borderline abnormal in some cases.53 Although a normal person may excrete as much as 20 times the baseline level of copper after administration of d-penicillamine, a patient with symptomatic Wilson disease will excrete considerably more. In the standard provocative test with administration of d-penicillamine, urinary copper excretion of 25 μmol (1600 μg) or more per 24 hours is diagnostic of Wilson disease; however, the test lacks sensitivity for diagnosing Wilson disease and for identifying asymptomatic affected siblings.54 Hepatic tissue copper concentration, which usually is measured by neutron activation analysis or atomic absorption spectrometry, may provide important diagnostic information. A hepatic copper content greater than 250 μg/g dry weight of liver is considered diagnostic of Wilson disease. On the basis of a large series of genetically diagnosed patients, a value of greater than 70 μg/g dry weight has been proposed as a better diagnostic threshold, although some specificity is lost.27 Hepatic parenchymal concentrations of less than 40 μg/g dry weight in a large enough sample are regarded as strong evidence against a diagnosis of Wilson disease. Liver biopsy samples must be collected without extraneous copper contamination, but in general, ordinary disposable liver biopsy needles can be used. Importantly, the sample submitted must be adequate—at least 1 cm in length. In the early stages of Wilson disease, when copper is distributed diffusely in the liver cell cytoplasm, this measurement may clearly indicate hepatic copper overload. In later stages of hepatic Wilson disease, the measurement of hepatic copper is less reliable because copper is distributed unequally in the liver (see earlier). Moreover, liver biopsy may not be safe in such patients because of coagulopathy or ascites; a transjugular biopsy may be performed, or hepatic copper measurement may be omitted. Some heterozygotes have minor elevations of liver tissue copper. An elevated hepatic copper concentration is not specific for Wilson disease; patients with chronic cholestasis or Indian childhood cirrhosis may also have elevated hepatic copper levels. Specifically, patients with multidrug resistance protein 3 (MDR3) deficiency may be misdiagnosed as having Wilson disease because of severe hepatic copper retention (see Chapter 64)55-58; genetic diagnosis is the least invasive way to distinguish the 2 diseases (see later). 

Approach In view of the numerous available diagnostic tests, a methodical approach is required. The classic patient with Wilson disease,

1185

whether displaying hepatic or neurologic findings, may be considered as someone between 6 and 40 years of age with a serum ceruloplasmin level less than 5 mg/dL ( PBG, coproporphyrin Stool: coproporphyrin

Variegate porphyria

Protoporphyrinogen oxidase

Autosomal dominant

Neurologic, cutaneous

Liver

Urine: ALA > PBG, coproporphyrin Stool: coproporphyrin, protoporphyrinogen

Autosomal recessive

Cutaneous

Bone marrow

Urine and stool: coproporphyrin I

Cutaneous Porphyrias Uroporphyrinogen III Congenital cosynthase erythropoietic porphyria Erythropoietic protoporphyria

Ferrochelatase

Various

Cutaneous, rarely neurologic

Liver, bone marrow

Stool: protoporphyrin, coproporphyrin

Hepatoerythropoietic porphyria

Uroporphyrinogen III decarboxylase

Autosomal recessive

Cutaneous

Liver, bone marrow

Urine: uroporphyrin, 7-carboxylate porphyrin Stool: isocoproporphyrin

Autosomal dominant or acquired

Cutaneous

Liver

Urine: uroporphyrin, 7-carboxylate porphyrin Stool: isocoproporphyrin

Porphyria cutanea tarda Uroporphyrinogen III decarboxylase ALA, 5-aminolevulinic acid; PBG, porphobilinogen.

The porphyrias are commonly classified according to clinical features into 2 main groups: acute porphyrias, which are due to hepatic overproduction of the porphyrin precursors and characterized by dramatic, potentially life-threatening neurologic symptoms, and cutaneous porphyrias, which result from overproduction of photosensitizing porphyrins and typically cause few or no neurologic symptoms but instead give rise to a variety of severe skin lesions (Table 77.1). In 5 of the porphyrias, the liver is the major site of expression; in 2 others, both the liver and bone marrow are involved; and in one only the bone marrow is involved.102 

Acute Porphyrias The symptoms and signs of the acute neurovisceral attacks that occur in the 4 acute porphyrias vary considerably. Abdominal pain is present in more than 90% of patients, followed in frequency by tachycardia and dark urine in about 80% of patients. Neuropsychiatric features include hysteria, depression, psychosis, confusion, hallucinations, seizures, and coma, although little evidence suggests that chronic psychiatric illness occurs. An inability to concentrate may be the initial presenting complaint.103 Other features are constipation, extremity pain, paresthesias, nausea, vomiting, urinary retention, hypertension, peripheral sensory deficits (often in a “bathing trunk” distribution), and weakness leading to ascending paralysis or quadriplegia. These neurologic attacks appear to be related to the overproduction of ALA and porphobilinogen (PBG), which leads to higher serum and tissue levels of these neurotoxic products. Acute episodes are about 5 times more common in women than men and may be precipitated by many factors, most commonly drugs, alcohol ingestion, and smoking.104 Other inciting factors are fasting, infections, and pregnancy; some women report greater problems during the luteal phase of their menstrual cycles. The disease is clinically latent in 65% to 80% of patients.

ALA dehydratase deficiency is a rare syndrome with autosomal recessive transmission in which the enzyme activity is less than 3%. The enzyme activity is 50% of normal in carriers, who are asymptomatic. Affected patients have severe, recurrent neurologic attacks that may be life threatening. They excrete large amounts of ALA in their urine. LT was reported to result in complete resolution of symptoms in one patient with ALA dehydratase deficiency.105 The 3 remaining acute porphyrias—acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), and variegate porphyria (VP)—result from partial deficiency of the enzymes PBG deaminase, coproporphyrinogen oxidase, and protoporphyrinogen oxidase, respectively. All 3 disorders are inherited in an autosomal dominant fashion with variable expression. AIP is the most common, with the prevalence of mutations in Western populations of approximately one carrier per 2000 persons, and manifests primarily as derangements in the autonomic nervous system or as a psychiatric disorder.102,106 VP is more common in South Africa than elsewhere. Although HCP and VP give rise to neurologic symptoms similar to those of AIP, cutaneous lesions also occur in HCP and predominate in VP.107 

Cutaneous Porphyrias The cutaneous porphyrias differ from the acute porphyrias in that affected patients exhibit few or no neurologic symptoms. In these illnesses, excess porphyrins or porphyrinogens are deposited in the upper dermal capillary walls, where these photoreactive compounds cause tissue damage that manifests as cutaneous vesicles and bullae in areas exposed to light or excessive mechanical manipulation. Scarring, infection, pigment changes, and hypertrichosis can follow and even lead to severe mutilation. Porphyria cutanea tarda (PCT), the most common of the porphyrias, typically involves an 80% reduction in activity of the enzyme uroporphyrinogen III decarboxylase. Patients usually

77

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present after 40 years of age. Two types of PCT are recognized. Type I PCT affects 80% of patients and is a sporadic (acquired) form in which the enzyme deficiency is restricted to the liver. Type II, which affects the other 20% of patients, is familial and inherited in an autosomal dominant fashion with incomplete penetrance; the enzyme deficiency occurs in all tissues.108 Symptoms develop in fewer than 10% of patients with type II PCT. Type I PCT is associated strongly with high alcohol intake, estrogen therapy, and systemic illnesses, including systemic lupus erythematosus, diabetes mellitus, chronic kidney disease, and HIV infection. HCV infection is also a known susceptibility factor for PCT. HCV infection, which increases oxidative stress in hepatocytes and suppresses hepcidin production, increases iron absorption from the intestine and is associated with 50% to 70% of cases of PCT in the USA.109 The frequency of mutations of the HFE gene, which causes hereditary hemochromatosis, is increased in patients with types I and II PCT, and these mutations are susceptibility factors for clinical expression of the PCT phenotype (see Chapter 75).110 Iron overload enhances oxidation of uroporphyrinogen to uroporphomethene, an inhibitor of uroporphyrinogen III decarboxylase activity, thereby explaining the association of increased oxidative stress and the unmasking of the PCT phenotype.111 This association is consistent with pathologic findings in liver biopsy specimens from patients with PCT, of whom 80% have siderosis, 15% have cirrhosis, and most have evidence of iron overload. Patients usually do not show signs of overt clinical liver disease, apart from elevated serum aminotransferase levels. Hepatoerythropoietic porphyria (HEP) is a rare form of porphyria with a pathogenesis like that of PCT. HEP results from pathogenic variants in the uroporphyrinogen III decarboxylase gene with resulting uroporphyrinogen III decarboxylase deficiency, yielding less than 10% of normal enzyme activity. The cutaneous lesions, which resemble those of PCT and are characterized by blistering skin lesions, hypertrichosis, and scarring, are typically severe and mutilating. The disease usually manifests in the first year of life. As the patient ages, the dermatologic manifestations may subside, but liver disease, characterized by a nonspecific hepatitis, worsens.112 Congenital erythropoietic porphyria (CEP) is a rare form of porphyria with autosomal recessive transmission that is caused by deficiency of uroporphyrinogen III cosynthase, which mainly affects erythropoietic tissue. Patients typically present in the first year of life with blisters and disfiguring skin lesions in exposed areas and may present with pink urine and photosensitivity. As patients age, erythrodontia, a pathognomonic red or brownish discoloration of the teeth, is commonly seen. CEP can be distinguished clinically from HEP by the presence in some cases of a Coombs-negative hemolytic anemia, which can be quite severe. Splenomegaly is common. Gain-of-function mutations in the ALA synthase 2 (ALAS2) gene in patients with CEP suggest that ALAS2 is a modifier gene for CEP disease by increasing the flux of ALA production.113 Erythropoietic protoporphyria (EPP) is caused by partial deficiency of the enzyme ferrochelatase, the final step in the heme synthetic pathway. EPP is the second most common type of porphyria and has been thought to be inherited in an autosomal recessive manner.114,115 Although the bone marrow is the predominant source of excess protoporphyrin, with a variable contribution from the liver and other tissues, the skin is the primary site of deposition of this phototoxic compound in patients with EPP. Therefore, the principal clinical manifestation is exquisite photosensitivity, which may present during infancy and can lead to a wide spectrum of symptoms (e.g., itching, burning, pain) and to scars and lichenification of the skin. Vesicles are rare. Patients with EPP may have a mild hypochromic, microcytic anemia.114 Clinical liver disease, reported in the patient’s medical history or determined by elevated serum aminotransferase levels, has been reported in up to 33% of patients with EPP and results

from progressive hepatic accumulation of protoporphyrin.114,116 Liver disease typically occurs after age 30 but has been described in children. The liver appears black and nodular, with hepatocellular necrosis, portal inflammation, cholestasis, and extensive deposits of dark brown pigment in hepatocytes, Kupffer cells, and biliary structures; birefringence of pigment deposits is seen on polarization microscopy.117 Biochemically, total erythrocyte protoporphyrin (ePPIX) levels can be measured. Increased levels have been shown to be a significant determinant of disease severity and liver dysfunction. Patients with higher ePPIX levels (>2000 μg/dL) should be monitored more closely for evidence of liver disease.114 

Hepatic Involvement Hepatic involvement in porphyria is variable; in general, patients with acute porphyria may have elevated serum aminotransferase and bile acid levels, with further increases during acute episodes. Liver biopsy specimens may show steatosis and iron deposition. Although these changes are minor, patients with acute porphyria are at increased risk for the development of primary liver cancers.118 

Diagnosis The approach to the diagnosis of the porphyrias is summarized in Table 77.1. Clinical features alone are usually not specific enough to confirm a diagnosis or distinguish among the various forms of porphyrias. The diagnosis of porphyria should be considered in patients with recurrent bouts of severe abdominal pain, dark urine, constipation, and neuropsychiatric disturbances or in patients with typical dermatologic findings. To differentiate among the different porphyrias, urine and stool samples should be obtained for porphyrin studies and a urine specimen collected for quantitative ALA and PBG determinations. In AIP, elevated PBG levels in urine or plasma are specific, reaching up to 150 times the upper limit of normal during an acute flare.102 Patients with HCP and VP excrete high levels of ALA and PBG in the urine; in contrast to those with AIP, these patients excrete more ALA than PGB. A “spot” urine test to detect urinary PBG is recommended to diagnose the acute porphyrias, except for the rare patient with ALA dehydratase deficiency.119 Fecal coproporphyrins are increased in both HCP and VP, whereas only in VP is the amount of fecal protoporphyrin also increased. Once a diagnosis of porphyria is biochemically confirmed, gene sequencing should be performed.120 Many gene mutations have been identified for several acute porphyrias, including AIP, VP, and HCP. Specific gene sequencing can be performed in the setting of a specific biochemical profile, and when results are incomplete or not definitive, multigene panels are available.120 Given the high degree of genetic heterogeneity, the lack of clear genotype-phenotype correlations, and the failure to find mutations in 5% to 10% of families with available techniques, genetic testing is not recommended as a general screening tool.108,120 If an index case of porphyria is identified, screening of asympto­ matic family members, together with appropriate genetic counseling, may be helpful. 

Treatment The overall survival of patients with acute porphyria is good. Consensus guidelines for the treatment of acute porphyria attacks are available.119,121 Generous fluid and glucose administration (preferably 10% dextrose in 0.45% saline) is recommended during acute attacks and can elicit the “glucose effect” that diminishes ALA synthase activity. Antiemetic agents, analgesic agents, and, if indicated, antiseizure medications are administered.102 IV

CHAPTER 77  Other Inherited Metabolic Disorders of the Liver

administration of hematin, a congener of heme, is the only current specific treatment for acute attacks. The medicine is generally effective at a dose of 3 to 4 mg/kg given once per day, with a notable decrease in PBG levels by day 3 of treatment. Resolution of pain and nausea typically follows, and patients can be discharged once weaned from narcotics and tolerating oral intake.102 Notably, hematin has several shortcomings, including instability in solution, the need for rapid infusion following constitution, the requirement for use of a large vein or central catheter for administration, negative effects on platelet function and coagulation, and the potential for hepatic iron buildup, with resulting iron overload-induced injury.102 Therefore, alternatives to the use of IV hematin are being developed. Both viral vector gene therapy and small interfering RNA approaches are under investigation. Small studies in humans have been performed with each approach. A pilot investigation using viral gene therapy demonstrated the therapy to be well tolerated from a safety perspective, but no effect on levels of ALA or PBG was seen following delivery of a normal hydroxymethylbilane synthase gene.122 A phase 1 study of small interfering RNA therapy directed against ALA synthase 1, which aimed to reduce production of ALA, demonstrated decreased expression of ALA synthase 1 within 24 hours and lasting for at least 1 month.102 Future efforts to determine the efficacy in patients with recurrent acute attacks may enable improved clinical management for patients with these devastating diseases. Recommendations for the long-term management of acute hepatic porphyrias are also available.120 A baseline physical examination, including complete dermatologic and neurologic assessments, and laboratory testing should be performed. Iron deficiency, not related to the porphyria, is common and should be treated when present, because it can contribute to chronic symptoms.123 Patients should be monitored for the development of porphyria-related nephropathy, typically manifest as chronic tubulointerstitial nephropathy or focal cortical atrophy.124-126 Important in the overall management of patients with porphyria is the identification, with subsequent avoidance or elimination, of precipitating factors that can trigger or worsen an acute attack. Particular attention should be paid to medications that have been demonstrated to be unsafe or risky in patients with porphyria, and publicly available drug databases are available (http://www. porphyriafoundation.com/drug-database, http://www.drugsporphyria.org/). LT has been successful in patients with severe, intractable disease that has not responded to more traditional therapeutic approaches. Because of the associated increase in morbidity and mortality and because of the risk of reaccumulation of toxic metabolites in the graft, LT should be considered a treatment of last resort.120,127-130 Because of the increased frequency of HCC, patients with AIP with recurrent attacks or past symptoms should undergo surveillance liver imaging at 6- to 12-month intervals after age 50 (see Chapter 96).120 Patients with AP and advanced renal disease tolerate and benefit from renal transplantation. Some patients with both repeated attacks and end-stage renal disease have undergone combined liver-kidney transplantation.131 The dermatologic sequelae of porphyrias are best managed with sunlight avoidance. The wavelengths of light that excite the porphyrins (410 nm) are common to many light sources, and patients affected by porphyria are at risk from exposure not only to sunlight, but also to household and fluorescent lights. Furthermore, because this wavelength passes through window glass, patients are also sensitive to indoor sunlight. Patients must therefore use special sunscreen lotions that block rays in the 400to 410-nm range. Skin trauma should be minimized as much as possible; early treatment of skin infections can decrease scarring. Special screens may be especially useful for protection against indoor lighting. Some patients have incurred severe or lethal internal burns during surgery, including LT; therefore, appropriate precautions must be taken.102,132

1199

Treatment of PCT initially consists of removal of any offending agent. Historically, treatment has included phlebotomy to decrease iron overload and hepatic siderosis. This approach, combined with restriction of alcohol, tobacco, and estrogen, has been shown to produce remission.102 In patients who cannot tolerate or who have adverse reactions to phlebotomy, chelation therapy has demonstrated some efficacy.133 An alternative to iron depletion therapy is chloroquine, which complexes within hepatocytes to mobilize porphyrins to facilitate its urinary excretion, but the drug is potentially hepatotoxic and caution is indicated in patients with cirrhosis or renal insufficiency.134 The efficacy of chloroquine has been variable in patients with PCT who are homozygous for mutations in the HFE gene; for these patients, phlebotomy should be first-line therapy.102 Importantly, two thirds of patients with PCT have HCV coinfection and reports have suggested that eradication of HCV can lead to resolution of the skin manifestations of PCT.135 Treatment strategies for HEP are similar to, but have not been as successful as, those for PCT. Several therapeutic interventions have been reported to lead to varying degrees of clinical improvement in patients with EPP, but long-term resolution has not been demonstrated. Based on the observation that skin-related symptoms are inversely related to skin pigmentation, agents such as oral β-carotene have been suggested to improve sunlight intolerance; however, systemic reviews have found insufficient evidence to confirm efficacy.136 Newer agents such as afamelanotide, a congener of α-melanocyte-stimulating hormone, which increases production of eumelanin to darken the skin, has shown benefit in phase 3 controlled studies.137,138 LT has been carried out in patients with EPP and ESLD with mixed results, as the erythropoietic defect persists and the allograft remains at risk for EPP-related damage.139,140 A retrospective review of all 20 patients with EPP who have undergone LT in the USA revealed unique perioperative complications, including light-induced tissue damage in 4 patients and neuropathy in 6, as well as recurrent EPP-associated liver disease in 65% of patients who survived more than 2 months. Overall patient and graft survival rates were statistically similar to those for all other patients transplanted in the USA during the same period.141 Similar results were reported in a European study of 34 liver transplant recipients with EPPassociated liver disease.140 Therefore, LT must be considered symptomatic therapy, except in patients with ALF, given the high risk of recurrent disease in the graft and the added risk of intraoperative photodynamic injury to internal organs. Hematopoietic stem cell transplantation, which can correct the underlying enzymatic defect, performed after LT has been reported to be successful in both children and adults with EPP-induced ESLD.142,143 

TYROSINEMIA Four known human diseases are caused by enzymatic deficiencies in the catabolic pathway for the amino acid tyrosine: alkaptonuria and hereditary tyrosinemia (HT) types I, II, and III. Although all the enzymes involved in this pathway are found in the liver, only HT-1 leads to progressive liver dysfunction. Formerly known as hepatorenal tyrosinemia, HT-1 also affects other organ systems, in particular the kidneys and peripheral nerves. A disease with autosomal recessive transmission, HT-1 has a worldwide incidence of about 1 in 100,000. The incidence is higher in northern Europe (1 per 8000) and in the SaguenayLac-St. Jean region of Quebec, Canada (1 per 1846), where a founder effect has been documented.144 Advances in our understanding of the pathophysiology of the disease process and new treatment options, such as an inhibitor of an early step in the degradation pathway, have improved the clinical course of affected persons dramatically.

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PART IX  Liver

Pathophysiology The pathway for tyrosine metabolism is shown in Fig. 77.5. The enzymatic defect in patients with tyrosinemia has been identified in fumarylacetoacetate hydrolase (FAH), the final step in the tyrosine degradation process. More than 100 mutations in FAH have been found in patients with HT-1, but no clear correlation between FAH genotype and HT-1 phenotype has been appreciated.145 FAH deficiency leads to accumulation of the upstream metabolites fumarylacetoacetate (FAA) and maleylacetoacetate, which are then converted to the toxic intermediates succinylacetoacetate (SAA) and succinylacetone (SA). FAA has been shown to deplete blood and liver of glutathione, the consequence of which may be augmentation of the mutagenic potential of FAA. SA inhibits renal glucose and amino acid transport and the degradation of ALA to PBG, probably via direct modification of amino acids in enzyme active sites. SA also inhibits DNA ligase activity in fibroblasts isolated from patients with HT-1.146 Over time, the combined effects of high levels of FAA and SA on the integrity of DNA and cellular repair mechanisms may account for increased chromosomal breakage in fibroblasts isolated from patients with HT-1, as well as an increased risk of HCC.147 

Clinical and Pathologic Features Patients with HT-1 present either acutely with liver failure or with chronic liver disease, with or without HCC. In the acute form of HT-1, patients manifest liver disease in the first 6 months of life; symptoms include those associated with severe hepatic synthetic dysfunction, such as hypoglycemia, ascites, jaundice, and coagulopathy, as well as anorexia, vomiting, and irritability. Laboratory studies show elevations of serum aminotransferase, GGTP, and bilirubin levels and decreased levels of coagulation factors. Serum tyrosine, methionine, and AFP levels are elevated. Analysis of the urine may reveal phosphaturia, glucosuria, hyperaminoaciduria, renal acidosis, and increased excretion of SA, SAA, ALA, and phenolic acids. The acute form of HT-1 is potentially fatal within the first 2 years of life. In a multicenter study, van Spronsen and associates showed that 77% of patients with tyrosinemia presented before the age of 6 months. The 1- and 2-year survival rates were 38% and 29%, respectively, if patients presented between birth and 2 months of age, and 74% and 74%, respectively, if they presented between 2 and 6 months. Survival for both time intervals rose to 96% if the first symptoms appeared after age 6 months. The cause of death was usually recurrent bleeding and liver failure; however, HCC and neurologic crisis accounted for some deaths.148 Patients with the chronic form of HT-1 classically have symptoms that are similar to, but milder than, those with an acute presentation; serum aminotransferase levels as well as plasma tyrosine and methionine levels may be within the normal range. These patients usually present after one year of age with hepatomegaly, rickets, nephromegaly, hypertension, and growth retardation. They also are likely to have neurologic problems and to develop HCC. The pathologic changes in the liver differ between the acute and chronic forms of the disease. In the acute form, the liver may appear enlarged with a pale nodular pattern or may be shrunken, firm, and brown. Micronodular cirrhosis, fibrotic septa, bile duct proliferation and plugging, steatosis, pseudoacinar and nodular formations, and giant cell transformation may be found on histologic examination. Varying amounts of FAH enzyme activity have been found in liver tissue from patients with HT-1 because of spontaneous reversion of FAH gene mutations. Patients with the chronic form of the disease have a higher level of reversion and a lower frequency of liver dysplasia.148 In the chronic form of tyrosinemia, the liver appears enlarged, coarse, and nodular. In histologic specimens, micronodular and macronodular cirrhosis may be present, as may steatosis, fibrotic

septa, and a mild lymphoplasmacytic infiltrate. Cholestasis is less pronounced than in the acute form of HT-1. Large- or smallcell dysplasia may be present, reflecting premalignant changes. Because of the nodular changes, identification of progression to HCC can be difficult. The serum AFP value is elevated before HCC develops, and measurement of AFP is not helpful in the diagnosis. Imaging is required to screen for HCC. Renal involvement is nearly universal in patients with tyrosinemia. Findings include a decreased GFR, proximal renal tubular dysfunction, nephromegaly, phosphaturia (which is responsible for the development of rickets), glucosuria, and aminoaciduria. The toxic metabolites SA and SAA are thought to have a direct effect on kidney function. Some patients progress to renal failure and require renal transplantation.149 One third of patients develop cardiomyopathy, most commonly interventricular septal hypertrophy, which is reversible with either medical or surgical management of the disease.150 The neurologic manifestations may be the most concerning feature in older patients with tyrosinemia; affected patients may experience porphyria-like symptoms with neurologic crises.151 Further complications include delayed neurodevelopment and attention deficit disorders, which have been reported to occur despite early diagnosis and treatment.152,153 

Diagnosis Diagnosis and treatment recommendations are available.154 The diagnosis of tyrosinemia should be suspected in any child with neonatal liver disease or a bleeding diathesis or in any child older than one year with undiagnosed liver disease, rickets, or a hepatic mass. The diagnosis is suggested by increased serum tyrosine, methionine, phenylalanine, and AFP levels. Elevated serum and urine SA and urine ALA levels are regarded as pathognomonic for tyrosinemia. The diagnosis can be confirmed with an assay for FAH in lymphocytes, erythrocytes, skin fibroblasts, or liver tissue. Molecular genetic approaches and targeted mutation analysis are becoming more widely available and are recommended, if possible, for all cases in which SA elevations are detected on newborn screening. Prenatal diagnosis can be performed by determining SA levels in amniotic fluid or by measuring FAH activity in chorionic villus biopsy specimens. If the specific gene mutation in a family is known, early genetic diagnosis can be made from chorionic villus biopsy specimens as well.155 Improved newborn screening methodologies measure SA in addition to amino acid levels in dried blood specimens. HT-1 is included in both the Secretary of Health and Human Services’ Recommended Uniform Screening Panel and the American College of Medical Genetics and Genomics core panel of conditions for which every newborn in the USA should be screened.154,156 

Treatment In 1992, Lindstedt and associates published data on the treatment of tyrosinemia with the herbicide 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC).157 Later, Holme and Lindstedt published the results of a large, long-term study of 220 patients with HT-1 who were treated with this agent for up to 7 years.158 NTBC, known as nitisinone (Orfadin), is a potent inhibitor of 4-hydroxyphenylpyruvate dioxygenase, one of the initial steps in tyrosine metabolism (Fig. 77.6). Blocking the degradation of tyrosine to its downstream toxic metabolites (FAA, SA, and SAA) was postulated to lead to improved hepatic function. Treated patients exhibited improved liver synthetic function, as reflected by a shortening of the prothrombin time, as well as decreased serum aminotransferase levels and a reduction in liver parenchymal heterogeneity and nodules on imaging. In addition, serum AFP and ALA levels decreased and renal

CHAPTER 77  Other Inherited Metabolic Disorders of the Liver

with serious liver injury, the basic genetic defect is located within the liver, and the manifestations can mimic those of other metabolic liver diseases.

Phenylalanine Phenylalanine hydroxylase Tyrosine

Pathophysiology

Tyrosine aminotransferase p-Hydroxyphenylpyruvate p-Hydroxyphenylpyruvate dioxygenase

NTBC

Homogentisate Homogentisate oxidase Maleylacetoacetate Maleylacetoacetate isomerase Fumarylacetoacetate Fumarylacetoacetate hydrolase

1201

Succinylacetoacetate + Succinylacetone

HT-1

Fumarate + Acetoacetate Fig. 77.6  Pathway of tyrosine metabolism.  The location of the enzymatic defect in hereditary tyrosinemia type I (HT-1) and the site of action of 2-(2-nitro-4-trifluoro-methylbenzoyl)-1,3-cyclohexanedione (NTBC) are shown. Enzymes are shown in italics.

tubular dysfunction reversed.159 Therefore, elevated AFP levels in a patient receiving NTBC therapy should raise concern about the patient’s nonadherence to therapy or the development of HCC.160 Long-term results have demonstrated continued improvement in all parameters noted in the earlier reports, as well as a reduction in the need for LT.161 Cognitive impairment resulting in learning problems may be a complication of long-term use of NTBC in this patient population, possibly from the effects of chronic hypertyrosinemia.162 NTBC should be started as soon as the diagnosis of HT-1 is suspected, starting at 1 mg/kg/day. The total calculated amount of NTBC should be divided into 2 doses daily in the first year of life. Thereafter, single daily dosing can be considered.154 Use of NTBC requires careful clinical and biochemical monitoring. A rapid liquid chromatography coupled with negative electrospray ionization tandem mass spectrometry method has been developed and validated for the quantification of NTBC in heparinized human plasma.163 The minimum dose of NTBC should be used to achieve a blood concentration of 40 to 60 μmol/L and/or blood SA level within the normal range of the reference laboratory.154 LT retains a role in the management of HT-1 in patients with malignancy or decompensated liver disease refractory to NTBC or in those for whom NTBC is not available.154 When indicated, LT provides a metabolic cure. A review of 125 patients with HT-1 in the UNOS database who were transplanted before 2008 showed 1- and 5-year survival rates of 90.4%.164 

UREA CYCLE DEFECTS The urea cycle consists of 5 enzymes that, through several steps, process ammonia derived from amino acid metabolism to urea. Genetic defects in each of these enzymes have been reported, and their overall incidence has been estimated to be 1 in 35,000 births, although partial defects may make the number much higher.165 Although the syndromes related to the UCDs are not associated

The steps of the urea cycle are illustrated in Fig. 77.7. Carbamyl phosphate synthetase (CPS) I forms carbamyl phosphate from ammonium and bicarbonate. This step requires the cofactor N-acetyl glutamate, which is synthesized from N-acetyl CoA and glutamic acid by N-acetyl glutamate synthetase. Ornithine transcarbamylase (OTC) combines carbamyl phosphate with ornithine to form citrulline. A second nitrogen enters the cycle as aspartate, which combines with citrulline by the action of argininosuccinate synthetase (AS) to form argininosuccinate, which is then converted to arginine and fumarate by argininosuccinase, or argininosuccinate lyase (AL). Arginase then catalyzes the breakdown of arginine to urea and ornithine in the final step of the pathway. Several amino acid transporters, such as citrin, an aspartate/glutamate carrier protein that supplies aspartate to the urea cycle, are involved in shuttling metabolites into the urea cycle.166 CPS II, through the pyrimidine synthetic pathway, leads to the formation of orotic acid. Excess carbamyl phosphate can be used by this pathway if a block occurs distal to OTC in the metabolic pathway. Excess nitrogen in the form of amino acids can be shunted to alternative pathways of waste-nitrogen excretion by the medicinal use of sodium benzoate and sodium phenylacetate, leading to the generation of hippurate and phenylacetylglutamine, respectively. Enzymatic defects have been identified in all 5 steps of the urea cycle. Deficiency of 4 of the enzymes is transmitted through autosomal recessive inheritance, whereas OTC deficiency is transmitted as an X-linked trait. More than 417 different mutations in the OTC gene give rise to OTC deficiency, the most common UCD.167 Numerous defects in the other enzymes or amino acid transporters of the cycle (e.g., N-acetylglutamate synthetase, citrin) have been characterized as well.165 Moreover, numerous mRNA instability mutations have been found in patients with CPS I deficiency.168 A UCD has 2 main biochemical consequences: Arginine becomes an essential amino acid (except in arginase deficiency [see later]), and nitrogen accumulates in a variety of molecules, some of which can have deleterious toxic effects. 

Clinical Features The spectra of clinical presentations in patients with any of the UCDs are virtually identical; in the neonatal period, these disorders classically manifest as acute life-threatening events. Later presentations (>30 days) have been reported in up to two thirds of patients,169,170 and late-onset adult presentations have been reported in cases associated with an illness or dietary change171,172 or with psychiatric symptoms, which may be the initial presenting feature.173 With the neonatal presentation, affected infants appear normal for the first 24 to 72 hours until they are exposed to their first feeding, which provides the initial protein load that fosters ammonia production. Symptoms include irritability, poor feeding, vomiting, lethargy, hypotonia, seizures, coma, and hyperventilation, all secondary to hyperammonemia.174 Initially, neonates may be mistakenly thought to have sepsis, despite the absence of perinatal risk factors, and thus diagnostic laboratory testing can be delayed.175 Plasma ammonia levels should be obtained whenever an evaluation for sepsis is initiated in a neonate; levels may exceed 2000 μmol/L (3400 mg/dL), with normal levels of 50 μmol/L (85 mg/dL) or less. For all age groups, overall survival decreases as the peak plasma ammonia level rises for a given episode of hyperammonemia, with survival rates of 98% and 47% for peak ammonia

77

1202

PART IX  Liver +

NH 4 Glycine

Glutamine

+

+

Benzoate

Phenylbutyrate

HCO 3

–

Carbamyl phosphate synthetase Carbamyl phosphate Orotic acid

Hippurate

Ornithine transcarbamylase

Phenylacetylglutamine Ornithine

Citrulline Aspartate Argininosuccinate synthetase

Urea

Urine

Arginase Arginine

Argininosuccinate

Argininosuccinase Fumarate

levels of less than 200 μmol/L and greater than 1000 μmol/L, respectively.176 Newborns have a survival rate of 73% after their presenting episode of hyperammonemia, whereas patients older than 30 days of age have a survival rate of 98%. Male patients with OTC deficiency have a survival rate of 91% following an episode of hyperammonemia, a rate significantly less than those (93% to 98%) of all other forms of UCDs. Blood gas analysis shows respiratory alkalosis secondary to the hyperventilation caused by the effects of ammonia on the central nervous system. Blood urea nitrogen levels are typically low but can be elevated during times of dehydration or hypoperfusion. Serum levels of liver enzymes are usually normal or minimally elevated, although ALF, reflected in severe coagulopathy not corrected by vitamin K, has been reported in up to 50% of patients.176,177 OTC deficiency is the most common UCD (57% to 62%), followed by argininosuccinic aciduria (AL deficiency, 11.5% to 18%) and citrullinemia (AS deficiency, 13% to 19%).178 Male patients with OTC deficiency have been diagnosed as late as 40 years of age with varied phenotypic presentations. As many as 20% of female carriers of OTC deficiency can have symptoms, which may be severe and fatal, although most female carriers have no symptoms or report only nausea after high-protein meals.167 Late-onset CPS deficiency has also been described,173 and the adult form of AS deficiency is relatively common in Japan.179 Symptoms and signs of late-onset UCDs, especially OTC and CPS deficiencies, include episodic irritability, lethargy, or vomiting; self-induced avoidance of protein such as milk, eggs, and meats; and short stature or growth delays. Neurologic symptoms, which can also be episodic, include ataxia, developmental delays, behavioral abnormalities, combativeness, biting, confusion, hallucinations, headaches, dizziness, visual impairment, diplopia, anorexia, and seizures. Acute hyperammonemic episodes can resemble Reye syndrome (see Chapter 88). Such episodes can be

Fig. 77.7  The urea cycle.  Alternative pathways that are used therapeutically for waste nitrogen disposal are also illustrated (dotted lines). Enzymes are shown in italics.

precipitated by high-protein meals, viral or bacterial infections, medications, trauma, or surgery. Infants may present after being weaned from breast milk to infant formulas, which have a higher protein content. Female adult-onset UCD, such as OTC and CPS deficiencies, have been reported to occur during pregnancy and in the postpartum periods secondary to increased physiologic stress and comorbidities such as hyperemesis gravidum.180,181 Citrin deficiency, caused by mutations in the SLC25A13 gene, can manifest in newborns as neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), in older children as failure to thrive and dyslipidemia caused by citrin deficiency, and in adults as recurrent hyperammonemia and neuropsychiatric symptoms in citrullinemia type II (CTLN2).182 NICCD is associated with a history of low birth weight with growth restriction and transient intrahepatic cholestasis, hepatomegaly, diffuse fatty liver, and parenchymal cellular infiltration associated with hepatic fibrosis, variable liver dysfunction, hypoproteinemia, decreased coagulation factors, hemolytic anemia, and/or hypoglycemia.182 Biochemically, NICCD has been shown to have significantly different indices from children with biliary atresia or idiopathic neonatal cholestasis with higher serum bile acid levels, lower aminotransferase levels, and lower direct bilirubin levels compared with disease controls.183 Other specific findings include increases in blood or plasma concentration of ammonia, plasma or serum concentration of citrulline and arginine, plasma or serum threonine-to-serine ratio, and serum concentration of pancreatic secretory trypsin inhibitor.182 In most patients with NICCD, all biochemical abnormalities resolve spontaneously or with minimal dietary restrictions (e.g., the use of lactosefree formulas); however, several affected infants have required LT before one year of age. Therefore, jaundiced infants with multiple abnormal newborn metabolic screen results must be observed closely because of the risk for development of ESLD

D o w n l o a d e d f o r R e d d y S a n d e e p ( v a n k i m t h a n h @ y o p m a i l . c o m ) a F o r p e r s o n a l u s e o n l y . N o o t h e r u s e s w i t h o u t p e r m i s s i o

CHAPTER 77  Other Inherited Metabolic Disorders of the Liver

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TABLE 77.2  Laboratory Values in Urea Cycle Defects Enzyme Deficiency

Ammonia (Plasma)

Citrulline (Serum)

Argininosuccinate (Urine or Serum)

Orotic Acid (Urine)

Arginine/Ornithine (Serum)

Carbamyl phosphate synthetase

↑-↑↑↑

↓

↓

↓

↓

Ornithine transcarbamylase

↑-↑↑↑

↓

↓

↑↑

↓

Argininosuccinate synthetase

↑-↑↑↑

↑↑↑

↓

Normal-↑

↓

Argininosuccinase

↑-↑↑↑

↑↑↑

↑↑↑

Normal-↑

↓

Arginase

↑

↑↑

↑↑

Normal-↑

↑↑

caused by NICCD; a chubby face outside the realm of normal may be a diagnostic clue.184 The diagnosis can be made by sequence analysis of the SLC25A13 gene.

Diagnosis Suggested guidelines for the diagnosis and management of the UCDs are available.174 Ultimately, a high index of suspicion is required for prompt diagnosis of UCDs. Symptoms can mimic those of other acute neonatal problems, such as infections, seizures, and pulmonary or cardiac disease. Later presentations can mimic other behavioral, psychiatric, or developmental disorders. The first clue may be an elevated serum ammonia level with near normal serum aminotransferase levels and without metabolic acidosis. Therefore, if a UCD is considered, the following laboratory measurements should be obtained: serum ammonia, arterial blood gases, urine organic acids, serum amino acids, and urinary orotic acid; Table 77.2 reviews the expected results. Urinary organic acid profiles are typically normal in patients with UCDs; however, the plasma amino acid profiles are distinctive, with abnormal levels of arginine, ornithine, and citrulline. Citrulline levels are barely detectable in OTC or CPS deficiencies but markedly raised in AS and AL deficiencies. AL deficiency can be distinguished from AS deficiency by the finding of argininosuccinic acid in the plasma and urine. OTC deficiency is differentiated from CPS deficiency by excessive urinary excretion of orotic acid. Direct enzyme analysis can be performed and can be useful in patients who have a partial deficiency or who present in adulthood. Early neonatal diagnosis leads to improved survival, so prenatal enzyme and genetic linkage analysis can be carried out in family members of known carriers to aid in early diagnosis.185 

Treatment All external protein intake should be discontinued in infants presenting acutely with a suspected or confirmed UCD. An attempt should be made to restore serum ammonia levels to normal. The use of oral lactulose to lower the nitrogen load has not been studied in this patient population. Given the extremely high ammonia levels often encountered, continuous arteriovenous hemodialysis or hemofiltration is frequently required. Exchange transfusions and peritoneal dialysis are ineffective. Alternative pathways for waste nitrogen disposal should be used, specifically IV administration of sodium benzoate and sodium phenylacetate; however, sodium benzoate should be used with caution in patients with cirrhosis, because a paradoxical rise in blood ammonia levels has been observed.186 Oral phenylbutyrate can be substituted for phenylacetate to improve palatability. Arginine, carnitine, and long-chain fatty acids are usually present in low levels in these patients and should be supplemented.174,187 Low-dose arginine (100 mg/kg/day) together with an ammonia scavenger is effective in repleting arginine

stores, maintaining low ammonia levels, and minimizing liver enzyme elevations compared with high-dose arginine (500 mg/ kg/day), although consensus guidelines recommend an intermediate dose of arginine (250 mg/kg/day).174,188 Once the patient stabilizes, low levels of dietary protein, 0.5 to 1 g/kg, may be introduced, with progressive increases as tolerated to provide sufficient protein for growth and tissue repair while minimizing urea production. Further therapy and protein restriction are then tailored to the patient; those with a severe disorder may need essential amino acids to supplement their protein intake. Long-term dietary treatment for UCD has been shown to vary significantly among conditions and centers. Further studies examining the outcome of treatment compared with the type of dietary therapy and nutritional support received are needed.189,190 The outcome for patients who present with hyperammonemic coma and a delayed diagnosis is poor.176 The level of ammonia at the time of the first hyperammonemic episode is a rough guide to the eventual neurodevelopmental outcome.191 The sooner the hyperammonemia is treated and the correct diagnosis is made, the better the long-term survival; however, for patients who survive the neonatal period, there remains a high risk of recurrence of severe hyperammonemic crises, often during intercurrent viral infections, which correspond to a high mortality rate.192 Patients with a UCD and deterioration or lack of improvement despite therapy have undergone either orthotopic or auxiliary LT successfully (see Chapter 97), with normalization of enzyme activity and ammonia levels, restored ability to tolerate a normal diet, and survival rates of 93%, 89%, and 87% at 1, 5, and 10 years, respectively.193 LT, if considered, should i­deally be done before neurologic damage is permanent, because the patient’s neurologic status is not thought to improve after transplantation. A possible exception to this is in patients transplanted before the age of one year, in whom developmental, and possible neurocognitive, outcomes may improve.194,195 Hepatocyte transplantation has demonstrated some success in patients with UCDs; however, metabolic cure has not been achieved.196,197 The importance of identifying the deleterious mutation in a patient with a UCD will likely become increasingly important not only as a means of allowing carrier testing and prenatal diagnosis, but also as an aid to treatment decisions. For example, patients with a mutation that results in the most severe OTC deficiency (e.g., abolished enzyme activity) may benefit preferentially from immediate LT to prevent severe mental retardation or death, whereas those with a mutation that leads to milder disease may be better managed medically with dietary restrictions and ammonia scavengers to facilitate growth before possible LT. Although the use of gene therapy has an ominous history with the UCDs,198 its use may need to be reconsidered in the future as success in correcting the underlying metabolic abnormalities has been demonstrated in knock-out mice.199 

77

1204

PART IX  Liver

Arginase Deficiency

TABLE 77.3  Inborn Errors of Bile Acid Synthesis and Transport

At least 2 forms of arginase activity occur in humans. Arginase I predominates in the liver and red blood cells, and arginase II is found predominantly in kidney and prostate. Arginase deficiency involving arginase I is the least common of the UCDs. Hyperammonemia is unusual in affected persons, but hyperammonemic coma and death have been reported.200 Clinical features are distinct from those of the other UCDs. The disease is characterized by indolent deterioration of the cerebral cortex and pyramidal tracts, leading to progressive dementia and psychomotor retardation, spastic diplegia progressing to quadriplegia, seizures, and growth failure. The syndrome is often confused with cerebral palsy.201 Laboratory studies may reveal elevated blood arginine values, mild hyperammonemia, and a mild increase in urine orotic acid excretion. Many guanidine compounds may accumulate in the blood and cerebrospinal fluid of these patients, which could play an important pathophysiologic role, and guanidinoacetate, a well-known potent epileptogenic compound, has demonstrated usefulness as a target for the therapeutic monitoring of patients with arginase deficiency.202 Varying amounts of urea are still produced in these patients secondary to the compensatory elevated expression of arginase II in the kidneys that ameliorates the clinical disorder. The diagnosis is confirmed by enzymatic analysis, which can be performed prenatally on cord blood samples. Treatment consists of protein restriction and, when needed, sodium phenylbutyrate.203 

Defects in Bile Acid Synthesis Alterations of the enzymes involved in modification of the steroid ring

BILE ACID SYNTHESIS AND TRANSPORT DEFECTS The pathways for bile acid synthesis and the mechanism of bile acid transport within the hepatobiliary system are complex, involving several enzymes and regulated transport processes located in multiple subcellular fractions of the hepatocyte (see Chapter 64). With advances in molecular biology, genetics, and mass spectrometry, several different inborn errors in bile acid synthesis and transport have been identified as causes of clinical disease.204 The classification of these disorders has been clarified, particularly in the clinically heterogeneous subset of cases that comprise progressive familial intrahepatic cholestasis (PFIC) syndromes. For some of the disorders, this progress has led to improved diagnosis and life-saving therapy. PFIC refers to a heterogeneous group of autosomal-recessive disorders that disrupt bile formation and present with cholestasis of hepatocellular origin. Historically, the diagnosis of PFIC has been imprecise; broad criteria have included the presence of chronic, unremitting intrahepatic cholestasis, exclusion of identifiable metabolic or anatomic disorders, and characteristic clinical, biochemical, and histologic features.205 Other symptoms and signs are severe pruritus, hepatomegaly, wheezing and cough, short stature, delayed sexual development, fat-soluble vitamin deficiency, and cholelithiasis. Affected persons exhibit severe and progressive intrahepatic cholestasis, usually manifesting within the first few months of life and often proceeding to cirrhosis and ESLD by the second decade of life. Specific types of PFIC due to defective bile acid synthesis or transport have been identified, and each is associated with mutations in enzymes or hepatocellular transport-system genes involved in bile formation. With the discovery of these specific defects and the development of sophisticated biochemical and molecular methodology and gene mutation analysis, precise characterization is now possible using techniques such as mass spectrometry, multigene cholestasis panels, and DNA sequencing by capillary electrophoresis. These complementary tests allow rapid, sensitive, and cost-effective bile acid profiling and mutation screening to aid clinical diagnosis in patients with intrahepatic cholestasis. Patients believed previously to have

3β-hydroxy-Δ5-C27-steroid oxidoreductase deficiency (HSD3B7) Δ4-3-oxosteroid 5β-reductase deficiency (AKR1D1) Oxysterol 7α-hydroxylase deficiency (CYP7B1) Cholesterol 7α-hydroxylase deficiency (CYP7A1) 12α-hydroxylase deficiency (CYP8B1)

Alterations of the enzymes involved in modification of the side chain

CTX-sterol 27-hydroxylase deficiency (CYP27A1) 2-methylacyl-CoA racemase deficiency (AMACAR) Bile acid–CoA: amino acid N-acyltransferase deficiency (BAAT) Bile acid–CoA ligase deficiency (BACL; SLC27A5) Sterol 25-hydroxylase deficiency (CH25H)

Organelle or cell injury

Peroxisomal biogenesis disorders Zellweger syndrome Neonatal adrenoleukodystrophy Infantile Refsum disease Rhizomelic chondrodysplasia punctata Disorders with loss of a single peroxisomal function Generalized hepatic synthetic dysfunction ALF (multiple causes) Neonatal iron storage disease Tyrosinemia Disorders of cholesterol metabolism Smith-Lemli-Opitz syndrome (DHCR7)

Defects in Bile Acid or Phospholipid Transport PFIC type I: FIC1 deficiency (ATP8B1, or FIC1) Byler disease Benign recurrent intrahepatic cholestasis Greenland familial cholestasis PFIC type II: BSEP deficiency (ABCB11) PFIC type III: MDR3 deficiency (ABCB4) TJP2 deficiency (TJP2) Farnesoid X receptor (NR1H4) Myosin VB (MYO5B) Corresponding genes are shown in italics. BSEP, bile salt export pump; FIC1, familial intrahepatic cholestasis 1; MDR, multidrug resistance protein; PFIC, progressive familial intrahepatic cholestasis; TJP, tight junction protein.

idiopathic neonatal hepatitis or an undiagnosed familial hepatitis syndrome may now be diagnosed accurately. Table 77.3 lists the known errors of primary and secondary bile acid synthesis and transport.

Bile Acid Synthesis Defects Defects in bile acid synthesis due to mutations in genes that encode the enzymes responsible for primary bile acid formation may have profound effects on hepatic and GI function and integrity. Disorders in bile acid synthesis and metabolism can be broadly

CHAPTER 77  Other Inherited Metabolic Disorders of the Liver

classified as primary or secondary. Primary enzyme defects involve congenital deficiencies in enzymes responsible for catalyzing key reactions in the synthesis of cholic acid and chenodeoxycholic acid (CDCA). The primary defects include cholesterol 7α-hydroxylase (CYP7A1) deficiency, 3β-hydroxy-C27-steroid oxidoreductase deficiency, Δ4-3-oxosteroid 5β-reductase deficiency, oxysterol 7α-hydroxylase deficiency, 27-hydroxylase deficiency or cerebrotendinous xanthomatosis (CTX), 2-methylacyl-CoA racemase deficiency, trihydroxycholestanoic acid CoA oxidase deficiency, amidation defects involving a deficiency in the bile acid–CoA ligase, and a side-chain oxidation defect in the 25-hydroxylation pathway for bile acid resulting in an overproduction of bile alcohols. Secondary metabolic defects that impact primary bile acid synthesis include peroxisomal disorders, such as cerebrohepatorenal syndrome of Zellweger and related disorders, and Smith-Lemli-Opitz syndrome. Typical biochemical abnormalities detected in patients with bile acid synthetic defects include elevated serum aminotransferase and conjugated bilirubin levels with normal GGTP levels; serum cholesterol concentrations are also usually normal. These disorders respond well to replacement and displacement therapy.206 Such therapy is based on the principle that inborn errors of bile acid biosynthesis lead to underproduction of normal trophic and choleretic primary bile acids and overproduction of hepatotoxic primitive bile acid metabolites.207 Replacement therapy is effective with cholic acid and potentially with UDCA. The former bypasses the enzymatic block and provides negative feedback to earlier steps in the synthetic pathways, whereas the latter displaces toxic bile acid metabolites and serves as a hepatobiliary cytoprotectant.208

Diagnosis Marked alterations in urinary, serum, and biliary bile acid composition and concentration may be found in infants and children with severe liver disease of any etiology. Therefore, determining whether these changes are primary or secondary to the liver dysfunction may be difficult, and a detailed biochemical evaluation is necessary. Initially, defects in bile acid synthesis were discovered with the use of liquid secondary ionization mass spectrometry; specifically, fast atom bombardment ionization mass spectrometry allowed direct analysis of bile acids from a drop of urine. More advanced mass spectrometry approaches, including electrospray ionization tandem mass spectrometry, as well as gene sequencing techniques, have subsequently been applied. The mass spectra generated permit accurate identification of the absence of primary bile acids and presence of atypical bile acids specific to each primary defect.209 

Disorders of Enzymes Involved in Modification of the Steroid Ring The most common inborn error of bile acid biosynthesis is 3β-hydroxy-Δ5-C27-steroid dehydrogenase/isomerase (3βHSD) deficiency. This disorder is caused by deficient activity of the second step in the bile acid synthetic pathway, the conversion of 7α-hydroxycholesterol into 7α-hydroxy-4-cholesten-3-one. This reaction is catalyzed by a microsomal 3β-hydroxy-Δ5-C27steroid oxidoreductase; deficiency of this enzyme results in the accumulation of 7α-hydroxycholesterol within the hepatocyte. The normal primary bile acids (cholic acid and CDCA) are not formed; instead, C24-bile acids that retain the 3β-hydroxy-Δ5structure are synthesized. Affected patients may present with pruritus, jaundice, hepatomegaly, steatorrhea, and fat-soluble vitamin deficiencies.207,209 Reports of 3β-HSD deficiency in adults not only highlights the clinical utility of homozygosity mapping in diagnosing autosomal recessive metabolic disorders, but also illustrates the wide variation in expressivity that occurs

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in 3β-HSD deficiency and underscores the need to consider a bile acid synthetic defect as a possible cause of liver disease in patients of all ages.210 Δ4-3-Oxosteroid 5β-reductase (AKR1D1) deficiency was first described in monochorionic twins born with marked and progressive cholestasis.211 This cytosolic enzyme is responsible for the conversion of 7α-hydroxy- and 7α,12α-dihydroxy-4-cholesten-3one into the corresponding 3-oxo-5β (H) analogs. Deficiency of Δ4-3-oxosteroid 5β-reductase usually leads to neonatal cholestasis, which rapidly progresses to synthetic dysfunction and liver failure.211,212 Cholesterol 7a-hydroxylase (CYP7A1) deficiency is associated with hypertriglyceridemia and gallstone disease in adults; it does not present as cholestatic disease. 

Disorders of Enzymes Involved in Side-Chain Modification Aberrant bile acid side-chain hydroxylation and oxidation may be manifested as neurologic disease and/or fat-soluble vitamin malabsorption; in general, liver disease is mild in affected patients (see Table 77.3).213 CTX, sterol-27-hydroxylase deficiency, is a rare autosomal recessive neurologic disease. Clinical symptoms and signs include adult-onset progressive neurologic dysfunction (i.e., ataxia, dystonia, dementia, epilepsy, psychiatric disorders, peripheral neuropathy, and myopathy) and premature non-neurologic manifestations (i.e., tendon xanthomas, childhood-onset cataracts, infantile-onset diarrhea, premature atherosclerosis, osteoporosis, and respiratory insufficiency).214 CTX is caused by a mutation in the sterol 27-hydroxylase gene (CYP27A1) and has been treated with CDCA (see Chapters 64 and 65).215 The classical symptoms and signs, namely elevated levels of cholestanol and bile alcohols in serum and urine, abnormal brain MRI, and the mutation in the CYP27A1 gene confirm the diagnosis of CTX.214 Prompt diagnosis and initiation of CDCA treatment is important in preventing neurologic damage and deterioration. After significant neurologic pathology is established, the effect of treatment is limited and deterioration may continue.216 2-Methylacyl Co-A racemase deficiency has been identified in an infant presenting with mildly elevated liver enzyme levels and low serum 25-hydroxy-vitamin D and vitamin E concentrations.217 Finally, bile acid synthesis culminates in conjugation with glycine and taurine, and genetic defects in conjugation and amidation have been identified using mass spectrometry analysis of urine, bile, and serum samples and sequence analysis of the genes encoding bile acid–CoA:amino acid N-acyltransferase and bile acid–CoA ligase (gene symbol SLC27A5).213 Affected persons exhibit fat-soluble vitamin deficiency and growth failure, indicating the importance of bile acid conjugation in lipid absorption. In some patients, liver disease with features of a cholangiopathy has been present. Oral glycocholic acid therapy has been shown to be safe and effective in improving growth and fat-soluble vitamin absorption in children and adolescents with these disorders.218 

Peroxisomal Disorders Peroxisomes are responsible for beta oxidation in the final steps of bile acid synthesis to yield the primary bile acids, cholic acid and CDCA. Defects in peroxisomal assembly and function have a significant impact on bile acid synthesis, because peroxisomes contain multiple enzymes required for the oxidation and conjugation of bile acids. The peroxisomopathies encompass a diverse group of genetic disorders caused by impairment in one or more peroxisomal functions. These disorders are subdivided into 3 main groups: (1) peroxisome biogenesis disorders (PBDs) that cause multiple abnormalities, (2) single peroxisomal protein (enzyme) deficiencies that result in limited dysfunction, and (3) single peroxisomal substrate transport deficiencies.219 PBDs comprise a group of disorders that share similar clinical and biochemical

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features; this group includes Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), infantile Refsums disease (IRD), and rhizomelic chondrodysplasia punctata, which is characterized by severe rhizomelic shortening of the limbs, severe skeletal abnormalities, cataracts, and facial abnormalities.219 PBDs are caused by defects in any of at least 14 different PEX (or peroxin) genes, which encode proteins involved in peroxisome assembly and proliferation. The single peroxisomal enzyme deficiency group consists of d-bifunctional protein and phytanoylCoA hydroxylase (adult Refsum disease) deficiencies, among others. The single peroxisomal substrate transport deficiency group consists of only one disease, X-linked adrenoleukodystrophy.220 These neurometabolic diseases are highly variable in age of onset and severity, with clinical and biochemical consequences dependent on the specific function of the affected protein in peroxisomal metabolism. The spectrum includes death in infancy, rapid functional decline, slow decline over a long term, and an apparently stable course. Leukoencephalopathy may be detected on cerebral MRI.221 Liver histologic changes are frequent in patients with peroxisomal disorders.222 Collectively, a comparison of different patients (and mouse models of disease) does not provide an unambiguous picture of the histologic findings. Whereas accumulating bile acid intermediates seem to underlie liver damage and failure with some disorders,217,223 comparable levels do not elicit pathology in other instances.224-226 Zellweger spectrum disorders (ZSD) include 3 separate entities considered different presentations within the same clinical and biochemical spectrum: ZS, NALD, and IRD.219 The multiple features of ZSD include distinctive dysmorphic features (hypertelorism, large anterior fontanelle, deformed earlobes), neonatal hypotonia, impaired hearing, retinopathy, cataracts, seizures, and skeletal changes. Patients with ZS often die within the first years of life, whereas those with NALD and IRD often reach their teens and even early adulthood.219 Hepatomegaly is common, and the progressive liver disease that develops in patients with ZS is similar to that identified in other errors of bile acid synthesis.227 Peroxisome biogenesis involves multiple PEX genes and requires the targeting and importation of cytosolic proteins into the peroxisomal membrane and matrix. Importation of proteins fated for the peroxisomal matrix requires guidance from 1 of 2 peroxisome-targeting signals, PTS1 and PTS2. Patients with ZSD display defects in the importation of proteins that use PTS1 and PTS2, whereas patients with rhizomelic chondrodysplasia punctata have a defect in the importation of proteins that use PTS2.228 The most common disorder of peroxisomes, adrenoleukodystrophy, is included in the second group of peroxisomopathies. This disorder results from a defect in the peroxisomal adrenoleukodystrophy protein, which is a member of the ATP-binding cassette (ABC) superfamily of membrane transporters (see Chapter 64).229 NALD, a distinct genetic disorder of autosomal recessive inheritance, must be distinguished from ZS and X-linked adrenoleukodystrophy; all 3 conditions lead to storage of verylong-chain fatty acids. Clinical features in NALD, present at birth, include hypotonia, severe psychomotor delay, and failure to thrive. These disorders are associated with multiple clinical abnormalities and a wide range of biochemical abnormalities. They are diagnosed through a combination of biochemical and histologic assessment, such as a search for very-long-chain fatty acids and ultrastructural abnormalities in tissue biopsy specimens, and genetic confirmation of suspected patients can be performed by sequencing candidate genes.219 DNA testing for PBDs may be used for carrier testing of relatives, early prenatal diagnosis or preimplantation genetic diagnosis, and counseling in families with a risk of recurrence for one of these disorders. 

Bile Acid Transport Defects The study of intrahepatic cholestasis syndromes has enhanced our understanding of hepatic excretory function and bile acid metabolism (see Chapter 64). The spectrum of diseases associated with mutations in genes involved in bile acid transport physiology is large and growing. The precise terminology used to describe these disorders continues to evolve as well (see Table 77.3). Historically, the PFIC family of diseases included a group of rare disorders presumably caused by specific defects in bile secretion. The 3 classic disorders of bile acid transport defects included familial intrahepatic cholestasis 1 (FIC1) disease (Byler disease, PFIC1), bile salt export pump (BSEP) disease (PFIC 2), and multidrug resistance protein 3 (MDR3) disease (PFIC 3).230 However, it was long suspected that additional genetic defects related to bile acid transport may be responsible for a similar phenotype, and at least 3 subsequent genetic diseases associated with low-GGTP intrahepatic cholestasis have been identified, including mutations in the genes for tight junction protein 2 (TJP2), myosin VB, and the nuclear bile acid farnesoid X receptor (FXR).231-234 Diagnosis has been aided by the development of a several resequencing chips that efficiently identify the most common disease-causing mutations. FIC1 disease (also called PFIC type I, or PFIC1) encompasses a continuum comprising intermediate phenotypes of at least 3 disease states: Byler disease, which generally presents in infancy and leads to progressive cholestasis often associated with severe pruritus; benign recurrent intrahepatic cholestasis (BRIC) type I, which gives rise to recurrent episodes of intrahepatic cholestasis beginning in childhood or adulthood that can last days to months and resolve spontaneously without causing detectable lasting liver damage; and intrahepatic cholestasis of pregnancy (ICP) type 1, which is a transient cholestasis limited to pregnancy with complete resolution after delivery.230 The occurrence of extrahepatic features in patients with FIC1 disease, including chronic diarrhea, deafness, and pancreatic insufficiency, suggests a biological cell function for the FIC1 protein. In patients with FIC1 disease, serum GGTP and cholesterol levels are normal or mildly elevated, and levels of bile acids are elevated in the serum and low in the bile. Serum aminotransferase and bilirubin levels are mildly elevated as well. Impaired bile acid transport in the intestine may account for the striking malabsorption and diarrhea in some patients. These intestinal clinical features do not resolve after LT and may worsen as cholestasis is improved and the terminal ileum is exposed to a normal bile acid constitution. Histology of liver tissue from patients with FIC1 disease typically shows bland canalicular cholestasis, with varying degrees of hepatocellular ballooning and giant cell transformation; portal fibrosis and eventually cirrhosis may be seen later in the course of the disease. (The liver histology of patients with BRIC type I and ICP type 1 is classically normal.) On electron microscopic evaluation of liver tissue from patients with FIC1 disease, characteristic coarse, granular bile deposits are seen in the canaliculus (“Byler’s bile”).230 FIC1 disease is caused by mutations in the ATP8B1 gene (initially named the FIC1 gene) that encodes the FIC1 protein, a P-type adenosine triphosphatase involved in ATP-dependent aminophospholipid transport.235 FIC1 protein is expressed on the hepatocyte canalicular membrane and in many other organs, including the intestine and pancreas. The mechanisms by which FIC1 protein dysfunction leads to the phenotype of low-GGTP cholestasis remains uncertain. Two pathophysiologic mechanisms have been proposed. The first involves the maintenance of canalicular membrane integrity via the enrichment of phosphatidylserine and phosphatidylethanolamine on the inner leaflet of the plasma membrane, including microvilli formation. In disease states, FIC1 dysfunction results in an abnormal constitution of lipids at the canalicular membrane with resulting disruption

CHAPTER 77  Other Inherited Metabolic Disorders of the Liver

of the biliary secretion of bile acids, which explains the reduced biliary bile acid concentrations found in patients with FIC1 disease.236 The second proposed mechanism stems from the finding that impaired ATP8B1 function can down-regulate the FXR, a nuclear receptor involved in the regulation of bile acid metabolism, with subsequent down-regulation of BSEP protein in the liver and up-regulation of bile acid synthesis and of the apical sodium bile salt transporter in the intestine (see Chapter 64).236 BSEP disease (PFIC type II, or PFIC2) is caused by a wide spectrum of mutations in the ABCB11 gene, which encodes an ABC protein that serves as the canalicular BSEP, the major transport protein governing the secretion of bile acids from hepatocytes into bile.230 BSEP, which is expressed exclusively in hepatocytes, is localized to the canalicular membrane and is therefore responsible for the bile salt-dependent bile flow, governing the transport of monovalent bile acids (see Chapter 64). Patients with the progressive form of BSEP disease present with high serum bile acid levels, but low or low-normal serum GGTP levels, and usually have intense pruritus, jaundice, poor weight gain, and hepatosplenomegaly.230 In addition, genetically distinct forms of BRIC and ICP (type II) are associated with mutations in ABCB11. Patients with BRIC type II commonly have cholelithiasis and lack other extrahepatic manifestations.237 Early in the course of BSEP disease, nonspecific giant cell hepatitis is found on histologic examination of the liver, and on electron microscopy amorphous bile deposits are seen in the canaliculi. For unclear reasons, patients with clinically severe, nonremitting intrahepatic cholestasis ascribed to ABCB11 mutations associated with absence or severe deficiency of BSEP expression have an increased risk of developing malignancies of the hepatobiliary system, such as hepatoblastoma, HCC, and cholangiocarcinoma.230 Children who undergo orthotopic LT for severe BSEP deficiency are at risk for post-transplantation episodes of cholestatic dysfunction that mimics the original disease secondary to the development of BSEP antibodies post-transplantation.238 This phenomenon has been termed antibody-induced BSEP deficiency, and remission can be achieved by intensifying immunosuppressive therapy or adding antibody-depleting medications to the regimen. MDR3 disease (PFIC type III, or PFIC3) is caused by mutations in the ABCB4 gene that encodes the MDR3 glycoprotein, an ABC phosphatidylcholine translocase expressed on the canalicular membrane of hepatocytes.230 This phospholipid translocator is involved in biliary phospholipid (phosphatidylcholine) excretion.235 MDR3 deficiency is thought to lead to cholestasis via decreased excretion of cytoprotective biliary phospholipids, leaving an increased pool of cytotoxic, detergent biliary bile acids that are not inactivated by phospholipids and giving rise to subsequent bile duct damage and proliferation and release of GGTP into the serum. Patients with MDR3 disease present with several disease phenotypes as well, ranging from neonatal cholestasis to the later presentation of cirrhosis, intrahepatic and gallbladder lithiasis, ICP, adult-onset ductopenic cholestatic liver disease, drug-induced cholestasis, and some cases of transient neonatal cholestasis, adult idiopathic cirrhosis, and cholangiocarcinoma.239,240 Patients with MDR3 deficiency present with high serum levels of GGTP and bile acids as well as bile ductular proliferation on routine microscopy. Some female patients with ICP have been shown to be heterozygous carriers of a mutation in ABCB4; other nongenetic factors are likely required for full expression of the disease.230 Identifying the genetic causes of cholestasis has led to advancements in the understanding of the pathophysiology of liver diseases. Other chronic intrahepatic cholestatic diseases with known genetic components include North American Indian childhood cirrhosis, which is caused by a single point mutation in the cirhin

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gene encoding a nucleolar protein of unknown function,241 neonatal icthyosis sclerosing cholangitis due to mutations in the gene encoding claudin-1,242 neonatal sclerosing cholangitis due to mutations in the gene encoding doublecortin domain–containing 2 protein,243 and arthrogryposis-renal dysfunction-cholestasis syndrome due to mutations in the VP533B (vacuolar protein sorting 33B) gene. Yet in many individuals, particularly those with normal-GGTP progressive cholestasis, genetic mutations have not been identified,244 and novel gene sequencing techniques are being applied to elucidate the genetic causes. Collectively, these efforts have led to the discovery of new genes for which dysfunction or absence of the encoded protein results in the phenotype of progressive cholestasis. Homozygous, truncating mutations in TJP2 with resulting absence of the TJP2 (also known as zona-occludens-2) has been reported in children with severe liver disease, often requiring LT.234,245 Mutations in NR1H4, which encodes FXR, a bile acid-activated nuclear hormone receptor that regulates bile acid metabolism through its promotion of BSEP trafficking to the canalicular membrane, can cause cholestatic liver disease.231 Clinical features of severe, persistent NR1H4-related cholestasis include neonatal onset with rapid progression to ESLD, vitamin K–independent coagulopathy, low-to-normal serum GGTP activity, elevated serum AFP levels, and undetectable liver BSEP expression.231 In a similar fashion, defects in myosin VB, encoded by MYO5B, previously identified as disease-causing mutations in children with microvillus inclusion disease, have been shown to impair the targeting of BSEP to the canalicular membrane, thereby resulting in hampered bile acid secretion and cholestasis. The intractable diarrhea that defines microvillus inclusion disease can be absent or mild, and MYO5B deficiency has been hypothesized to underlie up to 20% of previously undiagnosed cases of low-GGTP cholestasis.232,233 Classically, individuals with genetic-causing mutations resulting in cholestasis have presented in the neonatal period; however, as newer developments have been made, an expanded role for mutations in these genes has been identified in the development of both cryptogenic cholestasis in adults and in ICP.246

Treatment Symptomatic improvement in pruritus, optimization of nutritional status, and management of complications of chronic liver disease constitute the main medical approaches to treatment in patients with disorders of bile acid transport.247 Supportive treatment requires supplementation of fat-soluble vitamins (A, D, E, and K) and administration of medium-chain TGs, which are absorbed independently of bile acids. Antipruritic agents such as UDCA, rifaximin, hydroxyzine, cholestyramine, naloxone, and sertraline have demonstrated varying degrees of success (see Chapter 91).248 Surgical interruption of the enterohepatic circulation by ileal exclusion or partial biliary diversion has been shown to be well tolerated and generally, although not uniformly, results in improvement in pruritus and cholestasis249; however, the presence of cirrhosis at the time of diversion has been associated with poor outcomes, and recurrent, self-limited cholestasis episodes can occur.247 If all else fails, LT can lead to good overall outcomes, with normalization of bile acid synthesis and growth, even in patients who receive a live-donor organ from a potentially heterozygous parent.230 Extrahepatic manifestations of FIC1 deficiency, such as diarrhea, can worsen after transplantation. The resulting malnutrition has been linked to the development of fatty infiltration of the liver graft that can progress to the development of cirrhosis and require retransplantation. In these rare cases, internal and external biliary diversions have demonstrated some success in ameliorating the disease process.250 Additionally, antibody-induced BSEP deficiency can occur following transplantation for PFIC2, particularly in patients with severe truncating or early deleterious mutations. 

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TABLE 77.4  Hepatobiliary Disease in Patients with CF Specific to CF

Hepatic Focal biliary cirrhosis with inspissation Multilobular biliary cirrhosis with inspissation Biliary Microgallbladder Mucocele Mucous hyperplasia of the gallbladder

Secondary to extrahepatic disease

Hepatic (associated with cardiopulmonary disease) Centrilobular necrosis Cirrhosis Pancreatic Fibrosis (leading to bile duct compression/stricture)

Increased in frequency in patients with CF

Hepatic Drug hepatotoxicity Fatty liver Neonatal cholestasis Viral hepatitis Biliary Biliary sludge Cholangiocarcinoma Cholelithiasis Sclerosing cholangitis

Modified from Balistreri WF. Liver disease in infancy and childhood. In: Schiff ER, Sorrell MF, Maddrey WC, editors. Schiff’s diseases of the liver. 9th ed. Philadelphia: Lippincott-Raven; 1999. p 1379.

CYSTIC FIBROSIS Defects in the CFTR protein, found on the apical surface of cholangiocytes, lead to a wide spectrum of hepatobiliary conditions collectively referred to as CF-associated liver disease (CFLD).251 Although the pulmonary manifestations of CF historically have dominated the all-cause mortality, improvements in lung disease management have resulted in an increased frequency of extrapulmonary complications, and CFLD is now the third leading cause of mortality in patients with CF.252

Clinical and Pathologic Features The clinical features of CFLD are varied and have been noted to include liver enzyme elevations, hepatic steatosis, neonatal cholestasis, focal biliary cirrhosis (FBC), multilobular cirrhosis, gallbladder abnormalities, and cholangiopathy252; however, liver involvement in CF is not a universal feature of the disease. Although CF has been identified in fewer than 2% of patients with neonatal cholestasis, the diagnosis should be considered in any infant who presents with neonatal jaundice. Up to 30% of patients may have clinical or symptomatic liver disease after the neonatal period. In subjects with CFLD, disease usually develops early in childhood (approximately 10 years of age) and is more common in boys than in girls.253 Hepatobiliary diseases noted in patients with CF can be grouped into 3 categories (Table 77.4). The pathognomonic lesion of CF is FBC, with and without evidence of portal hypertension; an increasing frequency of noncirrhotic portal hypertension has been reported in patients with CF.254,255 At autopsy, FBC has been identified with a frequency of 11% to 50%.252 Progression to multilobular biliary cirrhosis occurs in 5% to 10% of patients with CF and leads to symptoms associated with portal hypertension, such as splenomegaly and variceal bleeding.256 Hepatic steatosis also develops in roughly half of patients but does not appear to correlate with outcome. Biliary abnormalities

range from microgallbladder, which is largely asymptomatic and is found in up to 20% of patients, to cholelithiasis and cholangiocarcinoma.257 The presence of liver disease does not necessarily correlate with the severity of pulmonary disease. 

Pathophysiology The pathogenesis of CFLD is complex. The pathognomonic lesion of CF, FBC, presumably results from defective function of the CFTR protein and is thought to result from obstruction of small bile ducts leading to chronic inflammatory changes, bile duct proliferation, and portal fibrosis. CFTR dysfunction has been shown to lead to fibrotic liver disease in a murine model.258 An additional mechanism by which a defective CFTR protein is thought to induce biliary disease is through a complex relationship among CFTR, Toll-like receptor 4, and the Rous sarcoma oncogene cellular homolog (Src). Under normal physiologic conditions, CFTR acts to regulate Toll-like receptor 4, which in turn inhibits Src activity. When CFTR is defective, however, Src can self-activate, leading to increased production of inflammatory cytokines and a loss of epithelial barrier function, thereby resulting in increased biliary epithelial inflammation and permeability.259 Although all patients with CF express defective CFTR in cholangiocytes, not all develop CFLD. There is no association between specific CFTR mutations and CFLD.260 The variable occurrence and clinical course of liver disease in patients with CF suggest that other genetic or environmental factors are involved in disease expression. For example, the α1-AT Z allele has been shown to be a risk factor for liver disease and portal hypertension in patients with CF,261 and hepatic expression of certain genes correlates with the severity of fibrosis.262 Differential expression of a number of genes is associated with hepatic fibrogenesis, including down-regulation of collagens, matrix metalloproteinases, and chemokines, thereby providing evidence of a transcriptional basis for the pathogenesis of CFLD.262 

Diagnosis A joint National Institutes of Health and Cystic Fibrosis Foundation Clinical Research Workshop on CFLD suggested criteria to diagnose progressive liver disease in patients with CF.252 If 2 or more of the following are present, a diagnosis of CFLD is established: (1) hepatomegaly (e.g., liver edge palpable >2 cm below the costal margin) and/or splenomegaly, confirmed by US; (2) elevations of ALT, AST, and GGTP above the laboratory upper limits of normal for greater than 6 months, after excluding other causes of liver disease; (3) ultrasonographic evidence of coarseness, nodularity, increased echogenicity, or portal hypertension, as described earlier; and (4) liver biopsy specimens showing FBC or multilobular cirrhosis (if liver biopsy is performed). Additional areas of focus and key points of interest in the field are the expansion of the definition to include patients with noncirrhotic portal hypertension and the incorporation of new technologies, such as ultrasound elastography, and novel serologic biomarkers to more accurately diagnose CFLD.251 

Treatment Children with CF should be screened yearly with physical examination, liver biochemical and function tests, and abdominal imaging to assess for CFLD.263 Those with suspected CFLD should be evaluated by a hepatologist to exclude other causes of liver disease. Once a diagnosis of CFLD is established, the inclusion of the liver specialist on a multidisciplinary care team is important for future management and potential interventions. Nutrition is a critical area of focus because fat malabsorption may be exacerbated by the cholestasis of CFLD. Additionally, optimizing overall liver health, through avoidance of alcohol, hepatotoxic

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medicines, and herbal and dietary supplements and vaccinations against hepatotropic viruses should be encouraged. The mainstay of treatment is to mitigate the complications of portal hypertension and cirrhosis. Although UCDA therapy is commonly prescribed, few trials have assessed its effectiveness, and evidence to justify its routine use in CF is insufficient.264 In some patients with CF, however, treatment with UDCA improves liver biochemical test levels, but the evidence that the drug halts progression to cirrhosis is inconclusive.252 Because patients with CF rarely have true hepatocellular dysfunction, the role of LT is often reserved for patients with clinically significant complications related to their portal hypertension. Clarity regarding the appropriateness for candidacy and optimal timing of transplantation is lacking, and guidelines are needed. The published data on LT reveal discrepancies relating to improved lung function, nutritional status, and quality of life in patients with CFLD.252 Long-term outcomes following LT are acceptable but are inferior to the outcomes of transplantation for other diseases. One study suggested that LT was neither beneficial nor detrimental to pulmonary function in patients with CF.265 A portosystemic shunt can be an effective treatment in patients with variceal bleeding; long-term outcomes are comparable to those for patients who undergo LT.266 

MITOCHONDRIAL LIVER DISEASES Many diseases associated with liver dysfunction have been attributed to defects in mitochondrial function. In addition to defects in mitochondrial enzymes involved in the urea cycle or energy metabolism, several mitochondrial hepatopathies involve respiratory chain/oxidative phosphorylation/electron transport defects or alterations in mitochondrial DNA (mtDNA) levels. The mitochondrial genome is especially vulnerable to oxidative injury not only because of its spatial relationship to the respiratory chain, but also because of its lack of protective histones and of an adequate excision and recombination repair system. mtDNA is inherited almost entirely from the maternal ovum; therefore, many primary mitochondrial deficiencies are inherited in a dominant fashion. Many nuclear genes, however, such as DNA polymerase-γ (POLG), thymidine kinase 2 (TK2), deoxyguanosine kinase (DGUOK), SCO1, BCS1L, and MPV17, encode proteins critical to maintaining proper amounts of mtDNA and to allowing normal mitochondrial respiratory function. Most mitochondrial diseases with primary involvement of the liver are caused by nuclear rather than mitochondrial gene mutations.267 Mitochondrial respiratory chain disorders can affect 1 in 5000 births, with liver involvement occurring in 10% to 20% of patients.267,268 Striking heterogeneity of clinical features, ranging from single-organ involvement to multisystem disease, can lead to a delayed or missed diagnosis and can confound therapeutic decision-making, for example, with respect to the advisability of LT. This heterogeneity of clinical presentations is likely due to the observations that mitochondrial quantity and function are uniquely influenced by both nuclear and mtDNA, and cells in various tissues can contain different mixtures of normal and abnormal mitochondrial genomes (heteroplasmy).267 The diagnosis of a mitochondrial respiratory chain defect should be considered in a patient with liver disease who has unexplained neuromuscular symptoms, including a seizure disorder; involvement of seemingly unrelated organ systems; a rapidly progressive course; or a chronic course that proves to be a diagnostic dilemma.267 In about 80% of patients, symptoms appear before age 2. The plasma lactate level and the ratio of lactate to pyruvate are often elevated, especially when the presentation is insidious.267,269 Given the complex array of tests that are useful for establishing a diagnosis of a mitochondrial hepatopathy, a tiered approach to the diagnostic workup has been proposed. The

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results of early screening tests, such as an acylcarnitine profile or urine organic acid levels, may provide clues to abnormalities in energy metabolism and may subsequently guide confirmatory testing to establish a molecular diagnosis. In selected cases, targeted exomic sequencing of a patient’s mitochondrial genes and a subset of nuclear genes or whole exome sequencing may lead to a definitive diagnosis.270,271 Infantile liver failure has been reported in numerous mitochondrial disorders, including cytochrome c oxidase deficiency, caused by mutations in the SCO1 or BCS1L genes; succinylCoA enzyme deficiency, caused by mutations in the SUCLG1 genes; mutations in the TRMU gene encoding the mitochondrial-specific tRNA-modifying enzyme; and mutations in the TSFM gene encoding the mitochondrial translation elongation factor EFTs.272-274 Although an elevated serum lactate and/or lactate-to-pyruvate ratio is often identified as a key features of these disorders, the clinical use of these markers in the setting of ALF may be less specific.275 Infants with Alpers-Huttenlocher syndrome (progressive neuronal degeneration in childhood with liver disease ascribed to mitochondrial dysfunction) experience vomiting, hypotonia, seizures, and liver failure, often beginning by 6 months of age. Frequently, the liver disease is unsuspected clinically and becomes evident late in the course of the disease. Alpers-Huttenlocher syndrome has been shown to be caused by mutations in POLG and in the FARS2 gene encoding a mitochondrial phenylalanyl transfer RNA synthetase.276 Alternatively, in mtDNA depletion syndrome (caused by mutations in the POLG, DGUOK, or MPV17 genes), hypoglycemia, acidosis, and liver failure develop early in infancy, and neurologic abnormalities are less prominent.277 Navaho neurohepatopathy has been shown to be caused by mtDNA depletion and a defect in the MPV17 gene product, which is involved in mtDNA maintenance and regulation of oxidative phosphorylation.278,279 Other multisystemic mitochondrial diseases with liver involvement are Pearson’s marrow-pancreas syndrome (caused by large deletions of mtDNA segments) and chronic diarrhea and intestinal pseudo-obstruction with liver involvement.280 Liver biopsy specimens in mitochondrial disorders typically show macrovesicular and microvesicular steatosis, with increased density and occasional swelling of mitochondria on electron microscopy. Immunohistochemical techniques are used more frequently (e.g., to diagnose cytochrome c oxidase deficiency). Cholestasis may be present, and conditions associated with chronic liver disease can show micronodular cirrhosis. Lactic acidemia may be constant, intermittent, or absent in mitochondrial disorders.281 Direct measurement of the enzymatic activity of the respiratory chain electron transport protein complexes can be performed on frozen tissue from the organ that expresses the clinical disease, although skin fibroblasts and lymphocytes may also be used. Few academic centers around the world can perform the assays for mitochondrial respiration (polarographic studies) or mtDNA analysis. No known effective therapy that alters the course of disease has been developed for mitochondrial respiratory chain disorders. Strategies proposed to delay the progression of these disorders include the use of antioxidants such as vitamin E or ascorbic acid; electron acceptors and cofactors, such as coenzyme Q10, thiamine, or riboflavin; and supplements proposed to work by other mechanisms, such as carnitine, creatine, or succinate. A Cochrane systemic review, however, failed to show any clear evidence to support their general use in mitochondrial disorders, but specific diseases, such as coenzyme Q deficiency, may respond to treatment.280,282 LT has generally been contraindicated in these patients, but some reports have demonstrated successful outcomes.269,270,280 Full references for this chapter can be found on www.expertconsult.com.

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222. Baes M, Van Veldhoven PP. Hepatic dysfunction in peroxisomal disorders. Biochim Biophys Acta 2016;1863:956–70. 223. Ferdinandusse S, Jimenez-Sanchez G, Koster J, et al. A novel bile acid biosynthesis defect due to a deficiency of peroxisomal ABCD3. Hum Mol Genet 2015;24:361–70. 224. Ferdinandusse S, Denis S, Overmars H, et al. Developmental changes of bile acid composition and conjugation in L- and D-bifunctional protein single and double knockout mice. J Biol Chem 2005;280:18658–66. 225. Jia Y, Qi C, Zhang Z, et al. Overexpression of peroxisome proliferator-activated receptor-alpha (PPARalpha)-regulated genes in liver in the absence of peroxisome proliferation in mice deficient in both L- and D-forms of enoyl-CoA hydratase/dehydrogenase enzymes of peroxisomal beta-oxidation system. J Biol Chem 2003;278:47232–9. 226. Smith EH, Gavrilov DK, Oglesbee D, et al. An adult onset case of alpha-methyl-acyl-CoA racemase deficiency. J Inherit Metab Dis 2010;33(Suppl. 3):S349–53. 227. FitzPatrick DR. Zellweger syndrome and associated phenotypes. J Med Genet 1996;33:863–8. 228. Shimozawa N. Molecular and clinical aspects of peroxisomal diseases. J Inherit Metab Dis 2007;30:193–7. 229. Corzo D, Gibson W, Johnson K, et al. Contiguous deletion of the X-linked adrenoleukodystrophy gene (ABCD1) and DXS1357E: a novel neonatal phenotype similar to peroxisomal biogenesis disorders. Am J Hum Genet 2002;70:1520–31. 230. Srivastava A. Progressive familial intrahepatic cholestasis. J Clin Exp Hepatol 2014;4:25–36. 231. Gomez-Ospina N, Potter CJ, Xiao R, et al. Mutations in the nuclear bile acid receptor FXR cause progressive familial intrahepatic cholestasis. Nat Commun 2016;7:10713. 232. Gonzales E, Taylor SA, Davit-Spraul A, et al. MYO5B mutations cause cholestasis with normal serum gamma-glutamyl transferase activity in children without microvillous inclusion disease. Hepatology 2017;65:164–73. 233. Qiu YL, Gong JY, Feng JY, et al. Defects in myosin VB are associated with a spectrum of previously undiagnosed low gamma-glutamyltransferase cholestasis. Hepatology 2017;65:1655–69. 234. Sambrotta M, Strautnieks S, Papouli E, et al. Mutations in TJP2 cause progressive cholestatic liver disease. Nat Genet 2014;46:326– 8. 235. Linton KJ. Lipid flopping in the liver. Biochem Soc Trans 2015;43:1003–10. 236. Jacquemin E. Progressive familial intrahepatic cholestasis. Clin Res Hepatol Gastroenterol 2012;36(Suppl. 1):S26–35. 237. van Mil SW, van der Woerd WL, van der Brugge G, et al. Benign recurrent intrahepatic cholestasis type 2 is caused by mutations in ABCB11. Gastroenterology 2004;127:379–84. 238. Stindt J, Kluge S, Droge C, et al. Bile salt export pump-reactive antibodies form a polyclonal, multi-inhibitory response in antibody-induced bile salt export pump deficiency. Hepatology 2016;63:524–37. 239. Gotthardt D, Runz H, Keitel V, et al. A mutation in the canalicular phospholipid transporter gene, ABCB4, is associated with cholestasis, ductopenia, and cirrhosis in adults. Hepatology 2008;48:1157–66. 240. Trauner M, Fickert P, Wagner M. MDR3 (ABCB4) defects: a paradigm for the genetics of adult cholestatic syndromes. Semin Liver Dis 2007;27:77–98. 241. Chagnon P, Michaud J, Mitchell G, et al. A missense mutation (R565W) in cirhin (FLJ14728) in North American Indian childhood cirrhosis. Am J Hum Genet 2002;71:1443–9. 242. Grosse B, Cassio D, Yousef N, et al. Claudin-1 involved in neonatal ichthyosis sclerosing cholangitis syndrome regulates hepatic paracellular permeability. Hepatology 2012;55:1249–59. 243. Grammatikopoulos T, Sambrotta M, Strautnieks S, et al. Mutations in DCDC2 (doublecortin domain containing protein 2) in neonatal sclerosing cholangitis. J Hepatol 2016;65:1179–87. 244. Davit-Spraul A, Fabre M, Branchereau S, et al. ATP8B1 and ABCB11 analysis in 62 children with normal gamma-glutamyl transferase progressive familial intrahepatic cholestasis (PFIC): phenotypic differences between PFIC1 and PFIC2 and natural history. Hepatology 2010;51:1645–55. 245. Sambrotta M, Thompson RJ. Mutations in TJP2, encoding zona occludens 2, and liver disease. Tissue Barriers 2015;3:e1026537.

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78

Hepatitis A Maria H. Sjogren, Joseph G. Cheatham

CHAPTER OUTLINE VIROLOGY ����������������������������������������������������������������������1210 EPIDEMIOLOGY��������������������������������������������������������������1211 PATHOGENESIS��������������������������������������������������������������1211 CLINICAL FEATURES������������������������������������������������������1212 ALF Caused by HAV Infection����������������������������������������1212 Extrahepatic Manifestations ����������������������������������������1212 Autoimmune Hepatitis after Acute Hepatitis A ��������������1213 DIAGNOSIS����������������������������������������������������������������������1213 PREVENTION AND TREATMENT��������������������������������������1213 Immunization Against HAV in Patients with Chronic Illnesses ������������������������������������������������������������������1215

Hepatitis A is the most common form of acute viral hepatitis worldwide.1 It is a self-limited infection caused by a cytopathic, nonenveloped, single-stranded RNA virus that is transmitted primarily by the fecal-oral route by contaminated food or water and sometimes results in epidemic outbreaks.1,2 HAV was first characterized in 1973, when scientists detected the virus in stools of human volunteers who were infected with HAV.3 The ensuing development of sensitive and specific serologic assays for the diagnosis of HAV infection and the isolation of HAV in cell culture4 permitted understanding of the epidemiology of HAV infection and, ultimately, control of the disease.

VIROLOGY In 1982, HAV was classified as an enterovirus belonging to the Picornaviridae family. Subsequent determination of the sequence of HAV nucleotides and amino acids led to the creation of a new genus, Hepatovirus.5 HAV has an icosahedral shape, measures 27 to 28 nm in diameter, is able to survive in acidic environments but is inactivated when heated to 85°C for 1 minute. HAV is capable of surviving in sea water (4% survival rate), dried feces at room temperature for 4 weeks (17% survival), and live oysters for 5 days (12% survival).6 HAV has only 1 known serotype and no antigenic cross-reactivity with the hepatitis B, C, D, or E virus or human pegivirus (see Chapters 79 to 83). The HAV genome consists of a positive-sense RNA that is 7.48 kb long, single-stranded, and linear (Fig. 78.1). The onset of HAV replication in cell culture systems takes from weeks to months. Primate cells, including African green monkey kidney cells, primary human fibroblasts, human diploid cells, and fetal rhesus kidney cells, are favored for cultivation of HAV in vitro. Two conditions control the outcome of HAV replication in cell culture.7 The first is the genetic makeup of the virus; HAV strains mutate in distinct regions of the viral genome as they become adapted to cell culture. The second is the metabolic activity of the host cell at the time of infection. Cells in culture, although infected simultaneously, initiate HAV replication in an asynchronous manner. This asynchronicity may be caused by differences in the metabolic activity of individual cells, but definitive evidence of cell-cycle dependence of HAV replication is lacking.8

1210

An initial step in the life cycle of a virus is its attachment to a cell surface receptor. The location and function of these receptors determine tissue tropism. Little is known about the mechanism of entry of HAV into cells. Some work has suggested that HAV could infect cells by a surrogate-receptor binding mechanism (involving a nonspecified serum protein). HAV infectivity in tissue culture has been shown to require calcium and to be inhibited by the treatment of the cells with trypsin, phospholipases, and β-galactosidase.9 A surface glycoprotein, HAVcr-1, on African green monkey kidney cells has been identified as a receptor for HAV. Blocking of HAVcr-1 with specific monoclonal antibodies prevents infection of otherwise susceptible cells. Experimental data suggest that HAVcr-1 not only serves as an attachment receptor but may also facilitate uncoating of HAV and its entry into hepatocytes.10 Once HAV enters a cell, the viral RNA is uncoated, cell host ribosomes bind to viral RNA, and polysomes are formed. HAV is translated into a large polyprotein of 2227 amino acids. This polyprotein is organized into 3 regions: P1, P2, and P3. The P1 region encodes structural proteins VP1, VP2, VP3, and a putative VP4. The P2 and P3 regions encode nonstructural proteins associated with viral replication (see Fig. 78.1). The HAV RNA polymerase copies the plus-RNA strand. The RNA transcript, in turn, is used for translation into proteins, which are used for assembly into mature virions. Down-regulation of HAV RNA synthesis appears to occur as defective HAV particles appear.11 In addition, a group of specific RNA-binding proteins has been observed during persistent infection.12 The origin and nature of these proteins is unknown, but they exert activity on the RNA template and are believed to play a regulatory role in the replication of HAV.13 Human HAV strains can be grouped into 4 different genotypes (I, II, III, and VII), whereas simian strains of HAV belong to genotypes IV, V, and VI.14 Despite the nucleotide sequence heterogeneity, the antigenic structure of human HAV is highly conserved among strains. The HAV VP1/2A and 2C genes are thought to be responsible for viral virulence, as demonstrated by experiments in which the genotypes and phenotypes of viruses were compared after animals were infected with 1 of 14 chimeric virus genomes derived from 2 infectious cDNA clones that encoded a virulent HAV isolate and an attenuated HAV isolate (HM175 strain), respectively.15 Among the many strains of HAV, the HM175 and CR326 human HAV strains were used for production of commercially available vaccines. In 1978, strain HM175 was isolated from human feces from Australian patients in a small outbreak of hepatitis A. CR326 was isolated from Costa Rican patients infected with HAV. The nucleotide and amino acid sequences showed 95% identity between the 2 strains. Vaccines prepared from these strains are thought to provide protection against all relevant human strains of HAV. Variations in the HAV genome are thought to play a role in the development of ALF during acute HAV infection. The 5′ untranslated region of the HAV genome was sequenced in serum samples from 84 patients with HAV infection, including 12 with ALF.16 The investigators observed fewer nucleotide substitutions in the HAV genome from patients with ALF than in those from patients without ALF (P < .001). The differences were most prominent between nucleotides 200 and 500, suggesting that nucleotide variations in the central portion of the 5′ untranslated region influence the clinical severity of HAV infection. 

CHAPTER 78  Hepatitis A HAV RNA Open reading frame

5'

3' AAA

VPg Translation

Noncoding

Noncoding

HAV polyprotein NH2

Nonstructural

Structural

P2

P1

P3

COOH

Proteins VP4?

3A (pre-VPg?)

2A

VP2 VP3

VP1

3B (VPg)

2B 2C

3C (protease) 3D (RNA polymerase)

Fig. 78.1  Genomic organization of HAV. VP, Viral protein; VPg, 5′ terminal protein. (From Levine JE, Bull FG, Millward-Sadler GH, et al. Acute viral hepatitis. In: Millward-Sadler GH, Wright R, Arther MJP, editors. Wright’s liver and biliary disease. 3rd ed. London: WB Saunders; 1992. p 679.)

EPIDEMIOLOGY Acute hepatitis A is a reportable infectious disease in all 50 states, as well as the District of Columbia and in U.S. territories. Incidence steadily declined by more than 95% from 1995 to 2011. In 2011, 1376 cases of acute HAV infection were reported, corresponding to a rate of infection of 0.4 cases per 100,000, compared with 6 cases per 100,000 in 200117,18 The decrease in rates of HAV infection is, in large part, caused by the expanded use of the HAV vaccine (see later). In 2006, the Centers for Disease Control and Prevention (CDC) recommended routine vaccination of children in all 50 states. Although the impact of HAV vaccination has been profound, coverage rates for the complete HAV vaccination series remain below rates for other routine childhood vaccines. In the USA in 2014, the HAV vaccination rate in children 19 to 35 months of age for the first dose was 87%, but only 57.5% of children received a second dose.19 More than 90% of persons who receive the 2-dose vaccination series will have persistent antibodies for 40 years, compared with 11 years if only 1 dose is received.20,21 The frequency of HAV antibodies in 32,502 Air Force recruits from 2013 to 2014 was greater than 50% in recruits from Alaska, Nevada, Utah, Arizona, and New Mexico. The frequency of HAV antibodies in recruits from the remaining 45 states was below 50%, with those from 16 states having rates lower than 35%.22 This low rate of adult HAV immunity in a low-endemic nation has resulted in susceptibility to infection from sporadic food-associated outbreaks or person-to-person transmission in a large portion of the adult population. From 2012 to 2018, the number of cases of HAV infection in the USA has fluctuated owing to large outbreaks. By 2018, the number of HAV infections in the USA surged by 28% compared with 2016 levels.23 Five states reported large outbreaks over that time period, the largest occurring in southern California with 704 cases (the largest outbreak in 20 years).23,24 The most notable city, San Diego, reported 587 cases, 402 hospitalizations, and 20 deaths. After the governor declared a state of emergency, San Diego and the California Department of Public Health addressed the outbreak successfully by providing epidemiologic analysis and monitoring; immunizing individuals experiencing

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homelessness and other high-risk populations; addressing homeless encampment hygiene and sanitation; and treating high-risk HAV-contaminated environmental surface areas with a sodium hypochlorite application.24 Historically, in the USA, the highest rate of reported disease has been among children 5 to 14 years of age. A rapid rate of disease decline among children has occurred since implementation of vaccination. When rates of HAV infection are compared between 2012 and 2016 by age groups, all groups saw an increase in rate except persons 0 to 9 years of age (0.1 cases per 100,000 in 2016). Persons 20 to 29 and 30 to 39 years of age had the highest rate (0.9 cases per 100,000), likely explained by a low prevalence of HAV antibodies in these groups. A transition has also occurred in the reported risk-exposure behaviors for persons with HAV infection; international travel was the most common risk factor from 2001 to 2007, whereas food and waterborne outbreaks were the most common in 2018.25 Globally, 1.5 million people are infected with HAV annually.26 The distribution of the virus is dependent upon socioeconomic factors such as housing, sanitation, vaccination programs, and water quality. With improvements in these factors, disease susceptibility has shifted from children to older adults.27 HAV infection generally follows 1 of 3 epidemiologic patterns.27,28 In countries where sanitary conditions are poor, most children are infected at an early age. Although earlier seroepidemiologic studies routinely showed that 100% of preschool children in these countries had detectable antibodies to HAV (anti-HAV) in serum, presumably reflecting previous subclinical infection, subsequent studies have shown that the average age of infection has risen rapidly to 5 years and older, when symptomatic infection is more likely. The second epidemiologic pattern is seen in industrialized countries where the prevalence of HAV infection is low among children and young adults. The third epidemiologic pattern is observed in closed or semiclosed communities, such as some isolated communities in the South Pacific, where HAV is capable (through epidemics) of infecting the entire population, which then becomes immune. Thereafter, newborns remain susceptible until the virus is reintroduced into the community.27 The primary route of transmission of HAV is the fecal-oral route, by either person-to-person contact or ingestion of contaminated food or water. Although rare, transmission of HAV by a parenteral route has been documented after transfusion of blood29,30 or blood products.31 Cyclical outbreaks among people who inject drugs, users of noninjection illicit drugs, and men who have sex with men (up to 10% may become infected in outbreak years) have been reported.32 Clinical sequelae of HAV infection are more severe in older than younger adults; therefore, developed countries with low endemicity and recent outbreaks have experienced high rates of hospitalization and increased costs.27 HAV is resistant to warming, freezing, drying, and acidic environments and has prolonged viability in feces, soil, and sewage. In the USA, efforts to provide effective sanitation services and facilities that offer maintenance of healthy personal hygiene habits in populations such as those affected by homelessness have been effective in combating transmission via fecal-oral contact with contaminated food and water or person-to-person contact during outbreaks.27,33 Successful initiatives that address homelessness and higher rates of completion of childhood vaccination series will have the most profound and durable impact on the frequency of HAV infection and other infectious outbreaks in the USA.34 

PATHOGENESIS After HAV is ingested and survives gastric acid, it traverses the small intestinal mucosa, reaches the liver via the portal vein, and is taken up by hepatocytes. In hepatocytes, virus particles replicate, assemble, and are secreted into the biliary canaliculus, from which they pass into the bile duct and back to the small intestine, with eventual

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excretion in the feces. The enterohepatic cycles of the virus lifecycle continue until neutralizing antibodies and other immune mechanisms interrupt the cycle.35,36 The pathogenesis of HAV-associated hepatocyte injury is not completely defined. The lack of injury to cells in cell culture systems suggests that HAV is not cytopathic. Immunologically mediated cell damage is more likely. The emergence of antiHAV could result in hepatic necrosis during immunologically mediated elimination of HAV. 

CLINICAL FEATURES Infection with HAV does not result in chronic infection but in an acute self-limited episode of hepatitis. Rarely, acute hepatitis A can have a prolonged or a relapsing course and, occasionally, profound cholestasis can occur.37 The incubation period is commonly 2 to 4 weeks, rarely up to 6 weeks. The mortality rate is low in previously healthy persons. Morbidity can be substantial in older children and adults. The most common clinical feature of cases of hepatitis A reported to the CDC in 2010 was jaundice in 68.1% of patients. The rates of hospitalization and death were 42.5% and 1%, respectively, possibly reflecting a reporting bias in favor of more severe cases. Adults and older adults are more likely to have profound hepatocellular dysfunction, require hospitalization, and have higher mortality rates.38 The increased morbidity and mortality in older adults may be caused by the reduced regenerative capacity of the liver with advanced age, increased comorbidity, and a decline in immune function, including decreased antibody affinity to antigens.39 By contrast, the rate of hospitalization in a younger population of active-duty U.S. Armed Forces members with acute HAV infection from 1991 to 2011 was 1.3 per 100,000 person-years. Because of a 1996 Department of Defense directive to provide HAV vaccine to all active-duty and reserve members, with the goal of immunization of the entire force by end of 1998, the rate of hospitalization fell to 0.2 to 0.7 per 100,000 patientyears from 2000 to 2011.40 Patients with HAV infection usually present with 1 of the following 5 clinical patterns: (1) asymptomatic without jaundice; (2) symptomatic with jaundice and self-limited after approximately 8 weeks; (3) cholestatic, with jaundice lasting 10 weeks or more37; (4) relapsing, with 2 or more bouts of acute hepatitis occurring over a 6- to 10-week period; and (5) ALF. Children younger than 2 years of age are usually asymptomatic; jaundice develops in only 20% of them, whereas symptoms develop in most children (80%) 5 years of age or older. HAV infection with prolonged cholestasis is a rare variant but occasionally leads to invasive diagnostic procedures (inappropriately) because the diagnosis of acute hepatitis may not be readily accepted in patients who have jaundice for several months, even in the presence of detectable anti-HAV of the immunoglobulin (Ig)M class (see later).37 A relapsing course is observed in 10% to 15% of patients with acute hepatitis A within a 6-month period after acute illness has resolved; however, this variant (or any other) does not result in the development of chronic HAV infection.41 Shedding of HAV in stool has been documented during the relapse phase.42 Neither the cholestatic variant nor relapsing hepatitis A is associated with an increase in mortality. In a retrospective observational multicenter study of 47 patients with acute HAV infection during the prodrome phase (from 3 to 30 days after infection), the most common symptoms were fever (87%), malaise (74%), and jaundice (62%).2 Additional prodromal symptoms included fatigue, weakness, anorexia, nausea, vomiting, and abdominal pain. Less common symptoms were fever, headache, arthralgias, myalgias, and diarrhea.43 Dark urine precedes other symptoms in approximately 90% of infected persons, a symptom that occurs within 1 to 2 weeks of the onset of prodromal symptoms. Symptoms of hepatitis may last from a

few days to 2 weeks and usually decrease with the onset of clinical jaundice. RUQ tenderness and mild liver enlargement are found on physical examination in 85% of patients; splenomegaly and cervical lymphadenopathy are each present in 15%. Complete clinical recovery is achieved in 60% of affected persons within 2 months and in almost everyone by 6 months. The overall prognosis of acute hepatitis A in otherwise healthy adults is excellent. Potentially fatal complications (e.g., ALF) develop in a small minority of patients.44 Acute hepatitis A, unlike hepatitis E (see Chapter 82), is not associated with a higher mortality rate in pregnant women; however, in a retrospective review of 13 cases of acute HAV infection during the second and third trimesters of pregnancy, gestational complications including premature contractions, premature rupture of membranes, placental separation, and vaginal bleeding developed in 9 patients (69%). In 8 of these patients, complications led to preterm labor at a median of 34 gestational weeks (range, 31 to 37 weeks).45 Acute HAV infection must be differentiated by appropriate serologic testing from other causes of acute viral hepatitis, autoimmune hepatitis (AIH), and other causes of acute nonviral hepatitis. In some cases, the diagnosis may be difficult to make because the patient may harbor another viral infection, such as chronic hepatitis B or chronic hepatitis C, with superimposed acute HAV infection.

ALF Caused by HAV Infection ALF due to HAV is rarely seen in children, adolescents, or young adults. The case-fatality rate in 2008 was calculated by the CDC to be 0.02 per 100,000 population, with the highest mortality rates in persons older than 75 (0.12 deaths per 100,000 population). Mortality rates were similar between blacks and other people of color, who had rates slightly higher than those of whites. From 2004 to 2008, the mortality rate of acute hepatitis A was consistently higher among male patients than female patients.46 In addition to age, risk factors for ALF and mortality include underlying liver disease and chronic viral hepatitis.47 Clinical predictors of ALF-associated mortality in a 2012 study were a serum creatinine level greater than 2 mg/dL, total bilirubin greater than 9.6 mg/dL, and albumin less than 2.5 g/L. Of these predictors, a serum creatinine level greater than 2 mg/dL had the best sensitivity and specificity for predicting ALF and mortality.2 ALF caused by HAV becomes manifest in the first week of illness in approximately 55% of affected patients and during the first 4 weeks in 90%; the onset of ALF rarely occurs after 4 weeks of illness.44 Late hepatic failure has been reported to occur in 1 patient 79 days after the onset of symptoms of HAV infection, with longterm survival achieved after live-donor LT (see Chapter 97).48 The contribution of HAV infection to ALF has been reported to be greater in populations classified as hyperendemic for HAV. In a report from India, where 276 patients with ALF were seen between 1994 and 1997, 10.6% of the cases among adults were caused by HAV. HAV had been responsible for only 3.5% of cases among 206 patients with ALF seen in the same community from 1978 to 1981.49 Although 2 reports since the late 1990s have described a decline in the number of cases of acute viral hepatitis among patients with ALF in the USA,50,51 this decline is attributable principally to the control of HBV infection. 

Extrahepatic Manifestations Extrahepatic manifestations are less frequent in acute HAV infection than in acute HBV infection and consist most commonly of an evanescent rash (14%) and arthralgias (11%) and, uncommonly, of leukocytoclastic vasculitis, glomerulonephritis, and arthritis, in which immune-complex disease is believed to play a pathogenic role. Cutaneous vasculitis is typically seen on the

CHAPTER 78  Hepatitis A

21 days after the onset of illness.32 The use of HCV RNA testing has been described in a report of 76 French patients with acute HAV infection seen between January 1987 and April 200058; 19 had ALF, 10 of whom required LT and 1 of whom died while awaiting LT. The HAV RNA status was determined in 39 of the 50 patients in whom sera and clinical data were available, including the 19 with ALF. HAV RNA was detected in 36 of these 50 patients (72%). The presence of low-titer HAV RNA in patients with severe acute hepatitis may signal an ominous prognosis and the need for early referral for LT. As in other studies, the genotype of HAV did not seem to play a role in the severity of clinical manifestations.59 

Jaundice symptoms Anti-HAV

Serum ALT HAV in feces

1213

IgM Anti-HAV

PREVENTION AND TREATMENT

0

1

2

3

4

5

6

12

14

Months after exposure Fig. 78.2  Typical course of a case of acute hepatitis A. Anti-HAV, antibody to HAV; IgM, immunoglobulin M. (From Hoofnagle JH, DiBisceglie AM. Serologic diagnosis of acute and chronic viral hepatitis. Semin Liver Dis 1991; 11:73-83.)

legs and buttocks; skin biopsies reveal the presence of IgM antiHAV and complement in blood vessel walls. The arthritis also appears to have a predilection for the lower extremities. Both vasculitis and arthritis have been associated with cryoglobulinemia, although cryoglobulinemia in general is more frequently associated with HCV infection. Cryoglobulins in acute hepatitis A have been shown to contain IgM anti-HAV. Other rare extrahepatic manifestations that may be immune-complex related include toxic epidermal necrolysis, fatal myocarditis, renal failure in the absence of liver failure, optic neuritis, transverse myelitis, polyneuritis, and cholecystitis. Hematologic complications include thrombocytopenia, aplastic anemia, and red-cell aplasia. Patients with more protracted illness appear to have a higher frequency of extrahepatic manifestations. 

Autoimmune Hepatitis after Acute Hepatitis A Several viruses have been reported to trigger the onset of AIH (see Chapter 90). In rare cases, acute hepatitis A has been followed by the development of type 1 AIH. AIH may also result in the detection of IgM anti-HAV for a prolonged period of time. Genetic predisposition is thought to play a role.52-57 

DIAGNOSIS Acute hepatitis A is clinically indistinguishable from other forms of viral hepatitis. The diagnosis of infection is based on detection of specific antibodies against HAV (anti-HAV) in serum (Fig. 78.2). A diagnosis of acute hepatitis A requires demonstration of IgM anti-HAV in serum. The test result is positive from the onset of symptoms55 and usually remains positive for approximately 4 months.56 Some patients may have low levels of detectable IgM anti-HAV for more than a year after the initial infection.56 IgG anti-HAV is also detectable at the onset of the disease, remains present usually for life, and after clinical recovery is interpreted as a marker of previous HAV infection (as demonstrated by a positive result on a commercial assay for total anti-HAV and negative result for IgM anti-HAV). Testing for HAV RNA is limited to research laboratories. HAV RNA has been detected in serum, stool, and liver tissue. Viral RNA can be amplified by PCR methodology.57 With a PCR assay, HAV RNA has been documented in human sera for up to

Recommendations concerning immunoprophylaxis against HAV were published by the CDC in December 1999 for persons in groups at increased risk for hepatitis A or its adverse consequences. In 2006, these recommendations were updated by the Advisory Committee on Immunization Practices (ACIP), which specifically recommended routine vaccination of children in the USA.32 The overall strategy is to protect persons from disease and to lower the incidence of HAV infection in the USA. The available monovalent vaccines were initially licensed for use in children older than age 2 but are now licensed for use after age 12 months.26,60 The decline in incidence rates, not surprisingly, has been greater in children than in adults, effectively removing children as a high-risk population and potentially removing the primary reservoir for the virus in the USA.19,32 Box 78.1 lists the populations now considered to be at highest risk of HAV infection. In June 2012, the WHO recommended deferring large-scale vaccination programs in highly endemic countries where almost all persons are asymptomatically infected with HAV in childhood, thereby effectively preventing clinical hepatitis A in adolescents and adults. In countries with intermediate HAV endemicity (or in those with high endemicity and rapidly improving socioeconomic status), a relatively large proportion of the adult population is susceptible to HAV infection, and large-scale HAV vaccination is likely to be cost-effective and is recommended. In countries with low or very low endemicity, the WHO has recommended targeted vaccination to provide individual health benefits. Groups for which vaccination should be offered include travelers to areas of intermediate or high endemicity, persons who require lifelong blood product transfusions, men who have sex with men, persons with chronic liver disease, workers in contact with non-human primates, and people who inject drugs.26 No specific medications are available to treat acute hepatitis A; symptomatic treatment is the rule. Historically, attention to sanitation and administration of serum immune globulin (IG) have been the mainstays of preventing HAV infection. The availability of excellent HAV vaccines, the high cost of IG, and the shortterm protection of IG through passive immunity have significantly limited the use of IG for pre-exposure prophylaxis. IG is still indicated in susceptible individuals traveling to intermediate or high endemic areas in less than 2 weeks (Table 78.1).61 In June 2007, the HAV vaccine was approved for use in the postexposure prophylaxis of immunocompetent persons, 12 months to 40 years of age, without chronic liver disease.62 This new indication for the HAV vaccine was based on results of a study that compared the efficacy of the HAV vaccine with that of IG for postexposure prophylaxis against HAV infection. Clinical hepatitis A developed in 4.4% of subjects in the vaccine group compared with 3.3% of those in the IG group.63 Analysis revealed no statistical difference between the 2 groups (95% confidence interval, 0.70 to 2.67) but likely excluded persons with asymptomatic infection. In the vaccine group, 162 persons with IgM HAV in serum were excluded, compared with 50 persons in the IG group, because of either a lack of symptoms or absence of

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an elevated serum ALT level of at least 2 times the upper limit of normal. The possibility exists that a number of persons with asymptomatic hepatitis A still posed an infectious risk to others. Although both HAV vaccine and IG appear to be effective when administered within 2 weeks of exposure to HAV, advantages of the HAV vaccine include long-term protection (when a second dose is subsequently administered), a good safety record, and wide availability.64 Postexposure prophylaxis with IG is still indicated in infants younger than 12 months of age and can be considered in individuals greater than 40 years of age; however, the vaccine is likely also effective in the latter group (see Table 78.1). In July 2017, prescribing recommendations for IG (GamaSTAN S/D [manufactured by Grifols Therapeutics, Inc., Clayton, NC], the only IG approved by the FDA for HAV prophylaxis) were updated taking into account the decreased concentration of HAV IgG (and thus IgG potency) among donors (see Table 78.1).61 Taking into consideration data from Canada and the United Kingdom, where the HAV vaccine has been used for postexposure prophylaxis since the early 2000s, the ACIP concluded that the HAV vaccine is safe and comparable to IG in protecting recipients against clinical hepatitis A. The ACIP guidelines allow persons who have recently been exposed to HAV, and who have not been vaccinated previously, to be given a single dose of single-antigen HAV vaccine or IG (0.01 mL/kg) as soon as possible within 2 weeks of exposure. The standard vaccine schedule is detailed in Table 78.2.61,62 Although IG is considered safe, the perception is widespread that it poses a risk because it is a blood-derived product. IG can cause fever and myalgias, just as the vaccine can, but pain at the injection site is usually more pronounced with IG than with the vaccine. Postexposure prophylaxis with IG can be administered at the same time as initiation of active immunization with the vaccine.64 The HAV vaccine was first licensed in the USA in 1995; 2 inactivated HAV vaccines are commercially available. Extensive use of the vaccines in clinical trials and postmarketing surveillance support the safety and efficacy of these products. HAVRIX

BOX 78.1 Groups at High Risk of HAV Infection Healthy persons who: Travel to endemic areas Work in occupations for which the likelihood of exposure is high Have infected family members Adopt infants or children from an endemic area Men who have sex with men Persons who have tested positive for HIV Persons with chronic liver disease Persons with a clotting factor disorder People who inject drugs or users of noninjection illicit drugs

is manufactured by GlaxoSmithKline Biologicals, Rixensart, Belgium, and VAQTA is manufactured by Merck & Co Inc., West Point, Pennsylvania. Both vaccines are derived from HAV grown in cell culture. The final products are purified and formalin-inactivated; they contain alum as an adjuvant. The basic difference between the 2 commercially available vaccines is the HAV strain used for preparation. HAVRIX was prepared with the HM175 strain, whereas VAQTA was prepared with the CR326 strain.65,66 The difference is of little practical importance because both vaccines are safe and immunogenic. The doses and schedule of immunization are shown in Table 78.2. After vaccination with HAVRIX, anti-HAV is estimated to remain detectable in serum for approximately 40 years; immunity may last longer.20 Among adults, the most common local side effects have been soreness at the injection site (56%), headache (14%), and malaise (7%). In children, the most common side effects have been soreness at the injection site (15%), feeding problems (8%), headache (4%), and induration at the injection site (4%).32 In the USA, during November 2012, the Vaccine Adverse Event Reporting System received 20,057 reports of unexplained adverse events after immunization with the HAV vaccine alone or in combination with other vaccines. Of the 20,057 reports, 1230 were considered serious and included Guillain-Barré syndrome, immune thrombocytopenic purpura, elevated serum aminotransferase levels, and seizures in children.32 No reported serious event, however, could be attributed definitively to the HAV vaccine, and the reported rates did not exceed the expected background rates. For example, the general population incidence of Guillain-Barré syndrome ranges from 0.5 to 2.4 cases per 100,000 person-years, and among adult HAV vaccine recipients, the incidence of Guillain-Barré was 0.2 cases per 100,000 person-years.32 A combined formulation of hepatitis A and B vaccines (TWINRIX, GlaxoSmithKline Biologicals, Rixensart, Belgium) is available and has an excellent record of efficacy and safety.67 Although some long-term studies have shown persistence of anti-HAV in children and adolescents, seroconversion rates for TWINRIX are apparently lower in children 1 to 6 years of age than those for standard monovalent vaccines.68 Currently, therefore, TWINRIX is approved only for persons 18 years of age and older. As a result of the reduction in endemic cases of hepatitis A in the USA, a large proportion of patients who now become infected with HAV are nonimmune adults traveling to endemic areas. Even if medical advice is sought before travel, the time is usually insufficient for completing the standard immunization schedule. HAVRIX and VAQTA are approved by the FDA for use in an accelerated vaccination schedule before planned travel. If given at least 2 weeks before travel, a single dose of either monovalent vaccine results in protective anti-HAV titers.62 IG is still indicated and highly effective passive immunity to those traveling in less than 2 weeks. In 2008, the FDA also approved an accelerated vaccination schedule for TWINRIX that can be completed

TABLE 78.1  Dosing Instructions for Immune Globulin for HAV Prophylaxis61 Indication

Circumstance(s)

Dose

Simultaneous Administration of HAV Vaccine

Pre-exposure prophylaxis

1 month of travel* to begin in 12 months and adults 18

1440 ELU

1

0, 6-12 months

Accelerated

≥1

Single age-appropriate dose

Age appropriate

≥2 weeks prior to travel†

Postexposure prophylaxis

≥1

Single age-appropriate dose

Age appropriate

18

50 U

1

0, 6-18 months

≥1

Single age-appropriate dose

Age appropriate

≥2 weeks prior to travel†

≥1

Single age-appropriate dose

Age appropriate

C Response to treatment with interferon-α: A > B ≥ C > D Precore/core promoter mutant frequency: B and D > A and C Active liver disease activity and risk of progression: C > B Evolution to chronic liver disease: non-A > A HCC risk: B > C in younger age group in Taiwan, but C > B in older age group in Japan HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen.

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Cases of genotype G have been reported in the USA and France. Genotype H has been described in Mexico. Genotypes I and J are the most recently discovered and have been observed in Vietnam and the Ryukyu Islands in Japan, respectively.31 Clinical associations appear to exist with the various genotypes (see Box 79.1).33 The strongest clinical associations appear to be that (1) HBeAg seroconversion occurs earlier in patients with HBV genotype B than in those with genotype C, and (2) the response to therapy with interferon (IFN) is better with genotypes A and B than with C and D (see later).34 The viral genotype also has implications for the frequency of precore and core mutations (see later) and may have an effect on the frequency of HCC. There is no compelling evidence that genotypes affect the HBV DNA response to nucleoside analogs (see later). The clinical associations with the various genotypes have become increasingly clear but have not led to specific recommendations for routine testing because genotype classification does not generally lead to a difference in management. One exception to this rule, however, occurs when a patient is being considered for pegylated IFN (PegIFN) therapy. In patients who are suitable candidates based on age and other factors (see later), genotype testing may have clinical value because genotypes A and B are associated with higher rates of a sustained virologic response and HBsAg clearance.35 

Mutations Most mutations in the HBV genome that are identified by comparing nucleotide sequences with those of wild-type HBV are silent or do not alter the amino acid sequence in a particular ORF. Some mutations have potentially important disease associations, however, and are described later.

Hepatitis B Surface Antigen HBsAg gene mutants result from a primary mutation in the HBsAg gene or a mutation in the overlapping DNA polymerase gene arising during nucleoside antiviral therapy (see later). Once the mutation appears, mutated virions can become selected immunologically as the dominant form of the virus. Mutations in the HBsAg gene between amino acid positions 124 to 147 are potentially important because this region of the HBsAg gene includes the major “a” epitope that binds to neutralizing antibody to HBsAg (anti-HBs). The mutation can lead to failure to detect HBsAg by commercial assays, which depend on binding to anti-HBs, and to failure of neutralization by HBIG or of vaccination. Infection with HBsAg gene-mutant HBV is accompanied by detection of anti-HBc. Serum HBV DNA levels can vary to the same extent seen in HBsAg carriers (see later). These mutants need to be distinguished from cases of “occult” hepatitis B, which has been linked to cryptogenic cirrhosis and an increased risk of HCC.36,37 In occult HBV infection, HBsAg-negative persons have detectable HBV DNA in serum.36 Some of these persons may lack evidence of other serologic markers of infection (e.g., anti-HBc). Occult HBV infection is thought to result from active suppression of viral replication by the host immune system; as a result, when HBV DNA is detectable in serum, it is present in low levels (stage 3 fibrosis).128,129 Transient mild serum ALT elevations may not be associated with significant disease, but persistent or prolonged serum ALT ­elevations for more than 3 to 6 months are more likely to be associated with significant liver injury. Therefore, some form of fibrosis assessment in patients with normal serum ALT levels is necessary to determine the presence of hepatic fibrosis to make an informed treatment decision. For both HBeAg-positive and HBeAg-negative patients, treatment should be considered when the HBV DNA is higher

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than 2000 IU/mL. Older studies suggested that progressive liver damage occurs once the serum HBV DNA level increases above a level of approximately 2000 IU/mL.130,131 Although liver injury is uncommon if the serum HBV DNA level is below 2000 IU/ mL, some patients may have HBV-induced liver disease at low viral loads. In this setting, liver biopsy may be needed to exclude an alternative diagnosis and to confirm viral-induced liver injury. Table 79.1 shows the differential diagnosis of an elevated serum ALT level in patients known to have chronic hepatitis B. Furthermore, serum HBV DNA levels may fluctuate, so that repeated measurements are required. A serum HBV DNA level greater than 2000 IU/mL accompanied by an elevated serum ALT level in an HBeAg-negative chronic hepatitis B patient and warrants treatment; this form of chronic hepatitis B is associated with more advanced liver disease and rarely remits completely. 

Timing Young adults who are HBeAg-positive usually have high viral loads (>107 IU/mL), with variable serum ALT levels.132,133 These patients usually have no or minimal liver disease on liver biopsy specimens. Those who have elevated ALT levels may not require immediate treatment because they may undergo spontaneous HBeAg seroconversion. It is often difficult to predict, however, which individuals will lose HBeAg with remission of disease prior to the development of significant liver injury. HBeAg-positive patients with a normal serum ALT level and high viral load (immune tolerant phase, or HBeAg-positive chronic infection) generally do not warrant treatment but instead should undergo regular monitoring as per current treatment guidelines. Figure 79.6 provides an algorithm for identifying individual patients who require antiviral treatment. Treatment guidelines vary in their ALT and HBV DNA thresholds for initiation of antiviral therapy.108–110 The AASLD recommends starting therapy when the serum ALT level is persistently above 2× ULN (ULN, 35 U/L for men and 25 U/L for women), whereas other guidelines recommend therapy when the serum ALT level is greater than 1× ULN. Serum HBV DNA levels above 2000 IU/mL are thought to be associated with progression of liver disease and serve as the threshold to start therapy, according to European Association for the Study of Liver Disease guidelines. Although liver biopsy is not mandatory to stage fibrosis, treatment

HBsAg-positive HBeAg-positive or negative

Fig. 79.6  Algorithm for the selection of patients with chronic hepatitis B for antiviral therapy. Indications for antiviral treatment include persistently elevated serum ALT levels greater than the ULN, serum HBV DNA levels greater than or equal to 2000 IU/mL, and some degree of hepatic fibrosis. For patients who have normal serum ALT levels or HBV DNA levels less than 2000 IU/mL, additional assessment, including liver biopsy, to exclude other causes of liver disease may be necessary.  *First-line agents for HBeAg-positive patients: PegIFN, TDF, TAF, or entecavir; first-line agents for HBeAg-negative patients: TDF, TAF, or entecavir.  HBeAg, hepatitis B e antigen; PegIFN, pegylated interferon; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate.

Serum HBV DNA stage 2 fibrosis by METAVIR [see Chapters 74 and 80]). Noninvasive assessment of fibrosis, such as transient elastography, MR elastography, or serum markers of fibrosis, may be helpful when liver biopsy is either not possible or contraindicated (see earlier).134 In summary, the decision to treat requires consideration of several factors: the patient’s age, serum HBV DNA levels, HBeAg status, and evidence of significant liver disease in the form of ­persistent or intermittent elevation of the serum ALT level, ­significant hepatic fibrosis or inflammation on a liver biopsy specimen, or evidence of significant hepatic fibrosis on noninvasive assessment. Ultimately, patient adherence to therapy and follow-up will have a major impact on the success of antiviral treatment for chronic hepatitis B. 

PegIFN and nucleos(t)ide analogs each have advantages and disadvantages that should be considered when making a treatment decision, as outlined in Table 79.4. One major advantage of PegIFN is that treatment duration is limited to 6 to 12 months, and virologic responses tend to be quite durable, especially in patients with HBeAg-positive hepatitis B.135,136 However, the drug must be administered subcutaneously and has been associated with unpleasant side effects. The shorter duration of treatment is an important factor for younger patients of childbearing potential who wish to be medication-free during the family planning years. Table 79.5 illustrates the relative potency of the different antiviral agents from various clinical trials in a nonhead-to-head comparison. 

Nucleoside and Nucleotide Analogs

Drugs The latest generation of nucleos(t)ide analogs—TDF, TAF, and entecavir—are highly potent and have a high genetic barrier to resistance. They are effective when used as monotherapy in both HBeAgpositive or HBeAg-negative patients. In most treatment guidelines, TDF, TAF, entecavir, and PegIFN are recommended as first-line treatment options.108–110 However, in resource-­constrained regions of the world, less preferable agents such lamivudine and adefovir are often used due to their lower cost and availability.

Nucleos(t)ide analogs have become the standard of care for treatment of most patients with treatment-naïve and treatment-experienced chronic hepatitis B. The lack of side effects and high efficacy of first-line agents such as TDF, TAF, and entecavir make them particularly attractive. Approximately 70% and 95% HBeAg-positive and HBeAg-negative patients, respectively, will achieve undetectable HBV DNA during the first year of treatment with TDF.137 Virologic responses progressively increase with longer duration of therapy, although

TABLE 79.4  Advantages and Disadvantages of Pegylated Interferon-α (PegIFN-α) Compared with Nucleos(t)ide Analog Therapy Agent

Advantages

Disadvantages

PegIFN-α

Finite duration of treatment (6-12 mo) Immunomodulatory and antiviral properties Higher rate of HBsAg loss or seroconversion compared withnucleos(t)ide analogs Durable off-treatment response Lack of known resistance mutations

Subcutaneous injection Frequent unpleasant side effects Loss of HBsAg in only a small minority of patients depending on HBV genotype Potential risk of ALT flares in patients with advanced liver fibrosis Contraindicated in advanced/decompensated cirrhosis, uncontrolled autoimmune disease, and mood disorders Relative contraindication in older patients and those with comorbid illnesses High cost of therapy

Nucleos(t)ide analogs

Excellent long-term safety Convenient oral administration Potent and rapid viral inhibition Negligible risk of antiviral resistance among treatment-naïve patients receiving first-line therapy (entecavir or tenofovir)

Slight risk of nephropathy with nucleotide analogs (adefovir, tenofovir) Antiviral resistance with low–genetic barrier drugs (lamivudine, telbivudine) Long-term/indefinite duration of treatment needed for both HBeAg-positive and HBeAg-negative patients High cost of therapy (over many years)

HBsAg, hepatitis B surface antigen.

TABLE 79.5  Results of First-Line Therapies for Treatment-Naïve Patients with Chronic Hepatitis B After 1 Year of Treatment HBeAg-Positive Chronic Hepatitis B (Immune Active Phase) Outcome (%)

PegIFN-α*

ETV

TDF

TAF

Viral suppression

32 (50 g/day) of alcohol for a minimum of 6 months, a serum bilirubin level greater than 3 mg/dL, an elevated serum AST level (50 to 400 U/L), a serum AST:ALT ratio greater than 1.5, and no other obvious cause for hepatitis.135 This consensus statement proposed classifying patients with alcohol-associated hepatitis as definite when a liver biopsy was used to establish the diagnosis, probable when the clinical and laboratory features were present without potential confounding problems, and possible when confounding problems were present.

History Most patients with fatty liver are asymptomatic. Although patients with alcohol-associated hepatitis and cirrhosis may be asymptomatic, many present with a variety of complaints including anorexia, nausea and vomiting, weakness, jaundice, weight loss, abdominal pain, fever, and diarrhea. 

Physical Examination The most detailed clinical information on ALD in the USA comes from studies of hospitalized patients who were assigned the diagnosis on the basis of classical histologic features.136,137 The most common physical finding in patients with fatty liver and alcoholassociated hepatitis is hepatomegaly, which is detectable in more than 75% of patients, regardless of disease severity. Patients with alcohol-associated hepatitis and cirrhosis also may have hepatic

1343

TABLE 86.1  Symptoms and Signs in Hospitalized Patients with AlcoholAssociated Liver Disease* Patients Affected (%) Disease Severity Symptom or Sign

Mild (n = 89)

Moderate* (n = 58)

Severe† (n = 37)

Overall

Hepatomegaly

84.3

94.7

79.4

86.7

Jaundice

17.4

100

100

60.1

Ascites

30.3

79.3

86.5

57.1

Hepatic encephalopathy

27.3

55.2

70.3

44.6

Splenomegaly

18.0

30.9

39.4

26.0

Fever

18.0

31.0

21.6

22.8

*Moderate disease was defined by a serum bilirubin level >5 mg/dL. disease was defined by a serum bilirubin level >5 mg/dL and a prolonged prothrombin time >4 sec. Data from Mendenhall CL. Alcoholic hepatitis. Clin Gastroenterol 1981; 10:417–41.

†Severe

tenderness, an audible bruit over the liver, spider angiomata, splenomegaly, and peripheral edema. Jaundice and ascites, which are found in approximately 60% of patients, are more frequent in patients with severe disease (Table 86.1). Various degrees of hepatic encephalopathy can be seen, usually in the most severely ill patients. Some patients with alcohol-associated hepatitis have a fever, with temperatures as high as 104°F, that can persist for weeks (likely mediated by proinflammatory cytokines such as IL-1 and TNF). In patients with well-compensated cirrhosis, the physical examination can be normal; however, most patients have obvious hepatomegaly and splenomegaly. As the disease progresses, the liver decreases in size and has a hard and nodular consistency. Patients with decompensated cirrhosis typically have muscle wasting, ascites, spider telangiectasias, palmar erythema, and Dupuytren contractures. Enlarged parotid and lacrimal glands are often seen, and severely ill patients may have Muehrcke lines or white nails. Patients with hepatopulmonary syndrome often have digital clubbing (see Chapter 92). 

Laboratory Features Only one third of hospitalized patients with fatty liver have laboratory abnormalities, which usually consist of mild increases in serum AST and ALT levels. As illustrated in Table 86.2, surprisingly modest elevations of serum aminotransferase levels are seen in patients with alcohol-associated hepatitis and cirrhosis, even when the disease is severe.136,137 Serum AST levels are almost always less than 400 U/L and typically are associated with trivial elevation of serum ALT levels, resulting in an AST/ALT ratio greater than 2. A ratio greater than 2 is characteristic of ALD, in part because of deficiency of pyridoxal 5′ phosphate (a cofactor disproportionately affecting serum ALT activity) in alcoholic patients (see Chapter 73). Serum alkaline phosphatase levels can range from normal to values greater than 1000 U/L. Serum bilirubin levels range from normal to 20 to 40 mg/dL, and serum albumin levels may be normal or depressed to a value as low as 1.0 to 1.5 g/dL. Most patients with ALD are anemic and have some degree of thrombocytopenia. By contrast, the white blood cell count usually is normal or elevated, occasionally to levels consistent with a leukemoid state. Severely ill patients usually have marked prolongation of the prothrombin time—often expressed as the INR—and often have an elevated serum creatinine value. 

86

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PART IX  Liver

TABLE 86.2  Typical Laboratory Values in Hospitalized Patients with Alcohol-Associated Liver Disease* Disease Severity Laboratory Test

Moderate* Mild (n = 89) (n = 58)

Severe† (n = 37)

Hematocrit value (%)

38

36

33

MCV (μm3)

100

102

105

WBC count (per

mm3)

8000

11,000

12,000

Serum AST level (U/L)

84

124

99

Serum ALT level (U/L)

56

56

57

Serum alkaline phosphatase level (U/L)

166

276

225

Serum bilirubin level (mg/dL)

1.6

8.7

13.5

Prolongation of prothrombin time (sec)

0.9

2.4

6.4

Serum albumin level (g/dL)

3.7

2.7

2.4

*Moderate disease was defined by a serum bilirubin level >5 mg/dL. †Severe disease was defined by a serum bilirubin level >5 mg/dL and a prolonged prothrombin time >4 sec. MCV, mean corpuscular volume. Data from Mendenhall CL. Alcoholic hepatitis. Clin Gastroenterol 1981; 10:417-41.

Histopathology The clinical diagnosis of ALD is quite sensitive and specific; therefore, liver biopsy is usually not needed to establish the diagnosis. A liver biopsy is useful, however, in selecting patients for clinical trials, determining the severity of hepatic injury, and clarifying the diagnosis in atypical cases (see Fig. 86.2). Centrilobular and perivenular fatty infiltration is seen in most persons who drink more than 60 g of alcohol daily. Classic histologic features of alcohol-associated hepatitis include ballooning degeneration of hepatocytes, alcoholic hyaline (Mallory, or Mallory-Denk, bodies) within damaged hepatocytes, and a surrounding infiltrate composed of neutrophils.14,15,17 Most patients have moderate to severe fatty infiltration. Varying degrees of fibrosis may be present, and many patients exhibit an unusual perisinusoidal distribution of fibrosis, at times with partial or complete obliteration of the terminal hepatic venules (sclerosing hyaline necrosis).17,22 Cirrhosis can be identified by the presence of nodules of hepatic tissue that are completely surrounded by fibrous tissue. Alcohol-associated cirrhosis typically is micronodular or mixed micro- and macronodular. In patients with coexisting alcohol-associated hepatitis, alcoholic hyaline is almost universal, and sclerosing hyaline necrosis and moderate-to-severe fatty infiltration are common. In patients with alcohol-associated cirrhosis who abstain from alcohol for long periods, a frequent finding is a gradual transformation to macronodular cirrhosis, which is indistinguishable from cirrhosis caused by other forms of liver disease (see Chapter 74).16,17,22

NAFLD NAFLD is the most difficult condition to differentiate from ALD (see Chapter 87). There is considerable overlap between the histologic features of NAFLD and ALD.17,138 As a consequence, the differentiation between the 2 conditions requires careful clinicopathologic correlation. Patients with ALD typically manifest clinical features of more advanced liver disease. Patients with NAFLD are more likely to have features of the metabolic syndrome including peripheral insulin resistance, obesity, hypertension, and dyslipidemia, although these features are not invariably present.139,140 They also should have weekly alcohol intake of fewer than 21 drinks for men and 14 for women.141 When a patient’s alcohol intake is questionable, differentiating the 2 conditions can be difficult, if not impossible. The use of structured questionnaires to assess alcohol intake is recommended in this situation.141 

Hereditary Hemochromatosis On occasion, distinguishing patients with ALD and secondary iron overload from those with liver disease caused by hereditary hemochromatosis can be difficult (see Chapter 75). Patients with end-stage liver disease from alcohol-associated cirrhosis can have elevated serum iron and ferritin levels and increased hepatic iron levels suggestive of hereditary hemochromatosis.142 To complicate matters further, 15% to 40% of patients with hereditary hemochromatosis consume more than 80 g of alcohol daily.143 The overlapping clinical features of hereditary hemochromatosis and ALD include hepatomegaly, testicular atrophy, cardiomyopathy, and glucose intolerance. Testing for mutations in the gene for hereditary hemochromatosis (HFE) and measuring the hepatic iron index are the best methods for differentiating the 2 conditions. Few patients with alcohol-associated cirrhosis and iron overload are homozygous for C282Y or heterozygous for the C282Y and H63D HFE mutations, and few have hepatic iron index values greater than 1.9.142,144 

DILI DILI can occur in the setting of chronic alcohol consumption and ALD (see Chapters 88 and 89). The interaction between heavy alcohol consumption and acetaminophen toxicity has been well documented for almost 40 years145 (see later). Other interactions with drugs such as methotrexate, isoniazid, and certain antiretroviral agents have also been reported.146 Moreover, patients with ALD often consume drugs that frequently cause DILI, such as certain antibiotics. A meta-analysis of data from the Drug-Induced Liver Injury Network showed that anabolic steroids were the most common cause of DILI in individuals who were heavy alcohol consumers.146 When heavy drinkers were compared with nondrinkers, however, DILI was not associated with an overall greater proportion of liver-related deaths or LT. Because DILI can present in a variety of different ways, it is important to have a high index of suspicion in patients with alcohol use disorder or ALD who have abnormal liver biochemical test levels.

Conditions That May Resemble ALD

COFACTORS THAT MAY INFLUENCE PROGRESSION OF ALCOHOL-ASSOCIATED LIVER DISEASE

Although the clinical diagnosis of ALD usually is quite straightforward, the similarity of clinical and histologic features of other disorders to those of ALD sometimes causes diagnostic confusion. The most commonly encountered conditions that have clinical or histologic features in common with ALD are NAFLD, hereditary hemochromatosis, and Budd-Chiari syndrome.

Many people drink heavily, yet only a limited number (∼35%) develop more advanced diseases such as alcohol-associated hepatitis or cirrhosis. Therefore, there must be modifying factors that act to prevent or to facilitate disease activity and progression. These modifiers can either be fixed (e.g., genetics) or can be amenable to intervention (e.g., smoking, diet). Eleven disease modifiers of particular importance to ALD are shown in Box 86.1, and selected

CHAPTER 86  Alcohol-Associated Liver Disease 1.0

BOX 86.1 Disease Modifiers in Alcohol-Associated Liver Disease

86

0.9 Probability of survival

Age Continued drinking Diet/nutrition Genetics/epigenetics/family history Medications and drugs of abuse Obesity Occupational and environmental exposure Other liver diseases Race Sex Smoking

1345

0.8

0.7

0.6

0.5

modifiers are reviewed in this section. Some, such as continued drinking (the most important modifier) and genetics, are covered elsewhere in this chapter. Obesity and smoking are highly associated with ALD. Obesity is also an independent risk factor for disease progression in alcohol-associated hepatitis and cirrhosis.125,127,147,148 Patients with alcohol-associated cirrhosis who are overweight also appear to be at increased risk for developing HCC.149 Cigarette smoking has also been shown to accelerate the progression of fibrosis and risk of HCC.125,150,151 Diet and nutrition play a major role in ALD, and patients with ALD show various degrees of nutritional deficiency.152 Studies conducted by the Veterans Health Administration Cooperative Studies Program in patients with alcohol-associated hepatitis153-156 showed that almost every patient with alcohol-associated hepatitis showed some degree of malnutrition.154 Approximately 50% of patients’ energy intake came from alcohol. Although caloric intake was frequently not inadequate, the intake of protein and critical micronutrients was often deficient. Dietary fat represents a macronutrient dietary modifier for ALD. Dietary unsaturated fat, enriched in linoleic acid in particular, promotes alcohol-induced liver damage.157-159 Linoleic acid is enzymatically converted to bioactive oxidation products oxidized linoleic acid metabolites that are highly inflammatory and hepatotoxic. Deficiency of the micronutrient zinc also appears to occur early and to play a role in the development and progression of alcohol-associated liver injury.160 Alcohol and drugs (including prescription medications, overthe-counter agents, and illicit drugs) may interact to cause hepatotoxicity. For example, chronic alcoholics are more susceptible to acetaminophen hepatotoxicity for multiple reasons (see Chapter 88). Alcohol abuse can occur in HIV-infected patients, and alcohol abuse can enhance hepatotoxicity of certain antiretroviral regimens.161 Alcohol may also interact with illicit drugs such as 3,4-methylenedioxymethamphetamine (ecstasy), which is commonly used with alcohol.162 Exposure to potential toxins in the workplace or environment can cause hepatotoxicity, which can be exacerbated by alcohol. Vinyl chloride (VC) represents a potential industrial exposure the toxicity of which may be exacerbated by alcohol (see Chapter 89). VC-induced histologic steatohepatitis may be indistinguishable from alcohol-induced steatohepatitis and has been termed toxicant-associated steatohepatitis.163 VC is metabolized in a fashion similar to ethanol, which may account for the observed similarities between toxicant-associated steatohepatitis and alcoholassociated hepatitis. With environmental exposures, there are usually multiple contaminants rather than just one compound. Use of a cocktail of 22 clinically relevant contaminants (Northern Contaminant Mixture) showed that both a high-fat diet and alcohol intake increased the frequency of fatty liver and liver injury in exposed mice.164

40

80

120

160

200

240

280

Weeks No cirrhosis, no hepatitis n = 58 Cirrhosis, no hepatitis n = 42 No cirrhosis, hepatitis n = 19 Cirrhosis, hepatitis n = 98 Fig. 86.5  Survival of patients with alcohol-associated liver disease stratified by histologic severity of disease. (From Orrego H, Black JE, Blendis LM, Medline A. Prognosis of alcoholic cirrhosis in the presence or absence of alcoholic hepatitis. Gastroenterology 1987;92:208–14, with permission.)

Female gender is a well-accepted risk factor for the development and rapid progression of ALD.10,11,165 Studies in rats or mice chronically fed alcohol have also demonstrated that females are more susceptible to liver injury than males. Risk factors for the development of liver disease in females appear to include sex hormone levels, endotoxemia, lipid peroxidation, chemokines, and NF-κB activation. Decreased gastric ADH activity and first-pass metabolism may also contribute to higher blood alcohol levels in women than men. These risk factors are critical for determining “safe” levels of alcohol consumption in women. Indeed, many authorities consider any amount of alcohol above 20 g a day to be a risk factor for the development of liver disease in women. Race can influence susceptibility to ALD. Research from large multicenter Veterans Affairs studies has shown that alcoholassociated cirrhosis is more frequent in Hispanics (73%) than in non-Hispanic Whites (52%) and African Americans (44%). Moreover, African Americans have been consistently shown to be more likely to have hepatitis B or hepatitis C as confounders.166 Between one fourth and one third of patients with ALD also have hepatitis C.167 Liver disease is more severe, advanced disease develops at a younger age, and survival is shorter in patients with both ALD and HCV infection.7,125,127,167 In addition, alcohol and HCV act synergistically in the development of HCC (see Chapters 80 and 96).149,168,169 

PROGNOSIS The prognosis for individual patients with ALD depends on the degree of pathologic injury, the patient’s nutritional status, the occurrence of complications of advanced liver disease, the presence of other comorbid conditions such as obesity and HCV infection, and the patient’s ability to discontinue destructive patterns of drinking. Patients with fatty liver have the best outcome, those with alcohol-associated hepatitis or cirrhosis have an intermediate outcome, and those with cirrhosis combined with alcohol-associated hepatitis have the worst outcome (Fig. 86.5).170 Estimating the prognosis of

1346

PART IX  Liver

TABLE 86.3  Correlation of the Maddrey Discriminant Function (DF)* with Prognosis in Alcohol-Associated Hepatitis

TABLE 86.5  Correlation of the ABIC Score* and the 90-day Mortality Rate in Alcohol-Associated Hepatitis

Non-Severe Disease

Severe Disease

Severity

90-Day Mortality (%)

2X ULN), GGTP > 100 U/mL, albumin < 3.0 g/L, INR > 1.5, leukocyte count > 12,000/mm3

0.75 Probability of survival

Initial Findings That Support a Diagnosis of Alcohol-Associated Hepatitis Prolonged heavy alcohol intake, recentClinical presentation onset jaundice, malaise, ascites, edema, pruritus, fever, confusion/lethargy/ agitation, asterixis, tender hepatomegaly, splenomegaly, pedal edema

0.50

Exclusion of Other Causes of Jaundice Autoimmune hepatitis Exclude severe autoimmune hepatitis if first episode and/or clinical suspicion (see Chapter 90)

0.25

DILI

0.00

Ischemic hepatitis

Review detailed history of medication, supplements, pharmacy records Consult http://livertox.nih.gov (see Chapter 88) Suspect if hypotension, septic shock, massive bleeding, or recent cocaine use (see Chapter 85)

Mechanical obstruction

Rule out HCC, biliary obstruction, Budd-Chiari syndrome Perform Doppler abdominal US, and, if indicated, MRI

Viral hepatitis

Rule out acute hepatitis A, B, C, or E, especially if first episode or high clinical suspicion (see Chapters 78-82)

Treatment of Alcohol Abuse and Liver-related Complications Alcoholism Consult addiction specialist Moderate withdrawal symptoms: baclofen Severe withdrawal symptoms: benzodiazepines, phenobarbital Hepatic encephalopathy Assess for precipitant: GI bleed, infection, medication nonadherence Treat underlying precipitant, add lactulose, rifaximin, zinc (see Chapter 94) Infection

Rule out pneumonia, cellulitis, SBP, urinary tract infection, meningitis Obtain chest film Broad-spectrum antibiotics, if indicated

Renal insufficiency

Early detection and close monitoring Volume expansion with albumin Consider IV albumin plus a vasoconstrictor if progressive hepatorenal syndrome (see Chapter 94)

ULN, upper limit of normal.

do not appear to prevent the development of hepatorenal syndrome. Therefore, in patients who have contraindications to glucocorticoid therapy or any degree of renal disease, aggressive standard medical care with attention to factors such as nutrition, infection, and adequate perfusion should be pursued, and opportunities for clinical trials of LT should be considered (see later). Table 86.8 lists the factors that should be taken into account in the approach to patients with suspected severe alcohol-associated hepatitis.

Specific Therapy for Alcohol-Associated Cirrhosis Abstinence is the only treatment that clearly improves survival in patients with alcohol-associated cirrhosis. All patients should also receive optimal inpatient and outpatient nutritional support. A variety of treatments for which there is a specific rationale have

Transplanted: 58% 5-yr survival

Simulated: 35% 5-yr survival

Matched controls: 31% 5-yr survival

0

500

1000

1500

2000

Days Fig. 86.12  Improved probability of survival over 5 years in patients with Child-Turcotte-Pugh scores of 11 to 15 after 6 months of abstinence from alcohol who underwent LT (top line), compared with matched control subjects (P = 0.008) and simulated control subjects (i.e., predicted from a model) (P = 0.001). (Modified from Poynard T, Naveau S, Doffoel M, et al. Evaluation of efficacy of liver transplantation in alcoholic cirrhosis using matched and simulated controls: 5-year survival. Multi-centre group. J Hepatol 1999;30:1130-7.)

been investigated over the years, including silymarin, SAMe, betaine, colchicine, androgenic steroids, lecithin, vitamin E, and PTX. None, however, has been shown to improve survival.5,125

LT Alcohol-associated cirrhosis is the second most common indication for LT in the USA and Europe and is likely to become the most common in the USA due to the advent of DAAs for HCV infection (see Chapter 80).232 The outcome following LT is quite favorable (see also Chapter 97).233 Important factors that reduce survival after transplantation are concurrent HCV infection, smoking-related cancers, cardiovascular disease, and a return to destructive patterns of drinking.151,233-236 Although almost half of the transplant recipients drink some alcohol after LT, few return to destructive patterns of alcohol use.237 A multidisciplinary approach both before and after the operation, including addiction specialists, psychiatrists, and transplant professionals, appears to offer the best opportunity for patients with ALD to achieve longterm high quality of life after LT.238,239 Many patients with apparently advanced alcohol-associated cirrhosis can recover to the degree that LT is not required if they can abstain from drinking (Fig. 86.12).200 Because the benefits of abstinence can be so dramatic, requiring a period of abstinence before proceeding with transplantation is reasonable; however, if patients do not show evidence of significant recovery within 3 months, they are unlikely to survive without transplantation.232 Referral to a transplant center at that time for further evaluation of their alcoholism and candidacy for transplantation gives patients the best opportunity to be placed on the transplant waiting list after the traditional 6-month abstinence period required by many transplant centers and insurance companies. This “6-month rule” was initiated in 1997 to help ensure maximal hepatic recovery off alcohol and to document sobriety; however, this arbitrary time limit has not been shown to affect long-term survival or sobriety. It is important to be able to diagnose alcohol consumption accurately as part of the transplant evaluation process and

CHAPTER 86  Alcohol-Associated Liver Disease

1353

100

86 77%8%

Patients undergoing transplantation

Survival (%)

75 P < 0.001 at 6 mo (primary end point)

50

23%8%

25

71%9%

P < 0.001 at 24 mo (extended follow-up)

Matched controls

23%8%

0 0 No. at risk Patients undergoing transplantation 26 Matched controls

26

6

12

18

24

Months 20

15

14

13

6

6

5

4

Fig. 86.13  Kaplan-Meier estimates of survival in 26 patients with severe alcohol-associated hepatitis who failed corticosteroid therapy and underwent early LT compared with matched controls who did not undergo LT. (From Mathurin P, Moreno C, Samuel D, et al. Early liver transplantation for severe alcoholic hepatitis. N Engl J Med 2011;365:1790–800, with permission.)

following transplantation. As noted previously, various methods of history taking, unique biomarkers, and wearable alcohol sensors have been proposed. Studies have suggested that addiction experts may be better than hepatologists at uncovering alcohol intake post-transplantation,240 supporting a team approach to diagnosis and follow-up. Moreover, the phosphatidyl ethanol level has been reported to be 100% specific, detects more than 90% of moderate-to-heavy drinkers, and has been used to detect clandestine drinking post-transplantation.241 Patients with severe alcohol-associated hepatitis traditionally have not been considered to be appropriate candidates for LT because of recent drinking, the fear that they will return to drinking after the transplant, and the assumption that many will recover with abstinence or appropriate medical therapy.5,127,171 These assumptions were challenged by a multicenter FrenchBelgian study in which carefully selected patients with severe alcohol-associated hepatitis who failed to respond to glucocorticoid therapy were shown to have a dramatic improvement in survival with early LT compared with matched controls who did not undergo LT (Fig. 86.13).242 These initial results from Europe have been replicated in a single-center pilot program in the USA (100% survival at 6 months)243 as well as in the ACCELERATE-AH study from the American Consortium of Early Liver Transplantation for Alcoholic Hepatitis—12 centers in 8 UNOS regions (see Chapter 97).244 In that study, 1- and 3-year survival rates were excellent (94% and 84%, respectively), and sustained alcohol use was 17% at 3 years. With expanded indications and better multidisciplinary approaches, LT for ALD is likely to increase in frequency. 

Optimal Management Reducing the terrible morbidity and mortality associated with alcohol abuse will occur only if the global medical community makes a major commitment to early diagnosis of alcohol misuse. Systematic application of alcohol questionnaires at all points

of entry into medical care will be required to achieve this goal. Government programs that provide frequent monitoring and swift, certain, and modest sanctions for violations also show promise in reducing arrests for driving under the influence of alcohol and domestic violence.245 For patients with stable cirrhosis, maintaining abstinence is the most important aspect of management, because no drugs have been shown to improve survival. Nutritional support with evening snacks can be very beneficial. All patients should receive recommended vaccinations. In addition, they should undergo regular surveillance for HCC and screening for esophageal varices as appropriate (see Chapters 92 and 97). Weight control and cessation of smoking are also important. For hospitalized patients with alcohol-associated hepatitis or cirrhosis, electrolyte disturbances and vitamin deficiencies should be corrected and withdrawal symptoms treated when present. During the first few days of admission, the patient should be offered a nutritious diet if the patient’s mental status is adequate. Patients with severe alcohol-associated hepatitis should receive enteral feedings to ensure adequate calorie and protein intake. In patients with severe alcohol-associated hepatitis who do not have a systemic infection or GI bleeding, a short course of glucocorticoid therapy should be considered. Transfer to a liver transplant center for participation in a clinical trial should be considered in selected patients, including those who are not candidates for glucocorticoid therapy. Given the extremely poor prognosis of patients hospitalized with multiple organ failure, palliative care teams should be involved within the first few days after admission to provide appropriate support for both patients and families. LT is effective in providing prolonged survival with an excellent quality of life in carefully selected patients with alcohol-associated cirrhosis and, potentially, in patients with severe alcohol-associated hepatitis who fail to respond to medical therapy. Full references for this chapter can be found on www.expertconsult.com.

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180. Forrest E, Evans C, Stewart S, et al. Analysis of factors predictive of mortality in alcoholic hepatitis and derivation and validation of the Glasgow alcoholic hepatitis score. Gut 2005;54:1174–9. 181. Singal AK, Shah VH. Alcoholic hepatitis: prognostic models and treatment. Gastroenterol Clin North Am 2011;40:611–39. 182. Dominguez M, Rincon D, Abraldes JG, et al. A new scoring system for prognostic stratification of patients with alcoholic hepatitis. Am J Gastroenterol 2008;103:2747–56. 183. Jepsen P, Ott P, Andersen PK, Sorensen HT, Vilstrup H. Clinical course of alcoholic liver cirrhosis: a Danish population-based cohort study. Hepatology 2010;51:1675–82. 184. Bell H, Jahnsen J, Kittang E, et al. Long-term prognosis of patients with alcoholic liver cirrhosis: a 15-year follow-up study of 100 Norwegian patients admitted to one unit. Scand J Gastroenterol 2004;39:858–63. 185. Poynard T, Naveau S, Doffoel M, et al. Evaluation of efficacy of liver transplantation in alcoholic cirrhosis using matched and simulated controls: 5-year survival. Multi-centre group. J Hepatol 1999;30:1130–7. 186. Pessione F, Ramond MJ, Peters L, et al. Five-year survival predictive factors in patients with excessive alcohol intake and cirrhosis. Effect of alcoholic hepatitis, smoking and abstinence. Liver Int 2003;23:45–53. 187. Sarin SK, Kumar A, Almeida JA, et al. Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific Association for the Study of the Liver (APASL). Hepatol Int 2009;3:269–82. 188. Fleming KM, Aithal GP, Card TR, West J. The rate of decompensation and clinical progression of disease in people with cirrhosis: a cohort study. Aliment Pharmacol Ther 2010;32:1343–50. 189. Szabo G. More than meets the eye: severe alcoholic hepatitis can present as acute-on-chronic liver failure. J Hepatol 2018;69:269–71. 190. Tandon P, Garcia-Tsao G. Bacterial infections, sepsis, and multiorgan failure in cirrhosis. Semin Liver Dis 2008;28:26–42. 191. Belcher JM, Garcia-Tsao G, Sanyal AJ, et al. Association of AKI with mortality and complications in hospitalized patients with cirrhosis. Hepatology 2013;57:753–62. 192. Cholongitas E, Senzolo M, Patch D, et al. Risk factors, sequential organ failure assessment and model for end-stage liver disease scores for predicting short term mortality in cirrhotic patients admitted to intensive care unit. Aliment Pharmacol Ther 2006;23:883–93. 193. Das V, Boelle PY, Galbois A, et al. Cirrhotic patients in the medical intensive care unit: early prognosis and long-term survival. Crit Care Med 2010;38:2108–16. 194. Advisory Committee on Immunization Practices. Recommended adult immunization schedule: United States, 2013. Ann Intern Med 2013;158:191–9. 195. Seeff LB, Cuccherini BA, Zimmerman HJ, et al. Acetaminophen hepatotoxicity in alcoholics. A therapeutic misadventure. Ann Intern Med 1986;104:399–404. 196. Fontana RJ. Acute liver failure due to drugs. Semin Liver Dis 2008;28:175–87. 197. Stickel F, Kessebohm K, Weimann R, Seitz HK. Review of liver injury associated with dietary supplements. Liver Int 2011;31:595–605. 198. Purohit V, Rapaka R, Kwon OS, Song BJ. Roles of alcohol and tobacco exposure in the development of hepatocellular carcinoma. Life Sci 2013;92:3–9. 199. Bruix J, Sherman M, American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: an update. Hepatology 2011;53:1020–2. 200. Veldt B, Laine F, Guillygomarc’h A, et al. Indication of liver transplantation in severe alcoholic liver cirrhosis: quantitative evaluation and optimal timing. J Hepatol 2002;36:93–8. 201. Friedmann PD. Clinical practice. Alcohol use in adults. N Engl J Med 2013;368:365–73. 202. Jonas DE, Garbutt JC, Amick HR, et al. Behavioral counseling after screening for alcohol misuse in primary care: a systematic review and meta-analysis for the U.S. Preventive Services Task Force. Ann Intern Med 2012;157:645–54. 203. Addolorato G, Leggio L, Ferrulli A, et al. Effectiveness and safety of baclofen for maintenance of alcohol abstinence in alcohol-dependent patients with liver cirrhosis: randomized, double-blind controlled study. Lancet 2007;370:1915–22. 204. Spanagel R, Vengeliene V. New pharmacological treatment strategies for relapse prevention. Curr Top Behav Neurosci 2013;13:583–609.

References1353.e5 205. McClain CJ, Barve SS, Barve A, Marsano L. Alcoholic liver disease and malnutrition. Alcohol Clin Exp Res 2011;35:815–20. 206. Singal AK, Charlton MR. Nutrition in alcoholic liver disease. Clin Liver Dis 2012;16:805–26. 207. Cheung K, Lee SS, Raman M. Prevalence and mechanisms of malnutrition in patients with advanced liver disease, and nutrition management strategies. Clin Gastroenterol Hepatol 2012;10:117–25. 208. Plauth M, Cabre E, Riggio O, et al. ESPEN Guidelines on enteral nutrition: liver disease. Clin Nutr 2006;25:285–94. 209. Cabre E, Rodriguez-Iglesias P, Caballeria J, et al. Short- and longterm outcome of severe alcohol-induced hepatitis treated with steroids or enteral nutrition: a multicenter randomized trial. Hepatology 2000;32:36–42. 210. Sam J, Nguyen GC. Protein-calorie malnutrition as a prognostic indicator of mortality among patients hospitalized with cirrhosis and portal hypertension. Liver Int 2009;29:1396–402. 211. Plank LD, Gane EJ, Peng S, et al. Nocturnal nutritional supplementation improves total body protein status of patients with liver cirrhosis: a randomized 12-month trial. Hepatology 2008;48:557–66. 212. Schulz GJ, Campos AC, Coelho JC. The role of nutrition in hepatic encephalopathy. Curr Opin Clin Nutr Metab Care 2008;11:275–80. 213. Mohammad MK, Zhou Z, Cave M, et al. Zinc and liver disease. Nutr Clin Pract 2012;27:8–20. 214. Dick AA, Spitzer AL, Seifert CF, et al. Liver transplantation at the extremes of the body mass index. Liver Transpl 2009;15:968–77. 215. Englesbe MJ, Patel SP, He K, et al. Sarcopenia and mortality after liver transplantation. J Am Coll Surg 2010;211:271–8. 216. Louvet A, Thursz MR, Kim DJ, et al. Corticosteroids reduce risk of death within 28 days for patients with severe alcoholic hepatitis, compared with pentoxifylline or placebo-a meta-analysis of individual data from controlled trials. Gastroenterology 2018;155:458–68. 217. Smart L, Gobejishvili L, Crittenden N, et al. Alcoholic hepatitis: steroids vs. pentoxifylline. Curr Hepat Rep 2013;12:59–65. 218. Mathurin P, Abdelnour M, Ramond MJ, et al. Early change in bilirubin levels is an important prognostic factor in severe alcoholic hepatitis treated with prednisolone. Hepatology 2003;38:1363–9. 219. Louvet A, Naveau S, Abdelnour M, et al. The Lille model: a new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated with steroids. Hepatology 2007;45:1348–54. 220. Akriviadis E, Botla R, Briggs W, et al. Pentoxifylline improves shortterm survival in severe acute alcoholic hepatitis: a double-blind, placebo-controlled trial. Gastroenterology 2000;119:1637–48. 221. De BK, Gangopadhyay S, Dutta D, et al. Pentoxifylline versus prednisolone for severe alcoholic hepatitis: a randomized controlled trial. World J Gastroenterol 2009;15:1613–9. 222. Thursz MR, Richardson P, Allison M, et al. Prednisolone or pentoxifylline for alcoholic hepatitis. N Engl J Med 2015;372:1619–28. 223. Mitchell MC, Friedman LS, McClain CJ. Medical management of severe alcoholic hepatitis: expert review from the Clinical Practice Updates Committee of the AGA Institute. Clin Gastroenterol Hepatol 2017;15:5–12. 224. Szabo G. Clinical trial design for alcoholic hepatitis. Semin Liver Dis 2017;37:332–42. 225. Singh V, Keisham A, Bhalla A, et al. Efficacy of granulocyte colonystimulating factor and n-acetylcysteine therapies in patients with severe alcoholic hepatitis. Clin Gastroenterol Hepatol 2018;16:1650–6. 226. Philips CA, Phadke N, Ganesan K, Ranade S, Augustine P. Corticosteroids, nutrition, pentoxifylline, or fecal microbiota transplantation for severe alcoholic hepatitis. Indian J Gastroenterol 2018;37:215–25.

227. Philips CA, Phadke N, Ganesan K, Augustine P. Healthy donor faecal transplant for corticosteroid non-responsive severe alcoholic hepatitis. BMJ Case Rep 2017;2017. 228. Bukong TN, Iracheta-Vellve A, Saha B, et al. Inhibition of spleen tyrosine kinase activation ameliorates inflammation, cell death, and steatosis in alcoholic liver disease. Hepatology 2016;64:1057–71. 229. Ouyang X, Han SN, Zhang JY, et al. Digoxin suppresses pyruvate kinase M2-promoted HIF-1alpha transactivation in steatohepatitis. Cell Metab 2018;27:1156. 230. Ki SH, Park O, Zheng M, et al. Interleukin-22 treatment ameliorates alcoholic liver injury in a murine model of chronic-binge ethanol feeding: role of signal transducer and activator of transcription 3. Hepatology 2010;52:1291–300. 231. Ambade A, Lowe P, Kodys K, et al. Pharmacological inhibition of CCR2/5 signaling prevents and reverses alcohol-induced liver damage, steatosis and inflammation in mice. Hepatology 2019;69:1105–21. 232. Lucey MR. Liver transplantation in patients with alcoholic liver disease. Liver Transpl 2011;17:751–9. 233. Burra P, Senzolo M, Adam R, et al. Liver transplantation for alcoholic liver disease in Europe: a study from the ELTR (European Liver Transplant Registry). Am J Transpl 2010;10:138–48. 234. Pfitzmann R, Schwenzer J, Rayes N, et al. Long-term survival and predictors of relapse after orthotopic liver transplantation for alcoholic liver disease. Liver Transpl 2007;13:197–205. 235. Cuadrado A, Fabrega E, Casafont F, Pons-Romero F. Alcohol recidivism impairs long-term patient survival after orthotopic liver transplantation for alcoholic liver disease. Liver Transpl 2005;11:420–6. 236. Gallegos-Orozco JF, Charlton MR. Alcoholic liver disease and liver transplantation. Clin Liver Dis 2016;20:521–34. 237. DiMartini A, Dew MA, Day N, et al. Trajectories of alcohol consumption following liver transplantation. Am J Transpl 2010;10:2305–12. 238. Murray KF, Carithers Jr RL. Aasld. AASLD practice guidelines: evaluation of the patient for liver transplantation. Hepatology 2005;41:1407–32. 239. Lucey MR, Terrault N, Ojo L, et al. Long-term management of the successful adult liver transplant: 2012 practice guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation. Liver Transpl 2013;19:3–26. 240. Donnadieu-Rigole H, Olive L, Nalpas B, et al. Follow-up of alcohol consumption after liver transplantation: interest of an addiction team? Alcohol Clin Exp Res 2017;41:165–70. 241. Fleming MF, Smith MJ, Oslakovic E, et al. Phosphatidylethanol detects moderate-to-heavy alcohol use in liver transplant recipients. Alcohol Clin Exp Res 2017;41:857–62. 242. Mathurin P, Moreno C, Samuel D, et al. Early liver transplantation for severe alcoholic hepatitis. N Engl J Med 2011;365:1790–800. 243. Lee BP, Chen PH, Haugen C, et al. Three-year results of a pilot program in early liver transplantation for severe alcoholic hepatitis. Ann Surg 2017;265:20–9. 244. Lee BP, Mehta N, Platt L, et al. Outcomes of early liver transplantation for patients with severe alcoholic hepatitis. Gastroenterology 2018;155:422–30. 245. Kilmer B, Nicosia N, Heaton P, Midgette G. Efficacy of frequent monitoring with swift, certain, and modest sanctions for violations: insights from South Dakota’s 24/7 Sobriety Project. Am J Public Health 2013;103:e37–43.

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Nonalcoholic Fatty Liver Disease Dawn M. Torres, Stephen A. Harrison

CHAPTER OUTLINE EPIDEMIOLOGY. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1354 DEFINITIONS AND ASSOCIATIONS. . . . . . . . . . . . . . . . . . 1355 PATHOGENESIS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1356 Hepatic Steatosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1356 Steatohepatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1356 CLINICAL FEATURES AND DIAGNOSIS. . . . . . . . . . . . . . . 1358 Liver Biopsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1359 Imaging to Detect Fibrosis. . . . . . . . . . . . . . . . . . . . . . . 1359 Laboratory Tests for Fibrosis. . . . . . . . . . . . . . . . . . . . . 1360 Focal Fatty Liver . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1361 NATURAL HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1361 CLINICAL ASSOCIATIONS . . . . . . . . . . . . . . . . . . . . . . . . 1362 TREATMENT. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1362 Lifestyle Modification . . . . . . . . . . . . . . . . . . . . . . . . . . 1362 Bariatric Surgery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1364 Pharmacotherapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1364 LT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1365

The global obesity epidemic has dramatically increased the prevalence of NAFLD and made it the leading cause of chronic liver disease in Western nations. NAFLD is considered the hepatic manifestation of the metabolic syndrome and shares a strong association with type 2 diabetes mellitus, obstructive sleep apnea (OSA), and cardiovascular disease. Although cardiovascular disease is the leading cause of death in patients with NAFLD, the subset of patients who meet histopathologic criteria for NASH are those at greatest risk of liver-related morbidity and mortality. Ludwig and colleagues coined the term NASH in 1980 to describe a cohort of middle-aged patients with elevated serum liver enzyme levels who had evidence of alcohol-associated hepatitis on biopsy specimens in the absence of alcohol consumption.1 Subsequent study led to the proposed “2-hit” hypothesis in which a sequential progression from isolated fatty liver (IFL) to NASH involved the initial “hit” of hepatic steatosis followed by a second “hit” of oxidative stress resulting in liver injury.2 It was subsequently recognized that patients who have steatohepatitis on a liver biopsy specimen are at greatest risk for progression to cirrhosis compared with those who have IFL. Correspondingly, our understanding of the pathogenesis of NAFLD has evolved from the 2-hit hypothesis. NASH is expected to become the most common cause of cirrhosis and the leading indication for LT in the USA in the 2020s. As a major public health concern, an understanding of its epidemiology and pathogenesis is paramount to facilitate our ability to effectively diagnose and treat patients with NAFLD and NASH.

EPIDEMIOLOGY The rise of NAFLD has paralleled the rising rates of obesity. In 2016, 39% of adults in the USA qualified as overweight, and another 13% were obese (see Chapter 7). These figures are triple the rate of obesity described in 1975.3 Prevalence estimates vary widely depending on the information available in a given population and

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the diagnostic criteria used to establish the diagnosis (i.e., liver biochemical test levels, imaging study results, or liver biopsy findings). Because the majority of patients with NAFLD are asymptomatic, the prevalence of NAFLD in the USA and globally is not completely defined, although a meta-analysis in 2016 suggested a global prevalence of 25%.4 The first estimates of the prevalence of NASH came from autopsy studies, in which steatohepatitis was found in 18.5% of markedly obese and 2.7% of lean persons.5 Advanced hepatic fibrosis was seen in 13.8% of markedly obese persons compared with 6.6% of lean persons. High rates of NAFLD and NASH among the obese were subsequently confirmed in a study of patients undergoing bariatric surgery, in whom the frequency of NAFLD and NASH was reported to be as high as 91% and 37%, respectively.6 The Dallas Heart Study used magnetic resonance spectroscopy in more than 2200 adults to identify a 31% frequency of fatty liver disease in a cohort of asymptomatic persons.7,8 Subsequent population-based cohort studies from China, Japan, and Korea using US have reported NAFLD prevalence rates ranging from 10% to 24%.9-11 The largest study using US paired with hepatic histology evaluated a cohort of asymptomatic middleaged persons from San Antonio, Texas and revealed a 46% prevalence rate of NAFLD and a 12.2% prevalence rate of NASH.12 Most cases of NAFLD are discovered in middle age during the fourth to sixth decades of life, although NAFLD has also been described with increasing frequency in children and adolescents, in whom the frequency of overweight and obese persons has been reported to be 30% of the population.13 The prevalence of pediatric NAFLD cases has risen accordingly, with a meta-analysis demonstrating a pooled mean prevalence rate for NAFLD in the general pediatric population of 7.6%; in a pediatric obesity clinic, the frequency is as high as 34.2%.14 Most relevant studies have reported NAFLD to be more common in men than women and describe a later peaking prevalence in women than men, including a propensity for more advanced disease in postmenopausal women,15 suggesting a relationship with sex hormones and menopause.16 NAFLD (and specifically NASH) is often associated with diabetes mellitus, with an associated 60% to 76% prevalence rate for NAFLD and a 22% prevalence rate for NASH.17 This finding is not surprising because NAFLD is considered to be the hepatic manifestation of the metabolic syndrome as defined by the presence of 3 or more of the following: abdominal obesity, hypertriglyceridemia, low HDL levels, hypertension, and elevated fasting plasma glucose levels.18 The role of ethnicity is evolving. Early evidence from the Dallas Heart Study suggested that ethnicity was important, with Hispanics showing the highest prevalence of NAFLD (45%), compared with 33% in Caucasians and 24% in African Americans. Similar findings were reported by Williams and colleagues, with a 58.3% prevalence rate for NAFLD in Hispanics, compared with 44% in Caucasians and 35% in African Americans. The reason for these trends appears multifactorial. A study by the NASH Clinical Research Network found Hispanics with NASH to be younger, less active, and consuming a diet higher in carbohydrates when compared with Caucasians.19 A systematic review and meta-analysis confirmed that the prevalence of NAFLD is highest among Hispanics, followed by Caucasians and then African Americans, with similar proportions of liver fibrosis in the 3 ethnic groups.20

CHAPTER 87  Nonalcoholic Fatty Liver Disease

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87

Fig. 87.1  Histologic features of isolated fatty liver. The characteristic feature is diffuse macrovesicular steatosis without significant necroinflammation or fibrosis. Glycogenated nuclei are common (H&E). (Courtesy Dr. Gregory Y. Lauwers, Boston, MA.)

Lifestyle is important, and increased consumption of highfructose corn syrup and sugar-containing sodas, coupled with a sedentary lifestyle, has been associated with higher rates of NAFLD, and specifically NASH. Genetic influences on the development of NAFLD may prove to be equally important. Single nucleotide polymorphisms (SNPs) from specific genes have been found to be associated with an increased risk of NAFLD. The first of these SNPs to be identified was in the patatin-like phospholipase domain-containing protein-3 (PNPLA3) gene located on chromosome 22q13 and known to encode adiponutrin, a 481amino acid protein that mediates triacylglycerol synthesis.21 The allelic variant rs738409 results in a change from isoleucine to methionine at position 148 (I148M) and has been shown to be associated with increased hepatic steatosis as well as inflammation.22 This variant was more common in Hispanics followed by Caucasians and African Americans and may explain the higher rates of NASH seen in Hispanic populations. Subsequent study has confirmed the association of the I148M SNP with hepatic steatosis, NASH, and even fibrosis with a meta-analysis demonstrating an odds ratio (OR) of 3.26 (95% confidence interval (CI) CI, 2.14 to 4.95) for NASH and 3.25 (95% CI, 2.86 to 3.70) for hepatic fibrosis for persons with the I148M SNP.23 More recently, the membrane bound O-acyltransferase domain containing 7 (MBOAT7) locus has been shown to be associated with hepatic steatosis, steatohepatitis,24 and, potentially, the development of HCC.25 Numerous other genetic polymorphisms have been studied, including those encoding proteins involved in VLDL secretion (apolipoprotein B, apoB; transmembrane 6 superfamily 2, TM6SF2), de novo lipogenesis regulation (glucokinase regulatory protein, GCKR; Krüppel-like factor 6, KLF6), the innate immune system (interferon lambda 3, IFNL3), and mitochondrial oxidation (superoxide dismutase 2, SOD2).26 Ongoing research will provide a better understanding of the complex interplay between genetic and host factors that promote the development of hepatic steatosis and steatohepatitis. 

DEFINITIONS AND ASSOCIATIONS Macrovesicular fat accumulation in more than 5% of hepatocytes is the defining feature of NAFLD. As mentioned earlier, IFL compromises the majority of patients with NAFLD and is defined by hepatic steatosis in the absence of significant necroinflammation or fibrosis (Fig. 87.1). Hepatocyte ballooning

Fig. 87.2  Histologic features of NASH. Diffuse or perivenular macrovesicular steatosis is present. Lobular inflammation consists of neutrophils, lymphocytes, and other mononuclear cells. Hepatocyte ballooning and necrosis of varied degrees are hallmark features. Glycogenated nuclei are present. Mallory bodies, which may be small, sparse, and inconspicuous, are seen (H&E). (Courtesy Dr. Gregory Y. Lauwers, Boston, MA.)

degeneration and lobular inflammation of a mixed inflammatory cell infiltrate is required to meet criteria for NASH, and Mallory-Denk (or Mallory) bodies, iron deposition, ductular reaction, megamitochondria, periodic acid-Schiff-diastaseresistant Kupffer cells, and vacuolated nuclei in periportal hepatocytes may also be seen (Fig. 87.2).27 Fibrosis, if present, is predominantly perisinusoidal and pericellular (“chicken-wire fibrosis”) in acinar zone 3 (see Chapter 71), although it may extend to portal and periportal regions with disease progression (Box 87.1). Alcohol-associated steatosis and steatohepatitis (alcohol-associated hepatitis) are histologically indistinguishable from IFL and NASH (see Chapter 86), although expert pathologists describe more fibro-occlusive venous lesions and bile stasis in alcohol-associated steatohepatitis.28 Pediatric NAFLD is a somewhat distinct histologic entity marked by portal-based chronic inflammation and fibrosis with less frequent findings of hepatocyte ballooning and Mallory-Denk bodies.29 To reach consensus on the pathologic classification of NASH, the Pathology Committee of the National Institutes of Health NASH Clinical Research Network proposed a scoring system incorporating 14 histologic features in 2005.30 The NAFLD activity score (NAS) combines the unweighted sum of scores for steatosis, lobular inflammation, and hepatocellular ballooning on a scale of 0 to 8 (Table 87.1). A score of 0 to 2 is most suggestive of “not-NASH,” and a score of 5 or greater suggests that NASH is present. Although the NAS is primarily a research tool and NASH is not defined by an absolute score, NAS provides a framework to accurately detect changes in disease activity with therapy. Other conditions may promote hepatic steatosis and should be considered (Box 87.2). TPN, rapid weight loss, or starvation can lead to hepatic steatosis. Similarly, surgeries that lead to rapid and extreme intestinal malabsorption and weight loss, such as extensive small bowel resection, biliopancreatic diversion, or jejunoileal bypass, have been associated with hepatic steatosis. Medications such as amiodarone, valproic acid, methotrexate, tamoxifen, glucocorticoids, certain antiretrovirals, and tetracyclines have also been implicated, as have systemic conditions such as Wilson disease, abetalipoproteinemia, and lipodystrophy.

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PART IX  Liver

BOX 87.1 Histologic Features of NAFLD OBSERVED IN ALL OR MOST CASES Macrovesicular steatosis Diffuse or centrilobular steatosis; degree may correlate with BMI Parenchymal inflammation Polymorphonuclear neutrophils, lymphocytes, other mononuclear cells Hepatocyte necrosis Ballooning hepatocyte degeneration OBSERVED WITH VARIED FREQUENCIES Perivenular, perisinusoidal, or periportal fibrosis (37%-84%), moderate to severe in 15%-50%; most prevalent in zone 3 (perivenular) Cirrhosis (7%-16% on index biopsy specimen) Mallory bodies Glycogenated nuclei Lipogranulomas Stainable hepatic iron

TABLE 87.1  NAFLD Activity Score Steatosis (%) 5 5-33 33-66

1 2 3

Ballooning None Few Many

0 1 2

Lobular Inflammation Mild Moderate Severe

1 2 3

Total Score 0-2 3-4 5-8

Likely not NASH Intermediate Likely NASH

PATHOGENESIS The “2-hit hypothesis” proposed by Day and colleagues in 1988 (see earlier) has provided a framework for our current understanding of the increasingly complicated pathway to hepatic steatosis, steatohepatitis, and fibrosis. The 2-hit hypothesis states that dysregulation of fatty acid metabolism leads to steatosis, which is associated with several cellular adaptations and altered signaling pathways that render hepatocytes vulnerable to a second hit. The second insult may be 1 or more environmental or genetic perturbations that cause hepatocyte necrosis and inflammation. In a minority of cases, incompletely defined factors activate a fibrogenic cascade that leads eventually to cirrhosis. In light of the variety of conditions that have been associated with NAFLD, it is not surprising that no single mechanism has been identified and that numerous interacting and nonlinear pathways, influenced by a variety of environmental and genetic factors, promote hepatic steatosis, steatohepatitis, and fibrosis.

Hepatic Steatosis Hepatic steatosis is the hallmark histologic feature of NAFLD and the net result of excessive accumulation of free fatty acid

(FFA). Normally, FFA is supplied to the liver through intestinal absorption (in the form of chylomicron remnants) or from lipolysis of adipose tissue, where FFA is stored as TG. In the liver, FFA is oxidized by mitochondria, esterified into TG, synthesized into phospholipids and cholesteryl esters, and secreted from the liver as VLDL (see Chapter 72). Fatty acid metabolism is under tight regulatory control by catecholamines, glucagon, growth hormone, and insulin. Hepatic TG accumulation occurs when fatty acid metabolism shifts to favor net lipogenesis, rather than lipolysis. This shift occurs when the amount of FFA supplied to the liver from the intestine or adipose tissue exceeds the amount needed for mitochondrial oxidation, phospholipid synthesis, and synthesis of cholesteryl esters. TG also accumulate in the liver when synthesis of lipoprotein decreases or export of lipids from the liver is impeded. Insulin resistance from excessive accumulation of FFA is thought to be a primary factor in the development of steatosis in most patients with NAFLD. Impairment of insulin signaling in adipose tissue and the liver, along with increased dietary fat and de novo lipogenesis, contributes to hepatic steatosis in NAFLD.31 Dietary fructose is delivered directly via the portal vein to the liver, where it activates carbohydrate response element binding protein and sterol regulatory element binding protein-1 (SREBP) to promote de novo lipogenesis.32 The excess and dysfunctional visceral adipose tissue seen in NAFLD further promotes insulin hypersecretion secondary to insulin resistance. The increased secretion of specific proinflammatory cytokines, such as leptin, TNF-α, IL-6, resistin, and plasminogen activator inhibitor-1, has been described, along with decreased secretion of the anti-inflammatory cytokine adiponectin. Serum adiponectin levels are reduced in obesity, insulin resistance, diabetes mellitus, and the metabolic syndrome.33 Higher leptin and lower adiponectin levels have been associated with liver inflammation and fibrosis.34 Research into the pathogenesis of NAFLD has addressed the role of bile acids (BAs) and their nuclear hormone receptors as vital regulators of energy homeostasis during carbohydrate and lipid metabolism in hepatic and extrahepatic tissues (see Chapter 64). BAs absorbed from the distal ileum bind to these nuclear hormone receptors. The most studied nuclear hormone receptor is the farnesoid X receptor (FXR), which has been identified as the master regulator of BA synthesis. Activation of FXR has been shown to decrease de novo lipogenesis, impair VLDL synthesis and assembly, and increase β-oxidation of FFA.35 Other nuclear hormone receptors such as G-protein‒coupled bile acid receptor (TGR-5), sphingosine 1 receptor 2, and pregnane X receptor (PXR, NR1I2) also appear to be important and may offer future therapeutic targets.36 

Steatohepatitis Although insulin resistance and hyperinsulinemia are clearly pivotal to the development of steatosis, consensus is lacking on the subsequent insults that lead to steatohepatitis and fibrosis in some patients. Isolated steatosis may be considered to be an adaptive mechanism designed to mitigate the effects of long chain saturated fatty acids in the liver. If the protective processes are overwhelmed or faulty, lipotoxicity can develop, potentially activating numerous signaling pathways resulting in hepatocyte apoptosis and stellate cell activation. The precise signaling pathways are still being uncovered, but several key pathways have been defined. Cellular homeostasis, communication, and regulation involve lipids, which are an essential part of cell structure. Increased levels of FFA can be directly toxic to hepatocytes through a number of mechanisms. An excess of specific FFA, including palmitic acid, cholesterol, lysophosphatidylcholine, and ceramides, is particularly harmful to intracellular organelles.37 These toxic lipids promote oxidative and endoplasmic reticulum stress,

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BOX 87.2 Causes of Fatty Liver Disease ACQUIRED METABOLIC DISORDERS Diabetes mellitus Dyslipidemia Kwashiorkor and marasmus Obesity Starvation CYTOTOXIC AND CYTOSTATIC DRUGS L-Asparaginase Azacytidine Bleomycin Cisplatin 5-Fluorouracil Methotrexate Tetracycline* OTHER DRUGS AND TOXINS Amiodarone Antiretroviral therapy (didanosine, stavudine, zidovudine) Camphor Chloroform Cocaine Ethanol Ethyl bromide Estrogens Glucocorticoids Griseofulvin Lycopodium serratum (Jin bu huan, herbal supplement) Nifedipine Nitrofurantoin NSAIDs (buprofen, indomethacin, piroxicam, sulindac) Tamoxifen Valproic acid

87 METALS Antimony Barium salts Chromates Mercury Phosphorus Rare earths of low atomic number Thallium compounds Uranium compounds INBORN ERRORS OF METABOLISM Abetalipoproteinemia Familial hepatosteatosis Galactosemia Glycogen storage disease Hereditary fructose intolerance Homocystinuria Systemic carnitine deficiency Tyrosinemia Weber-Christian syndrome Wilson disease SURGICAL PROCEDURES Biliopancreatic diversion Extensive small bowel resection Jejunoileal bypass MISCELLANEOUS CONDITIONS IBD Industrial exposure to petrochemicals Jejunal diverticulosis with SIBO Partial lipodystrophy TPN

*Tetracycline is cytotoxic by virtue of inhibiting mitochondrial β-oxidation.

modify mitochondrial function, and induce autophagy, leading to activation of hepatic stellate cells and fibrosis.38 Autophagy is another housekeeping process within hepatocytes that involves autodigestion of unwanted proteins and organelles (see Chapter 72). Lipotoxicity in hepatocytes has also been shown to increase the inflammatory response through the release of cell-derived extracellular vesicles, which are bioactive molecules that appear to activate hepatic stellate cells and promote fibrinogenesis in NASH.39 The hedgehog signaling pathway, an important part of the liver’s usual synchronized response to wound healing, is another area of dysregulation involved in the pathogenesis of NAFLD. Lipotoxicity activates the hedgehog pathway, thereby promoting portal inflammation, hepatocellular ballooning, and hepatic fibrosis.40 Activation of the hedgehog signaling pathway leads to the conversion of quiescent hepatic stellate cells to myofibroblasts, which in turn produce chemoattractants for natural killer cells.41 Natural killer cells are responsible for secreting profibrotic cytokines that further activate myofibroblasts. The stage of hepatic fibrosis (see later, and Chapter 74) has been directly correlated with the degree of hedgehog pathway activation in patients with NASH,42 and mouse model studies have demonstrated that inhibition of the hedgehog pathway can reverse liver fibrosis.43 The role of the intestinal microbiota in the development of NAFLD is becoming increasingly appreciated with enhanced understanding of the close relationship between the GI tract and the liver. Organisms (mostly bacteria) in the GI tract contribute to digestion and act as important modulators of the immune

system (see Chapter 3). Dysbiosis is defined as an imbalance between protective and harmful bacteria and can lead to altered intestinal permeability and perturbations in immunity.44 Data also suggest the existence of a distinct gut microbiota in patients with NASH.45 SIBO in the setting of a surgical jejunoileal bypass or duodenal switch procedure (performed in the past to treat obesity) has been associated with the development of NASH, the risk of which is reduced with antibiotics or even eliminated with revision of the surgical procedure.46,47 Obesity and fructose consumption have been linked to gutderived endotoxin in humans.48,49 Yang and colleagues demonstrated that ob/ob mice with steatosis are highly vulnerable to endotoxin-induced hepatocyte damage, and NASH rapidly develops in these animals after exposure to low doses of bacterial lipopolysaccharide (LPS).50 The net result of increased endotoxin, particularly from Gram-negative bacteria, is an activation of Kupffer cells via toll-like receptor 4, which in turn up-regulates several inflammatory pathways, including activation of Jun N-terminal kinase and nuclear factor kappa B, and releases pro-inflammatory cytokines such as TNF-α and IL-1β. Follow-up studies of mice deficient in the LPS binding protein, compared with wild-type mice fed high-fructose, high-fat diets have supported the critical role of LPS in the development of NAFLD.51 Any 1 of the putative mechanisms discussed is unlikely to explain the pathogenesis of NAFLD in all affected patients. The precise interplay among various mechanisms remains to be elucidated. Our present understanding of the pathogenesis of NASH

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Fig. 87.3  Mechanism of action of pharmacologic treatments for NAFLD and NASH. The sites of action of available and experimental agents (some of which are discussed in the text) with metabolic, anti-inflammatory, and antifibrotic effects are shown. ACC, Acetyl-CoA carboxylase; AOC, amine oxidase, copper containing; DNL, de novo lipogenesis; ER, endoplasmic reticulum; FFA, free fatty acids; FGF, fibroblast growth factor; FXR, farnesoid X receptor; IL, interleukin; JNK, Jun N-terminal kinases; LPS, lipopolysaccharide; PPAR, peroxisome proliferator-activated receptor; ROS, reactive oxygen species; SIM, simtuzumab; SHP, small heterodimer partner; SREBP, sterol regulatory element binding proteins; TLR, toll like receptor; TR, thyroid receptor; UPR, unfolded protein response. (From Konerman MA, Jones JC, Harrison SA. Pharmacotherapy for NASH: current and emerging. J Hepatol 2018;68:362-75.)

is summarized in Fig. 87.3, with an emphasis on pathways with therapeutic targets under investigation. 

CLINICAL FEATURES AND DIAGNOSIS The clinical and laboratory features of NAFLD are summarized in Table 87.2. NAFLD is usually discovered incidentally because of elevated liver biochemical test levels or an incidental finding of hepatic steatosis on imaging. Most patients with NAFLD are asymptomatic, but some may describe vague RUQ pain, fatigue, and malaise. Hepatomegaly is commonly seen but is often difficult to appreciate on physical examination because of obesity. Stigmata of chronic liver disease, such as splenomegaly, spider telangiectasias, and ascites, are limited to patients with NASH cirrhosis (see Chapter 74). To establish a diagnosis of NAFLD, alcohol-associated liver disease must be excluded, and the diagnosis of NAFLD should be entertained only in the absence of significant alcohol use (consumption of less than 20 to 40 g of alcohol per day in most clinical studies). In patients with metabolic risk factors and significant alcohol use, it is impossible to determine which factor is paramount, and both can be assumed to be the cause of the liver disease. In metabolic fatty liver disease, mild-to-moderate (1.5- to 4-fold) elevations of the serum AST or ALT level, or both, is

common, although levels seldom exceed 10 times the upper limit of normal. The serum ALT level usually is greater than the AST level, in contrast with the pattern in alcohol-associated, in which the AST level is typically at least 2-fold higher than the ALT level. A large retrospective study of patients with NAFLD demonstrated a mean serum ALT level of 83 and AST level of 63 IU/mL.52 The alkaline phosphatase and GGTP levels may be elevated, but the serum bilirubin level, prothrombin time, and serum albumin level typically are normal, except in patients with NAFLD-associated cirrhosis. Up to one fourth of patients with NAFLD may have ANA in low titers (50 yr) Obesity Diabetes mellitus/insulin resistance Ethnicity (Hispanic) Hypertension LABORATORY AST/ALT ratio approaching 1 Serum ALT level > twice the upper limit of normal Serum AST level > 40 U/L HISTOLOGIC Necroinflammatory activity (hepatocyte ballooning, necrosis) Stainable iron Fibrosis *NASH and advanced fibrosis.

of more advanced fibrosis as the value approaches 1 in patients with NAFLD. Box 87.3 lists the common risk factors for advanced fibrosis in NAFLD. 

Focal Fatty Liver In contrast to NAFLD, which is a diffuse parenchymal process, focal fatty liver is a localized or patchy process that simulates a space-occupying lesion in the liver on imaging studies. This condition has been recognized increasingly in adults and children as a result of the improved sensitivity of abdominal imaging. Focal fatty liver has characteristic patterns on CT: usually a nonspherical shape, absence of mass effect, and CT attenuation values consistent with those of soft tissue.72 The density of focal fatty liver is close to that of water, unlike that of liver metastases, which have a density that is closer to that of hepatocytes. US and MRI can help confirm a diagnosis of focal fatty liver (Fig. 87.6). A presumptive diagnosis of focal fatty liver should not be made when a mass effect, areas of mixed hypo- and hyperechogenicity, an irregular shape, or a history of malignancy is present. In such cases, ultrasound-guided fine-needle biopsy is recommended. No evidence exists to suggest that the pathogenesis of focal fatty liver is similar to that of NAFLD. In fact, the pathogenesis of focal fatty liver is uncertain and may involve altered venous blood flow to the liver, tissue hypoxia, or intestinal malabsorption of lipoprotein. In the absence of accompanying liver disease, the lesion often regresses. No specific treatment is necessary. 

Fig. 87.6  Focal fatty liver. Focal fatty liver (arrow) on CT. The characteristic features are the nonspherical shape, absence of a mass effect, and CT attenuation values consistent with those of soft tissue. US and MRI also may confirm the diagnosis of focal fatty liver. (Courtesy Dr. Mukesh Harisinghani, Boston, MA.) NAFLD 80%

20%

Isolated fatty liver

NASH

~11% over 15 yr Cirrhosis ~31% over 8 yr

~7% over 6.5 yr

Decompensation

HCC

NATURAL HISTORY

Fig. 87.7  Natural history of NAFLD, including isolated fatty liver (IFL) and NASH. IFL rarely if ever progresses to cirrhosis and is not associated with an increased risk of death compared with the general population. NASH is associated with an increased risk of death due to cardiovascular disease, malignancy, and cirrhosis and its complications. Progression of fibrosis in NASH is associated with diabetes mellitus, severe insulin resistance, higher BMI, weight gain >5 kg, cigarette smoking, and rising serum aminotransferase levels. (Adapted from Torres DM, Williams CD, Harrison SA. Features, diagnosis and treatment of nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2012;10:837-58.)

The natural history of NAFLD is determined in large part by the histopathology of the liver at baseline, which identifies patients with NASH and quantifies the amount of hepatic fibrosis. The prognosis in patients with IFL in the absence of hepatocyte necrosis and fibrosis is clearly more favorable, with a low potential for histologic or clinical progression.73 Patients with NAFLD have been shown to have increased overall mortality compared with matched controls without NAFLD,74 and the increased liver-related mortality is confined to patients with NASH.75,76 Fibrosis appears to be the single most important predictor of disease-specific mortality, as shown in a cohort study of 229 patients with biopsy-proven NAFLD followed for up to 33 years in whom a fibrosis stage of 3 to 4, irrespective of the NAS, had an increased mortality with a hazard ratio of 3.3 (confidence interval [CI], 2.27 to 4.76).77 There is substantial variability in the rate of fibrosis

progression, and no clinical or laboratory data appear to reliably predict the disease course. A meta-analysis of 11 cohort studies has suggested annual fibrosis progression rates, from a baseline of stage 0, of 0.07 stages for IFL compared with 0.14 stages for NASH.78 This translates into progression of 1 stage over 14.3 years in patients with IFL and 7.1 years in patients with NASH. A reasonable estimate is that ∼11% of patients with NASH progress to cirrhosis over a 15- to 20-year period (Fig. 87.7).79 NAFLD and alcoholic hepatitis are similar histologically but differ substantially in clinical outcomes. The 5-year survival rate of patients with alcohol-associated hepatitis is only 50% to 75% because of the large proportion of patients (>50%) in whom cirrhosis and its complications develop (see Chapter 86). One study has shown that the long-term survival of patients with NASH is

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significantly better than that of patients with alcohol-associated hepatitis.80 In patients in whom NAFLD-associated cirrhosis develops, the outcome may be similar to that for other causes of cirrhosis. NAFLD is the likely cause of most cases of cryptogenic cirrhosis,81 is the second most common indication for LT,82 and is expected to become the leading indication for LT in the 2020s (see Chapter 97).83 In concert with rising rates of NASH cirrhosis, rates of NAFLD-related HCC are increasing, with one study showing a 9% annual increase84 and another suggesting that ∼7% of patients with NASH cirrhosis will progress to HCC over 6.5 years of follow-up.85 Reports of HCC developing in noncirrhotic patients with NASH86 pose a difficult diagnostic dilemma, because it may not be feasible to survey such a large population for HCC (see Chapters 74 and 97). 

CLINICAL ASSOCIATIONS As noted earlier, the metabolic syndrome and diabetes mellitus are associated with NAFLD. Other conditions, including cardiovascular disease, OSA, vitamin D deficiency, colonic adenomas, hypothyroidism, chronic kidney disease, and polycystic ovarian syndrome have also been associated with NAFLD. Cardiovascular disease has been shown to be the primary cause of death in this population. Although this is not surprising given the association of NAFLD with the metabolic syndrome, evidence points to NAFLD as an independent risk factor for cardiovascular disease with an OR of 2.05 (95% CI, 1.81 to 2.31).95 In 5121 asymptomatic individuals, NAFLD was an independent risk factor for subclinical coronary atherosclerosis as detected by coronary CT angiography.96 OSA is common in the general population with an estimated frequency of 1% to 4% and higher rates (25% to 35%) in obese populations. Chronic intermittent hypoxia was associated with a high NAS and increased hepatic fibrosis in a cohort of morbidly obese patients undergoing bariatric surgery.97 One study has demonstrated that obese patients with OSA have a greater than 90% frequency of NAFLD and that 50% of patients with NAFLD have symptoms suggestive of OSA.98 Vitamin D deficiency has been related to increased endotoxin exposure (see earlier), and the recognition of its widespread prevalence parallels that of NAFLD. The coexistence of NAFLD and vitamin D deficiency appears to go beyond a simple association because vitamin D deficiency is found in populations with NAFLD independent of age, gender, and serum TG and glucose levels,99 although a meta-analysis has suggested that vitamin D deficiency is not associated with the histologic severity of NAFLD.100 There are no prospective studies to suggest vitamin D replacement may improve NAFLD or NASH, but it has become common to check vitamin D levels and replete vitamin D as necessary in patients with NAFLD. Several retrospective and prospective studies have also suggested a relationship between NAFLD and colonic adenomas.101 One population-based study in Korea102 and one prospective study in China103 showed higher frequencies of colonic adenomas, as well as of advanced neoplasia such as cancer, high-grade dysplasia, or villous histology, in persons with NAFLD. A study of 26,540 patients undergoing first-time colonoscopy and same-day abdominal US demonstrated higher rates of advanced colorectal neoplasia in patients with NAFLD compared with patients without NAFLD (OR 1.2; 95% CI, 0.99 to 1.47).104 NAFLD has been reported to be associated with chronic kidney disease. A large meta-analysis demonstrated that NAFLD is associated with a 40% increase in incident chronic kidney disease.105 Similarly, in a cohort of middle-aged patients without chronic kidney disease assessed for NAFLD via the NAFLD fibrosis score and US,106 the risk of developing chronic kidney disease was greater in patients with NAFLD and increased with a greater NFS. 

TREATMENT The optimal therapy for NAFLD has not been established, although there is general consensus that treatment efforts should be targeted to patients with NASH, particularly with fibrosis. Each of the histologic or surrogate end points that have been used in treatment trials have limitations. Histologic improvement in steatosis, inflammation, and fibrosis is the ultimate goal of treatment, but a single drug is unlikely to produce all these effects. As fibrosis worsens, steatosis and inflammation often improve; therefore, NASH and fibrosis must be assessed separately. As discussed earlier, the NAS has been the most accepted scoring system for quantifying histologic improvement, and a 2-point improvement in the NAS, with 1 of the points coming from a reduction in hepatocyte ballooning, has been thought to indicate a successful intervention.107 Improvement in fibrosis (which is not part of the NAS) has become a primary end point of newer trials, although inclusion of this end point has lengthened the duration of treatment trials from 6 to 12 months to multiple years. Most trials with histologic end points target either a 2-point improvement in the NAS with stable fibrosis or improvement in fibrosis with a stable NAS. Although still the gold standard, liver biopsy is invasive and subject to interobserver variability as well as sampling error (see earlier). Therefore, interest has increased in biomarkers as potential surrogate end points for clinical treatment trials. Noninvasive markers of hepatic fibrosis, such as VCTE and MRE, are often used in clinical treatment trials. Controlled attenuation parameter software may be added on to VCTE to quantify steatosis. Biochemical markers such as CK-18 and scoring systems including the ELF and NAFLD fibrosis scores have also been used. Treatment trials using clinical end points are difficult but can be done when the trial is long in duration and focused on patients with end-stage liver disease, in whom outcomes such as variceal bleeding or encephalopathy can occur. Changes in portal venous pressure can be evaluated using directed measurement of the hepatic venous pressure gradient, particularly in clinical treatment trials focused on reducing fibrosis (see Chapter 92). Historically, the treatment of NAFLD has consisted of weight loss, removal of offending drugs and toxins, and control of associated metabolic disorders, including diabetes mellitus and hyperlipidemia. Treatment strategies are now grouped into lifestyle modification, surgical interventions for weight loss, and pharmacotherapy (Table 87.3).

Lifestyle Modification Lifestyle modification is often divided into a reduction in calories with a goal of weight loss, macronutrient modification, and physical activity, including aerobic and resistance activity. Most studies of calorie restriction include an exercise component, making it difficult to assess which approach is the most beneficial. Nutritional counseling and caloric restriction leading to weight loss have been shown to improve hepatic histology in several randomized controlled trials. One large prospective trial of 261 patients followed for 12 months demonstrated that all features of NASH improved with weight loss of at least 10%, and fibrosis stabilized or improved with weight loss of at least 5%.108 Similarly, a meta-analysis of 8 randomized controlled trials suggested a weight loss of at least 5% resulted in improvement in hepatic steatosis, and weight loss of at least 7% improved the NAS.109 Optimal approaches to obtain these weight loss goals remain undefined, and the ability to sustain weight loss over time is limited to a small minority of patients. The merits of specific diets such as the Mediterranean or lowcarbohydrate diets have not been well studied in patients with NASH. Although some data suggest that the Mediterranean diet may improve hepatic steatosis,110 there is no evidence to favor

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TABLE 87.3  Current and Future Treatment Options for NAFLD Modality

Effect

Comment(s)

Dietary Advice Weight loss 5%-10% Moderate caloric restriction with goal 500-750 kcal fewer per day

Improves most features of NASH

Difficult to sustain

Eliminate or reduce SFAs, high fructose corn syrup

High consumption risk factor for NASH and ↑ fibrosis

Prospective trials lacking

Consider omega-3 fatty acid replacement

Decreases hepatic steatosis improves serum triglycerides

Lack of histologic improvement in NAFLD/NASH Useful for hypertriglyceridemia

Consider regular coffee consumption, 2-3 cups per day

Decreased risk of fibrosis

Optimal amount unclear

Improves insulin resistance

Best results when leads to weight loss

Improves or resolves NASH in 60%-80% cases as well as fibrosis

Use only when failed lifestyle modification and comorbid conditions justify risk of surgery

Pharmacotherapy (Current) Vitamin E 800 IU daily

Improves NASH but modestly; no fibrosis benefit

Useful in nondiabetic populations ? Prostate cancer risk

Pioglitazone 30-45 mg daily

Improves NASH, possible fibrosis improvement

Side effect profile is often prohibitive (e.g., weight gain, osteoporosis, edema, congestive heart failure) Not FDA approved for NASH

Incretin mimetics (exenatide and liraglutide)

Improve insulin resistance, promote weight loss, modest histologic improvement in small trials

GI side effects Ongoing trial with semaglutide

Pentoxifylline

Possible NASH and fibrosis improvement

Small pilot trials

Statins

Does not improve NASH histology

Safe in NAFLD and reduces risk of cardiovascular disease

Ezetimibe

Modest improvement in pilot trial

Safe in NAFLD and can be used for hyperlipidemia but not as NAFLD/NASH therapy

Pharmacotherapy (Future) FXR agonists: Obeticholic acid Aldafermin

Improves NASH histology

Side effects: pruritus, increased LDL, lowered HDL

Ongoing phase 2 studies

Side effects: diarrhea, nausea, diabetes mellitus

Exercise Advice Aerobic and/or resistance training 3-4 times per wk with the goal of 400 kcal expended Bariatric Surgery Sleeve gastrectomy, RYGB, LABG

Antifibrotics: Ongoing phase 2 and phase 3 studies Cenicriviroc, emricasan, selonsertib, GR-MD-02

Promising but more data needed

PPAR-α/δ agonist: Elafibranor

Side effects: ↑ serum creatinine

Relatively modest efficacy

FXR, farnesoid X receptor; LAGB, laparoscopic adjustable gastric banding; PPAR, peroxisome proliferator-activated receptor; RYGB, Roux-en-Y gastric bypass; SFA, saturated fatty acid.

one approach over a general reduction of caloric intake. Limiting saturated fatty acids and high-fructose corn syrup may also be beneficial, because diets high in saturated fatty acids and fructose have been associated with NASH.111 A large retrospective study has even shown a correlation between daily fructose consumption and higher fibrosis stage, although no prospective trials have demonstrated histologic improvement with fructose restriction.112 Omega-3 fatty acids are approved in the USA to treat hypertriglyceridemia and have been investigated as a potential therapy for NAFLD. A meta-analysis of 9 studies of 355 patients demonstrated that omega-3 supplementation improved hepatic steatosis, although no histologic data were available.113 Reduction in steatosis occurred in the absence of weight loss with a median daily omega-3 supplement dose of 4 g. Other trials have failed to show benefit with omega-3 supplementation in NAFLD and NASH.114,115 Omega-3 supplementation requires further study as a treatment for NAFLD or NASH but can be considered for the treatment of hypertriglyceridemia in these patients.

A relationship between caffeinated coffee intake and chronic liver disease has been observed, and large retrospective studies have demonstrated a protective effect of coffee in alcoholic liver disease116 as well as chronic hepatitis C117 (see Chapters 74, 80, and 86). Preliminary studies suggest that this relationship holds true for patients with NAFLD as well, in whom coffee intake has been associated with lower stages of hepatic fibrosis.118,119 This benefit has been seen with 2 to 3 cups of caffeinated coffee daily and does not appear to carry over to other caffeinated beverages, decaffeinated coffee, or espresso.120 Patients with NASH are more sedentary and have less cardiovascular fitness compared with untrained sedentary controls.121 Physical activity is another lifestyle intervention that can be recommended in concert with nutritional counseling or as monotherapy. Moderate and vigorous physical activity have been shown to be effective in reducing intrahepatic TG content in a 12-month treatment trial, although the improvement appeared to be mediated largely by weight loss.122 Smaller trials and a metaanalysis have suggested that weight reduction is not required to

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improve intrahepatic TG content.123-125 The response of NASH to exercise is less certain, with analysis from a large retrospective cohort of biopsy-proved patients with NASH demonstrating that moderate intensity exercise (3.0 to 5.9 metabolic equivalents) did not improve the severity of NASH or fibrosis.126 Vigorous activity (≥6 metabolic equivalents) did improve NASH histology, and fibrosis improved with doubling of vigorous activity. Practice guidelines by the AASLD in 2018 recommended exercise in concert with caloric reduction, with the net goal of sustained weight loss over time.83 Specific recommendations on the type and intensity of exercise have not been made. Although lifestyle modification appears beneficial for NAFLD, no single particular lifestyle intervention can be recommended, and no one approach is likely to be suitable for all patients.127 Adequate weight loss of 5% to 10% is difficult to achieve and even more difficult to sustain over time. The AASLD practice guidelines83 and 2012 tri-society practice guidelines128 both recommend a hypocaloric diet in conjunction with increased physical activity with weight loss goal of 7% to 10% but omit specific recommendations on the composition of the diet or type of exercise.

Bariatric Surgery Bariatric surgery leads to substantial weight loss that results in improved metabolic parameters and hepatic histology in patients with NAFLD, according to numerous large retrospective and prospective cohort studies (see Chapter 8).128,129 In one study of 109 patients with NASH who underwent follow-up liver biopsy one year after bariatric surgery, 85% of patients had resolution of NASH, and 33% had improvement in fibrosis.130 Initial concerns that fibrosis would worsen with rapid weight loss were unfounded, as demonstrated in a meta-analysis in which fibrosis improved by 11.9% from baseline after bariatric surgery.131 Although bariatric surgery is not recommended as a treatment for NASH, the abundant positive data in its favor suggest that surgical weight loss is a viable option for patients with comorbid conditions that would warrant the surgery for other reasons. Patients with NASH cirrhosis are at potentially higher risk for surgical complications, although some centers have demonstrated encouraging results with sleeve gastrectomy in patients with Child-Pugh class A cirrhosis (see Chapter 8).132 

Pharmacotherapy A myriad of pharmacologic approaches has been investigated for the treatment of NAFLD and may be grouped into the broad categories of weight loss medications, insulin sensitizers, antioxidants, and cytoprotective or antifibrotic agents. 

Weight Loss Medications A limited number of medical therapies are available for weight loss, and even fewer have been studied in patients with NAFLD (see Chapter 7). The most studied to date is orlistat, a reversible inhibitor of pancreatic and gastric lipase. This medication promotes modest weight loss through intestinal fat malabsorption and is available by prescription (Xenical, Roche) as well as in a lower-dose overthe-counter version (Alli, GlaxoSmithKline). Pilot trials were initially promising, but subsequent larger randomized controlled trials demonstrated similar weight loss between patients receiving orlistat and those receiving placebo.133,134 A weight loss of 9% was shown to be the threshold required to produce histologic improvement in steatosis and necroinflammation regardless of treatment arm. Case reports of cholelithiasis, cholestasis, and, rarely, hepatic injury prompted the FDA to issue a post-marketing warning for orlistat in 2009. These observations, combined with only modest weight loss effect and side effects of oily stools and potential malabsorption of other medications, have limited the utility of this drug. Other weight loss agents, including phentermine, lorcaserin, and phentermine/topiramate, have not been studied in patients with NAFLD.

Antioxidants Medications that reduce the generation of reactive oxygen species in the liver to minimize oxidative stress are another potential avenue for therapy. The most studied antioxidant, vitamin E, an inexpensive yet potent antioxidant, has been examined as an agent for the treatment of NAFLD in adult and pediatric studies. In most adult and pediatric studies, vitamin E was well tolerated, improved serum aminotransferase levels, reduced hepatic steatosis, and, in nondiabetic populations, improved steatohepatitis but not fibrosis.135,136 Some concerns have been raised about the use of vitamin E in diabetic patients due to cardiovascular risk, and vitamin E is not recommended in diabetic patients with NAFLD.137 A reported increase in all-cause mortality in a metaanalysis138 was refuted by a larger, more comprehensive study.139 Despite lingering questions about a modest increase in prostate cancer rates,140 therapy with vitamin E can be considered in nondiabetic patients with NASH, as recommended by the AASLD.83 

Diabetic Medications The association between hyperinsulinemic insulin resistance and NAFLD provides a logical target for treatment. Metformin, thiazolidinediones (TZDs), and incretin mimetics are all diabetic medications that have been investigated in the treatment of NASH. Metformin, a biguanide that reduces hyperinsulinemia and improves hepatic insulin sensitivity, reduces hepatomegaly and hepatic steatosis in ob/ob mice141 but results in human NAFLD have been less impressive.142,143 The use of metformin is currently not recommended as a therapy for NAFLD or NASH. TZDs are potent peroxisome proliferator-activated receptor (PPAR)-γ agonists, a nuclear receptor that is expressed in adipose tissue, muscle, and liver. In adipocytes, PPAR-γ promotes cell differentiation and decreases lipolysis and FFA release. TZDs improve insulin resistance by increasing glucose disposal in muscle and decreasing hepatic glucose output. The TZDs rosiglitazone and pioglitazone have been investigated in several large, well-designed, randomized controlled trials, in which treatment was well tolerated and associated with improved insulin resistance, normalization of liver biochemical test levels, and histologic improvement in most patients.141,144,145 Pioglitazone has become the primary agent available, because rosiglitazone use is now limited because of an FDA warning that the frequency of coronary events is increased. A meta-analysis has confirmed that treatment with pioglitazone results in a significant benefit in reducing hepatic fibrosis in patients with NASH with or without diabetes mellitus.146 Drawbacks to TZD therapy include an average weight gain of 5 to 10 pounds over 1 to 3 years of therapy, as well as increased bone loss147 and possibly increased rates of bladder cancer.148 Continued treatment appears to be necessary because subsequent studies have demonstrated recurrent NASH after discontinuation of therapy.149 Fortunately, long-term treatment with pioglitazone for NASH was reported to be safe, effective, and well tolerated in both prediabetics and diabetics in a study of 101 patients followed for 36 months.150 The 2018 AASLD practice guidelines recommend pioglitazone as a therapy for patients with biopsy-proven NASH after a discussion with the patient of the risks and benefits of therapy.83 Incretin mimetics are another class of diabetic medications that have been less studied in NASH populations but have shown preliminary promise. Exenatide and liraglutide are glucagon-like protein-1 receptor (GLP-1) agonists that improve insulin sensitivity and serum glucose levels and promote modest weight loss. Exenatide has shown promise in animal models,151 as have human pilot trials.152,153 A randomized controlled trial of 52 patients in which liraglutide was compared with placebo showed significant histologic improvement, including resolution in NASH, in 39% treated with liraglutide compared with 9% in those treated with placebo.154 A phase 2b trial with another GLP-1 agonist

CHAPTER 87  Nonalcoholic Fatty Liver Disease

(semaglutide) is ongoing.155 GI side effects, including nausea and diarrhea, may contribute to the weight loss seen with these medications, and results from larger studies are awaited.  Cytoprotective Agents Cytoprotective agents are thought to prevent apoptosis and down-regulate the inflammatory cascade. UDCA, a cytoprotective agent, showed promise in smaller trials in patients with NASH,156,157 although the largest placebo-controlled trial demonstrated equal improvement with UDCA and placebo.158 UDCA is not currently recommended for the treatment of NAFLD or NASH. Pentoxifylline (PTX) is a cytoprotective agent that has also been studied in patients with NASH and that has been shown to inhibit proinflammatory cytokines (including TNF-α), leading to a reduced production of reactive oxygen species.159 Two pilot trials, as well as a randomized controlled trial, have shown varying degrees of histologic improvement as well as improvements in liver biochemical test levels and insulin resistance.160,161 Another small open-label study demonstrated improvement in the NAS but not in fibrosis with PTX for 1 year and lifestyle modification compared with lifestyle modification alone.162 Further study is required to determine whether PTX therapy is an appropriate primary NASH therapy. 

Lipid-Lowering Agents Because patients with NASH often have co-existing hyperlipidemia, the use of lipid-lowering agents in NAFLD has been studied as a potential duel-target therapy to address both conditions. The most commonly prescribed agents for hyperlipidemia are statins, which inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, a primary enzyme in cholesterol biosynthesis (see Chapter 64). Statins have shown modest benefit in pilot NASH treatment trials.163,164 Larger trials without the surrogate end points of liver enzyme levels or improved hepatic steatosis have also suggested a benefit and demonstrated improved cardiovascular outcomes with therapy.165,166 Statins can be recommended to treat concomitant hyperlipidemia in patients with NASH, but further study is needed before statins can be recommended as primary therapy for NASH. Ezetimibe is another lipid-lowering agent that has shown benefit in improving hepatic histology in animal models,167 as well as in 1 pilot trial in 24 patients with NAFLD.168 Again, more evidence is necessary before ezetimibe can be recommended as primary therapy for NAFLD. An expert panel recommended use of statins, alone or in combination with ezetimibe or pioglitazone, as a treatment for NAFLD and NASH pending forthcoming randomized clinical trials.169 

Other Therapies Angiotensin-receptor blockers (ARBs) are used routinely for the treatment of hypertension, heart failure, and chronic kidney disease—conditions that may be found in association with NAFLD. In animal models, ARBs have been shown to inhibit hepatic stellate cell activity, leading to a reduction in hepatic fibrosis in obese mice.170 One pilot trial suggested a similar benefit in humans, but a larger randomized controlled trial using losartan in addition to rosiglitazone failed to produce any additional histologic benefit beyond that seen with rosiglitazone alone.171 Additional study is necessary to determine if ARBs are efficacious for NASH. The importance of bile acid synthesis and transport in the pathogenesis of NAFLD, as discussed earlier, suggests novel targets for potential treatments (see Chapter 64). The nuclear hormone receptor FXR receptor is a master “conductor” that modulates lipid and glucose homeostasis. The FXR agonist obeticholic acid has shown promise as a treatment for NASH,

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with results from the large randomized controlled trial (the FLINT trial) demonstrating improved metabolic parameters and liver histology.172 Side effects, including pruritus, increased LDL levels, and lowered HDL levels led to a larger phase 3 study, in progress, to clarify the severity of these effects. The antifibrotic agents are potential therapies and are undergoing intense investigation. Targeting fibrosis is appealing because of the direct link between fibrosis and outcomes, although using fibrosis as a primary study end point often results in studies of long duration because it may take ∼7 years per stage of fibrosis progression in the absence of an intervention (see earlier).173 Numerous antifibrotic agents have been or are currently under study, including emricisan, selonsertib, aldafermin, and GF-MD-02. Although selonsertib was shown to improve fibrosis without worsening of the NAS in a phase 2 study, subsequent phase 3 studies failed to confirm its antifibrotic effect.174 Aldafermin demonstrated significant increases in fibrosis improvement and resolution of NASH compared with placebo in a phase 2 trial. Other novel therapeutic approaches may be derived from advances in our understanding of the pathogenesis of NASH. Alterations in gut flora and SIBO are thought to contribute to NASH and may provide a novel outlet for therapy. Elafibranor is a dual PPAR-α/δ dual agonist and has beneficial effects on glucose and lipid homeostasis. In a large published randomized controlled trial, treatment with elafibranor led to resolution of NASH without worsening of fibrosis in an intention-to-treat analysis and had a good side effect profile.175 Potential effects on the serum creatinine level with this medication and a relatively modest effect (19% improvement) necessitate that further study be undertaken. Most NASH treatment trials have involved single agents that usually target pathways that lead to inflammation or fibrosis. Combination therapies could approach multiple different targets and improve efficacy. A few phase 2 trials have begun using this approach in the hope that combination therapy will provide equal or greater efficacy than each agent alone would. In summary, present therapies for NAFLD rely heavily on lifestyle interventions that, when successful and sustained, can produce significant histology and biochemical benefits. Treatment of concomitant metabolic disease such as diabetes mellitus or hyperlipidemia may produce modest improvements in hepatic histology as well, although not enough to warrant their use as primary therapy for NASH. Pioglitazone and vitamin E can be considered in specific target populations. Bariatric surgery is an option for obese patients with NASH and comorbid conditions.

LT As described earlier, NASH cirrhosis is the second most common indication for LT and is expected to become the leading indication for LT in the 2020s.87 Comorbid conditions limit eligibility for transplantation, and although the 30-day transplant mortality is higher for NASH cirrhosis, 1- to 3-year mortality rates are similar to those for other indications for LT.88-90 Cardiovascular disease is found frequently in patients with NASH, and adequate preoperative cardiac risk stratification is important. Van Wagner and colleagues demonstrated an increased rate of cardiovascular events in NASH cirrhotics undergoing LT, particularly in the perioperative period, compared with patients with alcohol-associated cirrhosis, with an OR of 4.12 (95 CI, 1.91 to 8.90).91 The majority of patients have recurrent steatosis 5 years after LT, although only 5% have been reported to develop recurrent cirrhosis within that time.92Hepatic steatosis in donor grafts is an entirely different consideration that is increasingly common and is found in one third to one half of potential

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PART IX  Liver

liver and cadaveric liver transplant donors.93 Transplanted steatotic livers have been associated with primary graft nonfunction and poorer overall outcomes (see Chapter 97).94 Grafts with less than 30% steatosis are acceptable for use, and those with greater than 60% fat are generally considered unacceptable. Those with intermediate grades of steatosis (30% to

60%) are evaluated on a case-by-case and center-dependent basis. Liver biopsy and consultation with an expert pathologist prior to harvesting the organ can be useful for determining donor acceptability. Full references for this chapter can be found on www.expertconsult.com.

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Liver Disease Caused by Drugs Shivakumar Chitturi, Narci C. Teoh, Geoffrey C. Farrell

CHAPTER OUTLINE HEPATIC DRUG METABOLISM. . . . . . . . . . . . . . . . . . . . . 1367 Role of the Liver in Drug Elimination. . . . . . . . . . . . . . . 1367 Pathways of Drug Metabolism. . . . . . . . . . . . . . . . . . . . 1367 Effect of Liver Disease on Drug Metabolism. . . . . . . . . . 1369 LIVER DISEASE CAUSED BY DRUGS. . . . . . . . . . . . . . . . 1369 Definitions and Importance. . . . . . . . . . . . . . . . . . . . . . 1369 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1370 Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1373 Clinicopathologic Features. . . . . . . . . . . . . . . . . . . . . . . 1377 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1379 Prevention and Management. . . . . . . . . . . . . . . . . . . . . 1380 DOSE-DEPENDENT HEPATOTOXICITY. . . . . . . . . . . . . . . 1380 Acetaminophen. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1380 Other Causes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1382 DRUG-INDUCED ACUTE HEPATITIS. . . . . . . . . . . . . . . . . 1384 Immunoallergic Reactions. . . . . . . . . . . . . . . . . . . . . . . 1384 Metabolic Idiosyncrasy . . . . . . . . . . . . . . . . . . . . . . . . . 1387 DRUG-INDUCED GRANULOMATOUS HEPATITIS. . . . . . . . 1390 DRUG-INDUCED CHRONIC HEPATITIS. . . . . . . . . . . . . . . 1390 Diclofenac. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1390 Minocycline. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1392 DRUG-INDUCED ACUTE CHOLESTASIS . . . . . . . . . . . . . . 1392 Importance, Types of Reactions, and Diagnosis. . . . . . . 1392 Cholestasis without Hepatitis. . . . . . . . . . . . . . . . . . . . . 1392 Cholestasis with Hepatitis. . . . . . . . . . . . . . . . . . . . . . . 1392 Cholestatic Hepatitis with Bile Duct Injury. . . . . . . . . . . 1393 DRUG-INDUCED CHRONIC CHOLESTASIS. . . . . . . . . . . . 1393 Flucloxacillin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1394 Fibrotic Bile Duct Strictures. . . . . . . . . . . . . . . . . . . . . . 1394 DRUG-INDUCED STEATOHEPATITIS AND HEPATIC FIBROSIS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1394 Amiodarone. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1394 Tamoxifen and Other Causes of Drug-Induced Steatohepatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1395 Cyproterone Acetate. . . . . . . . . . . . . . . . . . . . . . . . . . . 1395 Methotrexate. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1395 DRUG-INDUCED VASCULAR TOXICITY. . . . . . . . . . . . . . . 1397 Azathioprine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1397 LIVER TUMORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1398

HEPATIC DRUG METABOLISM Role of the Liver in Drug Elimination By virtue of the portal circulation, the liver is highly exposed to drugs and other toxins absorbed from the intestine. Most drugs tend to be lipophilic compounds that are readily taken up by the

liver but cannot be easily excreted unchanged in bile or urine. The liver is well equipped to handle these agents by an adaptable (inducible) series of metabolic pathways. These pathways include those that alter the parent molecule (phase 1); synthesize conjugates of the drug or its metabolite with a more watersoluble moiety, such as a sugar, amino acid, or sulfate molecule (phase 2); and excrete in an energy-dependent manner the parent molecule, its metabolites, or conjugates into bile (phase 3). For any given compound, 1, 2, or all 3 steps may be necessary for drug elimination. Expression and subcellular location of the proteins (enzymes, membrane transporters) that mediate these steps are controlled by a set of nuclear receptors that function as transcriptional regulators and co-regulators, thereby accounting for coordinated regulation of the 3 phases of hepatic drug elimination.

Pathways of Drug Metabolism Phase 1 and Cytochrome P450 Phase 1 pathways of drug metabolism include oxidation, reduction, and hydrolytic reactions. The products can be readily conjugated or excreted without further modification.1,2 Most phase 1 reactions are catalyzed by microsomal drug oxidases, which contain a hemoprotein of the cytochrome P450 (CYP) gene superfamily as a key component. The apparent promiscuity of drug oxidases toward drugs, environmental toxins, steroid hormones, lipids, and bile acids results from the existence of multiple closely related CYP proteins. More than 20 CYP enzymes are present in the human liver.2,3 The reaction cycle involves binding of molecular oxygen to the iron in the heme prosthetic group, with subsequent reduction of oxygen by acceptance of an electron from nicotinamideadenine dinucleotide phosphate (NADPH) cytochrome P450 reductase, a flavoprotein reductase. The resulting “activated oxygen” is incorporated into the drug or another lipophilic compound. Reduction of oxygen and insertion into a drug substrate (“mixed function oxidation”) generates chemically reactive intermediates, including free radicals, electrophilic “oxy-intermediates” (e.g., unstable epoxides, quinone imines), and reduced (and therefore reactive) oxygen species (ROS). The quintessential example is the CYP2E1-catalyzed metabolite of acetaminophen, N-acetyl-p-benzoquinone imine (NAPQI), an oxidizing and arylating metabolite that is responsible for acetaminophen hepatotoxicity. Other examples of reactive quinone compounds include metabolites of troglitazone, quinine, and methyldopa. Likewise, hepatic metabolism of some plant toxins can generate potentially hepatotoxic epoxide metabolites of diterpenoids (see Chapter 89).4 ROS contribute significantly to tissue injury, particularly by generating oxidative stress and triggering tissue stress responses and cell death pathways, as discussed later. The hepatic content of CYP proteins is higher in acinar zone 3 than in zone 1. Localization of CYP2E1 is usually confined to a narrow rim of hepatocytes 1 to 2 cells thick around the terminal hepatic venule. This explains in part the zonality of hepatic lesions produced by drugs and toxins, such as acetaminophen and carbon tetrachloride, which are converted to reactive metabolites.

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Genetic and Environmental Determinants of Cytochrome P450 Enzymes Pharmacogenetics and Polymorphisms of Cytochrome P450 Expression. The hepatic expression of each CYP enzyme is genetically determined. This finding largely explains the 4-fold or greater differences in rates of drug metabolism among healthy subjects. Some CYPs, particularly minor forms, are also subject to polymorphic inheritance, with some individuals lacking the encoded protein. One example is CYP2D6, which metabolizes debrisoquine and perhexiline. Poor metabolizers lack CYP2D6 and accumulate perhexiline with usual doses; lack of CYP2D6 is the critical determinant in serious adverse effects of perhexiline, including chronic hepatitis and cirrhosis.5 Other examples include CYPs 2C9 and 2C19, which affect the metabolism of S-warfarin, omeprazole, and phenytoin and of S-mephenytoin, respectively2; 3% of white populations and 15% of Asians are poor metabolizers of S-mephenytoin.  Developmental Regulation and Constitutive Expression. Expression of several CYPs is developmentally regulated. During adult life, the expression of some CYPs declines slightly (by up to 10%) with advancing age, but this change is minor compared with the effects of genetic variation, environmental influences, and liver disease. Gender differences in the expression of CYPs 3A4 and 2E1 may explain the slightly enhanced metabolism of certain drugs (erythromycin, chlordiazepoxide, midazolam) in women, but whether this difference contributes to the increased risk of hepatic drug reactions in women remains unclear.  Nutrition and Disease-Related Changes. A person’s nutritional status influences the expression of certain CYPs, both in health and with liver disease.1,2,6 CYP2E1 expression is increased by obesity, high fat intake, diabetes mellitus, and fasting.2,6 Diseases that alter the expression of hepatic CYPs include hypothyroidism (decreased CYP1A), and hypopituitarism (decreased CYP3A4).2 Cirrhosis is associated with decreased levels of total cytochrome P450 and also with reduced hepatic perfusion; the result is a decrease in the clearance of drugs such as propranolol that are metabolized rapidly by the liver.2 The effects of cirrhosis vary, however, among individual CYP families (Table 88.1) and with the type of liver disease (e.g., CYP3A4 levels are preserved with cholestatic but lowered with hepatocellular liver disease).  Adaptive Response and Enzyme Induction. Exposure to lipophilic substances generates an adaptive response that usually involves transient liver cell injury (discussed later) as well as synthesis of new enzyme protein, a process termed enzyme induction. The molecular basis for genetic regulation of constitutive and inducible expression of CYP3A4, the major human hepatic cytochrome P450, has been determined.7 Drugs such as rifampin interact with the pregnane X-receptor (PXR), a member of the orphan nuclear receptor family of transcriptional regulators.7 Activated PXR and the analogous constitutive androstane receptor (CAR) in turn bind to cognate nucleotide sequences upstream to the CYP3A4 structural gene within a xenobiotic-regulatory enhancer module. This interaction regulates the CYP3A4 promoter downstream and ultimately the transcription of CYP3A4 protein. Similar control mechanisms apply to several other CYP pathways, particularly those involved in bile acid synthesis.7,8 Common examples of microsomal enzymes induced by environmental agents include cigarette and cannabis smoking (CYP1A2)8 and alcohol (CYP2E1 and possibly CYP3A4).9 Several drugs are potent inducers of CYP enzymes. Isoniazid induces CYP2E1, whereas phenobarbital and phenytoin increase the expression of multiple CYPs.2 Rifampin is a potent inducer of CYP3A4, as is hypericum,10 the active ingredient of St. John’s wort, a commonly used herbal medicine, thereby causing interactions between conventional medicines and a complementary and alternative medicine (CAM) preparation. Regulation of hepatic drug metabolizing enzymes is reviewed elsewhere.2,8

TABLE 88.1  Cytochrome P450 (CYP) Isoenzymes Involved in Phase I Drug Metabolism in Humans

CYP Isoenzymes Substrates

Effect of Liver Disease on CYP Activity

CYP1A2

Caffeine, theophylline, clonazepam

↓↓↓

CYP2A6

Halothane, methoxyflurane

↓↓

CYP2C9

Diclofenac, losartan, warfarin

↓

CYP2C19

Citalopram, diazepam, omeprazole

↓↓↓

CYP2D6

Codeine, haloperidol, metoprolol

↔

CYP2E1

Enflurane, halothane, acetaminophen

↓

CYP3A4

Amiodarone, carbamazepine, ↓↓↓ cyclosporine, terfenadine

The implications for drug-induced liver disease are 2-fold. First, enzyme induction often extends beyond the CYP system, possibly due to PXR and CAR activation. This induction may influence bile acid metabolism and liver growth and could account for increases in serum alkaline phosphatase and GGTP levels, which reflect “hepatic adaptation” to chronic drug ingestion. Second, the influence of one drug on expression and activity of drug metabolizing enzymes and drug elimination (phase 3) pathways can alter the metabolism or disposition of other agents. Such drug-drug interactions may be relevant to mechanisms of drug-induced liver injury.  Inhibition of Drug Metabolism. Some chemicals inhibit drug metabolism. In persons taking more than one medication, for example, competition for phase 2 pathways such as glucuronidation and sulfation facilitates the presentation of unconjugated drug to the CYP system. This may explain in part why agents such as zidovudine and phenytoin lower the dose threshold for acetaminophen-induced hepatotoxicity.  Other Pathways of Drug Oxidation In addition to CYP enzymes, mitochondrial electron transport systems can generate tissue-damaging reactive intermediates during drug metabolism. Examples include nitroradicals from nitrofuran derivatives (nitrofurantoin, cocaine). Subsequent electron transfer by flavoprotein reductases into molecular oxygen generates superoxide and other ROS. Some anticancer drugs (e.g., doxorubicin, imidazole antimicrobials) can participate in other oxidation-reduction (redox) cycling reactions that generate ROS. 

Phase 2 (Conjugation) Phase 2 reactions involve formation of ester links to the parent compound or to a drug metabolite to form hydrophilic conjugates that can be excreted readily in bile or urine. The responsible enzymes include glucuronyl transferases, sulfotransferases, glutathione S-transferases, and acetyl and amino acid N-transferases. Conjugation reactions are also regulated by CAR and other nuclear transcription factors, and can be retarded by depletion of their rate-limiting cofactors, such as glucuronic acid and inorganic sulfate; the relatively low capacity of these enzyme systems restricts the efficacy of drug elimination when substrate concentrations exceed enzyme saturation. In general, drug conjugates are nontoxic, and phase 2 reactions are considered to be detoxification reactions, with exceptions. For example, some glutathione conjugates can undergo cysteine S-conjugate

CHAPTER 88  Liver Disease Caused by Drugs

beta-lyase–mediated activation to highly reactive intermediates. In general, conjugation reactions are minimally affected by liver disease, with the possible exception of some reduction of enzyme activity and resulting drug clearance in decompensated cirrhosis; this is relevant to selection of major analgesics (morphine rather than pethidine) and hypnotics (oxazepam rather than diazepam). Little is known about the regulation of such enzymes or their potential significance for DILI. 

Phase 3 This phase involves secretion of drugs, drug metabolites, or their conjugates into bile. Several transporters participate in these pathways that involve ATP-binding cassette (ABC) proteins and are powered by energy from ATP hydrolysis (see Chapter 64). ABC transport proteins are widely distributed in nature and include the CF transmembrane conductance regulator and the canalicular and intestinal copper transporters (see Chapter 76). Multidrug resistance protein 1 (MDR1, gene symbol ABCB1) is highly expressed on the apical (canalicular) plasma membrane of hepatocytes, where it transports cationic drugs, particularly anticancer agents, into bile. Another family of ABC transporters, the multidrug resistance-associated proteins (MRPs), is also expressed in the liver. At least 2 members of this family excrete drug (and other) conjugates from hepatocytes: MRP-3 (gene symbol ABCC3) on the basolateral surface facilitates passage of drug conjugate into the sinusoidal circulation and MRP-2 (gene symbol ABCC2), expressed on the canalicular membrane, pumps endogenous compounds (e.g., bilirubin diglucuronide, leukotriene-glutathionyl conjugates, glutathione) and drug conjugates into bile. The bile salt export pump (BSEP) and MDR3 (gene symbols ABCB4 in humans and Mdr2 in mice) are other canalicular transporters involved, respectively, in bile acid and phospholipid secretion into bile. Polymorphisms involving these genes are associated with human cholestatic liver diseases. BSEP interacts with several drugs.11 Regulation of the membrane expression and activity of these drug elimination pathways is complex. Altered expression or impaired activity (by competition between agents, changes in membrane lipid composition, or damage from reactive metabolites or covalent binding) could lead to drug accumulation, impairment of bile flow, or cholestatic liver injury. This has been demonstrated for estrogens,12,13 troglitazone,14 terbinafine,15 and flucloxacillin16 and has wider mechanistic implications for druginduced cholestasis and other forms of liver injury.11 

Effect of Liver Disease on Drug Metabolism In considering the safety of prescribing medications in patients with liver disease, physicians need to understand the hepatic extraction ratio of the drug (its rate of uptake and metabolism), its disposition (hepatic, renal, other), the pathways involved if it is subject to hepatic drug metabolism, and whether there are potential interactions between drug effects (pharmacodynamics) and disease complications. In light of the complexity of hepatic drug handling, it is fortunate that most drugs are safe to use in most patients with liver disease. The contexts that will give rise to concern are liver disease associated with reduced hepatic blood flow (cirrhosis and portal hypertension), in which hepatic clearance of drugs with high clearance is reduced, and poor metabolic (synthetic) function of the liver. Apart from subjects already awaiting LT, this category includes patients with alcohol-associated hepatitis and cirrhosis, severe autoimmune hepatitis (AIH), and viral hepatitis with hepatic decompensation. In such patients, oral doses of high-clearance compounds must be reduced substantially because systemic bioavailability may increase 2- to 10-fold as a result of the reduced “first-pass” hepatic clearance. The best example is propranolol, which is usually prescribed in this context

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to lower portal venous pressure and reduce the risk of variceal bleeding. Instead of doses used for cardiovascular indications (such as 160 to 320 mg daily), the usual starting dose in a patient with cirrhosis should be 10 to 20 mg daily. Other high-clearance compounds affected by severe liver disease include pethidine, tricyclic antidepressants, and salbutamol. The pathways of hepatic drug metabolism and elimination most affected by liver disease are those involving CYP (see Table 88.1). As mentioned earlier, cholestatic forms of liver disease have little effect on CYP3A4 and therefore minimally affect hepatic metabolism of commonly used drugs, such as glucocorticoids, angiotensin-converting enzyme (ACE) inhibitors, cyclosporine, and HIV protease inhibitors. Drugs that rely on hepatic elimination through biliary excretion are minimally affected by liver disease, with the exception of cancer chemotherapeutic agents. Patients with jaundice are at increased risk of liver injury with such agents. By contrast, liver disease has much less effect on conjugation pathways (phase 2 drug metabolism), a property that can be exploited in the choice of sedatives or major analgesics (see later). Drugs known to precipitate liver complications should be avoided. Patients with cirrhosis have impaired creatinine clearance and are at risk of developing gentamicin nephrotoxicity. Another challenge is the appropriate choice of a sedative to manage alcohol withdrawal in a patient with alcohol-associated cirrhosis. Diazepam is a poor choice in this setting because it is extensively metabolized by CYPs; its clearance is delayed, and hepatic encephalopathy may be precipitated by its use. An alternative benzodiazepine that is metabolized by conjugation alone (e.g., oxazepam) would be a safer choice. Other adverse effects that are not usually related to hepatic drug metabolism include exaggerated effects on clotting factor synthesis (even though warfarin metabolism is not usually affected by liver disease); sodium and water retention by NSAIDs, which also confer high risk of GI bleeding; metabolic acidosis or profound hypoglycemia by metformin and other oral hypoglycemic agents; and hypotension after administration of an ACE inhibitor or major tranquilizer. Acetaminophen appears to be the safest analgesic agent to use in cirrhosis (see later). In general, however, most commonly used agents (antimicrobials, DAAs, antiepileptics, antidepressants, antihypertensives, statins, and oral contraceptives) are safe to use in patients with liver disease. 

LIVER DISEASE CAUSED BY DRUGS Definitions and Importance Drugs are a relatively common cause of liver injury, which usually is defined by abnormalities of liver biochemical test levels, particularly an increase in the serum ALT, alkaline phosphatase, or bilirubin level to more than twice the upper limit of normal (ULN). DILI can be difficult to define in clinical practice because the biochemical tests used to detect liver injury may also be elevated as part of a hepatic adaptive response. Indeed, evidence indicates that some forms of hepatic adaptation to drugs follow an earlier transient process of self-limiting liver injury, followed in turn by operation of innate immunity. Further, the severity of DILI varies from minor nonspecific changes in hepatic structure and function to ALF, cirrhosis, and liver cancer.17 The term drug-induced liver disease should be confined to cases in which the nature of the liver injury has been characterized histologically. With the exception of acetaminophen, anticancer drugs, and some botanical or industrial hepatotoxins, most cases of DILI represent adverse drug reactions or hepatic drug reactions. These effects are noxious and unintentional and occur at recommended doses. The latent period is longer (typically from 1 week to 3 to 6 months) than that for direct hepatotoxins (from hours to a few days), and extrahepatic features of drug hypersensitivity may be present.

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Although DILI is a relatively uncommon cause of jaundice or acute hepatitis in the community, it is an important cause of more severe acute liver disease, particularly among older people. The overall mortality rate among patients hospitalized for DILI is approximately 10%18 but varies greatly for individual drugs.19,20 Reported frequencies of individual hepatic drug reactions are underestimated because of the inadequacy of spontaneous reporting.19,20 With reliable prospective and epidemiologic techniques, the frequency (or risk) of most types of drug-induced liver disease is between 1 per 10,000 and 1 per 100,000 persons exposed.21 Because these responses to drug exposure are clearly rare and unpredictable, they are often termed idiosyncratic drug reactions. Their rarity blunts diagnostic acumen because most clinicians will see few, if any, cases and therefore do not have an appropriate level of clinical suspicion. This concern applies especially to CAM preparations (see Chapter 89). Failure to withdraw the causative agent after the onset of symptoms of drug hepatitis or reexposure to such a drug is a common and avoidable factor in ALF attributable to DILI.1,22-24 Another challenge is that DILI includes an array of clinical syndromes and pathologic findings that mimic known hepatobiliary diseases. Furthermore, although individual agents (and some drug classes) typically produce a characteristic “signature syndrome,” they can also be associated with other and sometimes multiple clinicopathologic syndromes. DILI is one of the most common reasons for withdrawal of an approved drug. The subject therefore has medico-economic, legal, and regulatory ramifications. Because most types of idiosyncratic hepatic drug reactions are infrequent, serious hepatotoxicity is not usually detected until post-marketing surveillance is conducted. Historically, drugs with a reputation for potential hepatotoxicity have usually been replaced by more acceptable alternatives. Examples include troglitazone, the prototypic thiazolidinedione, and bromfenac, an NSAID, both of which were withdrawn due to fatal hepatotoxicity.1,22,24-25 The burgeoning number of available conventional medications and CAM preparations now includes many hundreds that are cited as rare causes of drug-induced liver disease. This poses several challenges to clinicians,1,5,22-25 including concern about what constitutes an adequate level of patient information at the time a drug is prescribed and the reliability of evidence linking an individual agent to a particular type of liver injury.1,26,27 Another development is the appreciation that in the context of a complex medical setting, drug toxicity can interact with other causes of liver injury. Noteworthy examples of such situations are bone marrow transplantation; cancer chemotherapy; antiretroviral therapy (ART) for HIV infection; use of antituberculous drugs in patients with chronic viral hepatitis; rifampin hepatitis in patients with PBC; and NAFLD—particularly NASH—precipitated by tamoxifen. 

Epidemiology Frequency or risk, the number of adverse reactions for a given number of persons exposed, is the best term for expressing how common a drug reaction is. Time-dependent terms such as incidence and prevalence are not appropriate because the frequency is not linearly related to the duration of exposure. For most reactions, the onset occurs within a relatively short exposure time, or latent period, although some forms of chronic liver disease occur months or years later. The frequency of drug-induced liver disease is derived from post-marketing surveillance reports submitted to the manufacturers or adverse drug reaction monitoring bodies. In the USA, following approval by the FDA, drug companies are required to report serious adverse events (any incident resulting in death, a threat to life, hospitalization, or permanent disability [Code of Federal Regulations]). Surveillance becomes a more passive process, however, when a drug is approved for marketing and physicians and pharmacists are encouraged to

file voluntary written reports through the MedWatch program. Nevertheless, MedWatch receives reports for fewer than 10% of adverse drug reactions,19 similar to the rate of reporting in France (90% of cases, markers of subcellular injury (cytosolic, mitochondrial), apoptosis (M30 fragmentation product of cytokeratin [CK] 8/19), microRNA (miRNA)-122, DNA, and high-mobility group box-1 (HMGB1) increased; HMGB1 is a DAMP released in necrosis. The authors concluded that heparins as a class caused self-limited and mild necrosis with secondary activation of an innate immune response. Secondary reactions, including post-translational modification of proteins via adenosine diphosphate ribosylation or protease activation, cleavage of DNA by activation of endogenous endonucleases, and disruption of lipid membranes by activated phospholipases may also play a role in DILI.6 Some of these catabolic reactions could be initiated by a rise in the cytosolic ionic calcium concentration (Ca2+)i, as a result of increased Ca2+ entry or release from internal stores in the endoplasmic reticulum and mitochondria.6,36 The potential role of endoplasmic reticulum stress in DILI is less well defined.52,53 The concept that hepatotoxic chemicals cause hepatocyte cell death by a biochemical final common pathway (e.g., activation of catalytic enzymes by a rise in [Ca2+]i) has proved inadequate to explain the diverse processes that can result in lethal hepatocellular injury. Rather, a variety of processes can damage key organelles, thereby causing intracellular stress that activates signaling pathways and transcription factors. Mitochondrial injury, particularly that signaled via activation of the c-Jun N-terminal kinase (JNK), appears to be critically involved with acetaminophen and most likely several other hepatotoxins.49,54-56 In turn, the balance between these factors can trigger the onset of cell death or facilitate protection of the cell, as discussed later.  Types of Cell Death Apoptosis. Apoptosis is an energy-dependent, genetically programmed form of cell death that typically results in controlled deletion of individual cells. In addition to its major roles in developmental biology, tissue regulation, and carcinogenesis, apoptosis is important in toxic, viral, and immune-mediated liver injury.57-60 The ultrastructural features of apoptosis are cell and nuclear shrinkage, condensation and margination of nuclear chromatin, plasma membrane blebbing, and ultimately fragmentation of the cell into membrane-bound bodies that contain intact mitochondria and other organelles. Engulfment of these apoptotic bodies by surrounding epithelial and mesenchymal cells conserves cell fragments that contain nucleic acid and intact mitochondria. These fragments are then digested by lysosomes and recycled without release of bioactive substances. As a consequence, apoptosis in its purest form (usually found only in vitro) does not incite an inflammatory tissue reaction. The cellular processes that occur in apoptosis are often mediated by caspases, a family of proteolytic enzymes that contain a cysteine at their active site and cleave polypeptides at aspartate residues; non–caspase-mediated programmed cell death has also been described in experimental hepatotoxicity.

Apoptosis rarely if ever is the sole form of cell death in common forms of liver injury, such as ischemia-reperfusion injury, cholestasis, and toxic liver injury, all of which are typically associated with at least some necrosis and a hepatic inflammatory response. Whether activation of pro-death signals causes cell death depends on several factors, including pro-survival signals, the rapidity of the process, the availability of glutathione and ATP, and the role of other cell types. Some of these issues are discussed briefly here and are reviewed in more detail elsewhere.6,57-60 The operation of hepatocellular apoptosis can be determined by detection of the caspase-3-cleaved fragmentation product (M30) of cytokeratins 8 and 18 that is specific to hepatocytes. Hepatocytes undergo apoptosis when pro-apoptotic intracellular signaling pathways are activated, either because of toxic biochemical processes within the cell (intrinsic pathway) or because cell surface receptors are activated to transduce cell death signals (external pathway). Pro-apoptotic receptors are members of the TNF receptor superfamily, which possess a so-called death domain. These receptors include Fas, for which the cognate ligand is Fas-ligand (Fas-L), TNF-R1 receptor (cognate ligand is TNF), and TNF-related apoptosis-inducing ligand (TRAIL) receptors (cognate ligand is TRAIL). In addition to model hepatotoxins such as the quinone, menadione, and hydrogen peroxide, some drugs (e.g., acetaminophen, plant diterpenoids) have been shown to be converted into pro-oxidant reactive metabolites, thereby initiating the following sequence: CYP-mediated metabolism to form reactive metabolites → glutathione depletion → mitochondrial injury with release of cytochrome c and operation of the mitochondrial membrane permeability transition → caspase activation → apoptosis. Mitochondria play a pivotal role in pathways that provoke or oppose apoptosis.55,57,58,60 In the external pathway, activation of the death domain of pro-apoptotic receptors recruits adapter molecules, Fas-associated death domain and TNF receptorassociated death domain, which bind and activate procaspase 8 to form the death-inducing signaling complex. In turn, caspase 8 cleaves Bid, a pro-apoptotic member of the B cell lymphoma/ leukemia (Bcl-2) family, to tBid. Then, tBid causes translocation of Bax to the mitochondria, where it aggregates with Bak to promote permeability of the mitochondria.57 Release of cytochrome c and other pro-death molecules, including Smac (which binds caspase inhibitor proteins, such as inhibitor of apoptosis proteins [IAPs]) and apoptosis-inducing factor (AIF, also known as Apaf)58 allows formation of the “apoptosome,” which activates caspase 9 and eventually caspase 3 to execute cell death (Fig. 88.1). Intracellular stresses in various sites release other mitochondrial permeabilizing proteins (e.g., Bmf from the cytoskeleton and Bim from the endoplasmic reticulum), whereas members of the Bcl-2 family, Bcl-2 and Bcl-xL, antagonize apoptosis and serve as survival factors by regulating the integrity of mitochondria; the protective mechanism is not yet fully understood but involves myeloid cell leukemia sequence 1 (Mcl-1). Stress-activated protein kinases, particularly JNK, are also pro-apoptotic,59 targeting Mcl-1 degradation and phosphorylating and inactivating the mitochondrial protective protein Bcl-xL. Execution of cell death by apoptosis usually occurs via activation of caspase 3, but more than one caspase-independent pathway of programmed cell death has been described.60 Stresses to the endoplasmic reticulum can bypass mitochondrial events by activation of caspase 12, which in turn activates caspase 9 independently of the apoptosome. The final steps of programmed cell death are energy dependent. Therefore, depletion of ATP abrogates the controlled attempt at “cell suicide,” resulting instead in necrosis (see later) or an overlapping pattern that has been designated as “apoptotic necrosis” or “necrapoptosis.”61,62 Furthermore, when apoptosis is massive, the capacity for rapid phagocytosis can be exceeded, and “secondary” necrosis can occur.62

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88

Death ligand e.g., TNF, Fas, TRAIL

Death receptor e.g., TNF-R1

Plasma membrane Cytoplasm FLIP

FADD

Caspase 8 (FLICE)

TRADD

RIP DISC IAP

IAP Bid TRAF2 Bax

Bcl-xL Lipid mediators (ceramide)

Effector caspases

Apoptosis

Apoptosome

Mitochondrion MPT

Necrosis Fig. 88.1  Apoptosis and necrosis pathways in mammalian cells. See text for details. Bcl, B-cell lymphoma/ leukemia family (Bax, Bid, and Bcl-xL are members); DISC, death-inducing signaling complex; FADD, Fasassociated death domain; FLIP, FLICE-inhibitory proteins; IAP, inhibitor of apoptosis proteins; MPT, mitochondrial permeability transition; RIP, receptor-interacting protein; TNF, tumor necrosis factor; TNF-R1, TNF receptor-1; TRADD, TNF receptor-associated death domain; TRAF2, TNF receptor-associated factor-2; TRAIL, TNF-related apoptosis ligand.

Intracellular processes and activation of pro-apoptotic death receptors are not mutually exclusive pathways of cell death in toxic liver injury. In fact, drug toxicity could predispose the injured hepatocyte to apoptosis mediated by TNF-R or Fasoperated pathways by several mechanisms, including blockade of nuclear factorkappa B (NF-ĸB), which usually is a hepatoprotective transcription factor in hepatocytes, and inhibition of purine and protein synthesis. Furthermore, activation of Kupffer cells (e.g., by endotoxin) and recruitment of activated inflammatory cells can increase production of TNF. Caspase inhibition is an important protective mechanism against cell death. Such anti-apoptotic pathways include chemical blockade of the cysteine thiol group by nitric oxide (NO) or ROS and cellular depletion of glutathione.6 Protein inhibitors include IAP family members, heat shock proteins, and FLICE (caspase8)-inhibitory proteins (FLIP).57-59 FLIP inhibit caspase-8 activation as a decoy for Fas-associated death domain binding. Bcl-2 and Bcl-XL inhibit mitochondrial permeability, whereas phosphatidylinositol 3-kinase/Akt phosphorylates caspase 9 and activates NF-ĸB.  Necrosis. In contrast to apoptosis, necrosis has been conceptualized as a relatively uncontrolled process that can result from extensive damage to the plasma membrane with disturbance

of ion transport, dissolution of membrane potential, cell swelling, and eventually rupture of the cell. Drug-induced injury to the mitochondrion can impair energy generation, whereas membrane permeability transition can release stored Ca2+ into the cytosol and perturb other ionic gradients. Mitochondrial enzymes are a particular target of NAPQI, the reactive metabolite of acetaminophen. This has been clearly demonstrated both in rodent models and in human acetaminophen hepatotoxicity, in which mitochondrial injury with fragmentation of nuclear DNA by the released endonucleases has been documented.63 The initial mitochondrial injury can also activate various signaling pathways (JNK, glycogen synthase kinase -3β), thereby leading to further mitochondrial dysfunction.55 Reye syndrome–like disorders (e.g., toxicity caused by valproic acid; some nucleoside analogs, such as fialuridine, didanosine, zidovudine, zalcitabine; and possibly “ecstasy”) may also result from mitochondrial injury. Mitochondrial injury can result in cell death by either apoptosis or necrosis61,62; the type of cell death pathway may depend primarily on the energy state of the cell, as well as the rapidity and severity of the injury process. In the presence of ATP, cell death can proceed by apoptosis, but when mitochondria are deenergized, the mechanism of cell death is necrosis. This apparent dichotomy between cell death processes is probably artificial, and

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apoptosis and necrosis more likely represent the morphologic and mechanistic ends of a spectrum of overlapping cell death processes.36,62 One important way in which necrosis differs from apoptosis is that uncontrolled dissolution of the cell liberates dangeractivated molecular patterns (e.g., HMGB1) and macromolecular breakdown products, including lipid peroxides, aldehydes, and eicosanoids. The latter products act as chemoattractants for circulating leukocytes, which then partake in the inflammatory response in the hepatic parenchyma. Even before cell death occurs, oxidative stress produced during drug toxicity can upregulate adhesion molecules and chemokines that are expressed or secreted by endothelial cells. These processes contribute to recruitment of the hepatic inflammatory response, which is prominent in some types of drug-induced liver disease. Lymphocytes, polymorphonuclear leukocytes (neutrophils and eosinophils), and macrophages also may be attracted to the liver as part of a cell-mediated immune reaction.64  Role of Oxidative Stress. Although severe oxidative stress in hepatocytes, particularly when focused on mitochondria, is likely to induce necrosis, lesser (or more gradual) exposure can trigger apoptosis because ROS and oxidative stress can activate Fas signaling, JNK and other kinases, p53, and microtubular assembly and impair protein folding, thereby resulting in an unfolded protein response by the endoplasmic reticulum.64 Oxidative stress also may amplify cell death processes by uncoupling of the mitochondrial respiratory chain, release of cytochrome c, or massive oxidation and export of glutathione (intact glutathione is required for Fas signaling). Conversely, oxidative stress may protect against apoptosis in some circumstances through inhibition of caspase or activation of NF-ĸB. As a result of these opposing effects, predicting the consequences of hepatic oxidative stress in terms of liver injury is not straightforward.  Role of Hepatic Nonparenchymal Cells and the Innate Immune Response In addition to migratory cells, activation of nonparenchymal liver cell types is likely to play an important role in drug and toxininduced liver injury. Kupffer cells function as resident macrophages and antigen-presenting cells, whereas dendritic cells and natural killer (NK) T cells are also resident in the liver and play a role in antigen processing and innate immunity. Some of the toxic effects of activated Kupffer cells, as well as of recruited leukocytes, may be mediated by release of cytokines, such as TNFα, interleukin (IL)-1β and Fas-L, which under some circumstances can induce cell death in hepatocytes by apoptosis or necrosis.62 In addition, activated Kupffer cells release ROS, nitroradicals, leukotrienes, and proteases. It has been suggested, however, that the sterile inflammatory response may aid in clearing cell debris and pave the way for tissue repair.65 Endothelial cells of the hepatic sinusoids or terminal hepatic veins are vulnerable to injury by some hepatotoxins because of their low glutathione content. Such hepatotoxins include the pyrrolizidine alkaloids, which are an important cause of the sinusoidal obstruction syndrome (hepatic veno-occlusive disease).66 Other types of drug-induced vascular injury may be caused primarily by involvement of the sinusoidal endothelial cells. Hepatic stellate cells are the principal liver cell type involved in matrix deposition in hepatic fibrosis. Stellate cells are activated in methotrexate-induced hepatic fibrosis. The possibility that vitamin A, ROS, or drug metabolites can transform stellate cells into collagen-synthesizing myofibroblasts is of considerable interest. 

Immunologic Mechanisms Adaptation is an important phenomenon, and the mechanisms likely vary among agents.67 In general, agents with higher

intrinsic toxicity are more likely to cause ALT increases during the early phase of therapy; isoniazid is a classic example. Although such agents are associated with DILI in some cases, the frequency of DILI is typically of the order of only 0.01% to 1%, compared with a frequency of 3% to 30% for serum ALT elevations early in therapy. Therefore, the high proportion of cases of transient serum ALT elevations are associated with a process that is terminated and does not progress to clinically important liver injury– adaptation. Older concepts of how adaptation comes about related to the induction of cellular proteins that are protective against injury from a reactive metabolite, glutathione antioxidant pathways, and induction of conjugating enzymes, excretory pathways, or anti-cell death proteins. Subsequent concepts have focused on induction of innate immunity as the final pathway by which adaptation occurs. In this sense, drug reactions that can be explained by an immunoallergic mechanism may be regarded as a failure of adaptation. Immune attack involves liganding of death receptors, as discussed earlier, or porin-mediated introduction of granzyme.36,68 The hallmarks of drug allergy include (1) delayed onset after initial exposure and accelerated onset after rechallenge, (2) hepatic inflammatory infiltrates with neutrophils and eosinophils, and (3) fever, rash, lymphadenopathy, eosinophilia, and involvement of other organs. In some cases, the liver is implicated as part of a systemic hypersensitivity reaction, as described later for the drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, also termed drug-induced hypersensitivity syndrome and, formerly, reactive metabolite syndrome. Why the liver is the predominant site of injury in some persons whereas other organs are involved in other persons is unclear; genetic factors relevant to tissue-specific gene expression may be involved. One possible immunopathogenic mechanism for druginduced liver disease is the altered antigen concept, in which an initial interaction between drug metabolites and cellular proteins results in the formation of neoantigens (haptens) or drug-protein adducts. An example is the formation of trifluoroacetylated adducts after exposure to halothane or other haloalkane anesthetics (see Chapter 89). For these adducts to initiate tissuedamaging immune responses (1) processing should be presented in an immunogenic form (e.g., by Kupffer cells, in association with MHC molecules); (2) appropriately responsive CD4+ T cells must be present to provide help to induce an immune response; and (3) the drug-derived antigen, together with a class II MHC molecule, must be expressed on the target cells in order to attract CD8+ (cytotoxic) T cells. That bile duct epithelial cells are more likely to express class II MHC antigens may explain why they are possible targets in drug-induced cholestatic hepatitis. Although antibodies directed against trifluoroacetylatedprotein adducts circulate in the majority of patients following recovery from halothane-induced liver injury,69 the specificity and pathogenicity of these antibodies remain in doubt. Alternatively, circulating drug-induced antibodies could cause immunemediated lysis of hepatocytes through molecular mimicry of host enzymes.70 Experimental evidence suggests that for diclofenac, antibody-dependent cell-mediated immunity could operate as a mechanism for drug-induced liver disease.71 Finally, for drugs that do not act as haptens, immune-related liver injury can still result either through noncovalent direct interactions of the drug with MHC molecules (e.g., ximelagatran with HLA DRB1*07:01)72 or by drug modification of the MHC binding groove so that endogenous peptides are perceived as non-self and induce an immune response.73 A second type of immunopathogenic mechanism is dysregulation of the immune system, termed drug-induced autoimmunity.74 This mechanism can lead to the formation of drug-induced autoantibodies (e.g., anti–liver-kidney microsome [LKM] antibodies) directed against microsomal enzymes. For tienilic acid, CYP2C9 is the target of anti-LKM, whereas for halothane

CHAPTER 88  Liver Disease Caused by Drugs

hepatitis, anti-LKM is directed against CYP2E1. Non–tissuespecific autoantibodies (e.g., ANA, smooth muscle antibodies) may be detected in patients with nitrofurantoin, methyldopa, or minocycline hepatitis. Like spontaneous autoimmunity, druginduced autoimmunity results from genetically determined anomalies of immune tolerance. 

Clinicopathologic Features Classification Hepatic drug reactions mimic other liver diseases, but classification is often difficult because of overlap among categories. Although a classic (“signature”) syndrome is associated with many individual agents, a given drug can be associated with more than one clinicopathologic syndrome. Furthermore, the clinical and laboratory features of liver disease and the liver histology may be discordant. Therefore, although recognition of specific patterns or syndromes is vital, the chronologic relationship between administration of the drug and liver injury is more important in making a diagnosis. Drugs are often divided into dose-dependent, or predictable, hepatotoxins and dose-independent, or unpredictable (idiosyncratic), hepatotoxins. Dose-dependent hepatotoxins generally require metabolic activation to toxic metabolites or interfere with subcellular organelles and biochemical processes at key sites, such as mitochondria or canalicular bile secretion.12 Liver injury usually occurs rapidly (within hours), is characterized by zonal necrosis or microvesicular steatosis, and is reproducible in other species. By contrast, idiosyncratic hepatotoxins cause a wide range of histologic changes and do not reliably cause injury in other species; in addition, the latent period is variable in duration. The distinction between dose-dependent and idiosyncratic hepatotoxins is blurred with agents such as dantrolene, flucloxacillin, cyclophosphamide, nucleoside analogs, anticancer drugs, and cyclosporine. Liver injury caused by each of these drugs is partly dose dependent, but reactions occur in only a minority of exposed persons. Two general types of mechanisms account for idiosyncratic hepatotoxicity: metabolic idiosyncrasy and immunoallergy. Metabolic idiosyncrasy refers to the susceptibility of rare persons to hepatotoxicity from a drug that, in conventional doses, is usually safe. Such susceptibility may result from genetic or acquired differences in drug metabolism or canalicular secretion, mitochondrial defects, or cell death receptor signaling. Immunoallergy indicates involvement of the immune system in mediating the response to a drug. These 2 mechanisms may be interrelated (see Metabolic Idiosyncrasy). Other pathogenic mechanisms may include indirect mediation of liver injury, as in vascular and possibly hyperthermic changes produced by cocaine, ecstasy, intraarterial floxuridine, and possibly anesthetics (see Chapter 89). The most practical classification of drug hepatotoxicity is based on clinical and laboratory features and liver histology, as summarized in Table 88.4. This classification provides a framework for discussing drug-induced hepatic disease in comparison with other hepatobiliary disorders but is imperfect because the clinical and pathologic features are not always congruent. Moreover, much overlap between categories exists, particularly in the spectrum from severe necrosis (which may result from dosedependent or idiosyncratic hepatotoxicity) to focal necrosis with lobular inflammation (hepatitis) to cholestasis. Many drugs produce a spectrum of syndromes from hepatitis to cholestasis, and some authorities include a further category of mixed cholestatichepatocellular reactions. Granulomatous hepatitis has a liver biochemical test profile that is indistinguishable from those typical of hepatitis, cholestasis, or mixed reactions. Drugs can alter liver biochemical test results without causing significant liver injury. Such adaptive responses include

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hyperbilirubinemia associated with rifampin, cyclosporine, and indinavir and raised serum GGTP and alkaline phosphatase levels associated with phenytoin and warfarin.1,22 The latter effect is probably attributable to microsomal enzyme induction. For other agents, transient ALT or AST elevations are probably related to hepatocellular necrosis (discussed earlier for heparins), but with some agents such as isoniazid, the distinction between adaptation and minor injury is blurred; adaptation in such cases may be a response to oxidative injury. Conversely, liver tumors or hepatic fibrosis may develop insidiously without significant abnormalities of liver biochemical tests—the former in association with sex steroids or vinyl chloride monomer and the latter with methotrexate, arsenic, or hypervitaminosis A. The duration of the disorder is another consideration in classifying drug-induced liver diseases. In general, chronic liver disease is much less commonly attributable to drugs and toxins than are acute reactions, but not to consider drugs as a possible etiology of chronic liver disease can lead to a missed diagnosis, with serious clinical consequences.24,25 In contrast to most liver disorders, drugs and toxins constitute the most important cause of hepatic vascular lesions. Drugs also have been associated with chronic cholestasis, chronic hepatitis, steatohepatitis, hepatic fibrosis, cirrhosis, and benign and malignant liver tumors. 

Histopathologic Features Although no pathognomonic hallmarks of DILI have been identified, certain histologic patterns are suggestive.75 These include zonal necrosis or microvesicular steatosis (accompanying mitochondrial injury) and mixed histologic features of hepatocellular necrosis and cholestasis. Necrotic lesions that are disproportionately severe compared with the clinical picture also indicate a possible drug cause, whereas destructive bile duct lesions, prominent neutrophils, and eosinophils (at least 25% of the inflammatory cells) suggest drug-induced cholestatic hepatitis. Hepatic granuloma formation is another common type of hepatic drug reaction. In cases of steatohepatitis, hepatic fibrosis, or liver tumors, no specific clues to a drug cause have been recognized, although sex steroids increase the vascularity of hepatic tumors and are frequently associated with sinusoidal dilatation or peliosis hepatis. Drug-induced steatohepatitis caused by amiodarone and perhexiline tends to be associated with severe lesions that more closely resemble alcohol-associated hepatitis than NASH.76 Other drugs (e.g., tamoxifen, methotrexate) cause lesions that are indistinguishable from NASH. Although detection of “signature” lesions can helpful, most patients with DILI are not subject to liver biopsy unless the reaction is severe or unexpected or improvement fails to occur after cessation of the drug. Liver histology is often sought when AIH is a possibility, but the limitations of liver histology should be recognized. In one study, 4 expert hepatopathologists reviewed 35 cases of AIH and 28 cases of DILI. The inter-observer agreement based on histology alone was only 46% but improved modestly (up to 71%) by including conventional clinicopathologic criteria. The best results were achieved using a model that combined certain selected histologic characteristics.77 

Clinical Features The history and physical examination can provide important clues to the diagnosis of hepatic drug reactions. Most important is the temporal pattern of disease evolution in relation to exposure to drugs or toxins. The identification of specific risk factors for hepatotoxicity (e.g., chronic excessive alcohol intake in a person taking acetaminophen) and the presence of systemic features of drug hypersensitivity may indicate the correct diagnosis. Systemic features include fever, rash, mucositis, eosinophilia, lymphadenopathy, a mononucleosis-like syndrome, bone marrow suppression, vasculitis, acute kidney injury, pneumonitis, and

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TABLE 88.4  Clinicopathologic Classification of Drug-Induced Liver Disease Category

Description

Implicated Drugs: Examples

Hepatic adaptation

No symptoms; raised serum GGTP and AP levels (occasionally raised ALT)

Heparins, phenytoin, warfarin

Hyperbilirubinemia

HIV protease inhibitors, rifampin

Dose-dependent hepatotoxicity

Symptoms of hepatitis; zonal, bridging, and massive necrosis; serum ALT level >5-fold increased, often >2000 U/L

Acetaminophen, amodiaquine, hycanthone, nicotinic acid

Other cytopathic toxicity, acute steatosis

Microvesicular steatosis, diffuse or zonal; partially dose dependent, severe liver injury, features of mitochondrial toxicity (e.g., lactic acidosis)

ART agents, didanosine, fialuridine, L-asparaginase, some herbal and dietary supplements, valproic acid

Acute hepatitis

Symptoms of hepatitis; focal, bridging, and massive necrosis; serum ALT level >5-fold increased; extrahepatic features of drug allergy in some cases

Acebutolol, dantrolene, disulfiram, etretinate, halothane, ipilimumab, isoniazid, ketoconazole, nitrofurantoin, nivolumab, pembrolizumab, phenytoin, sulfonamides, terbinafine, troglitazone

Chronic hepatitis

Duration >3 mo; interface hepatitis, bridging necrosis, fibrosis, cirrhosis; clinical and laboratory features of chronic liver disease; autoantibodies with some types of reaction

Diclofenac, etretinate, minocycline, nefazodone, nitrofurantoin (see Table 88.8)

Granulomatous hepatitis

Hepatic granulomas with varying hepatitis and cholestasis; raised serum ALT, AP, and GGTP levels

Allopurinol, carbamazepine, hydralazine, quinidine, quinine (see Table 88.7)

Cholestasis without hepatitis

Cholestasis, no inflammation; serum AP levels > twice normal

Androgens, oral contraceptives

Cholestatic hepatitis

Cholestasis with inflammation; symptoms of hepatitis; raised serum ALT and AP levels

Amoxicillin-clavulanic acid, chlorpromazine, cyproterone acetate, erythromycins, tricyclic antidepressants

Cholestasis with bile duct injury

Bile duct lesions and cholestatic hepatitis; clinical features of cholangitis

Chlorpromazine, dextropropoxyphene, flucloxacillin

Chronic cholestasis

Duration >3 mo

VBDS

Paucity of small bile ducts; resembles PBC, but AMA negative

Chlorpromazine, flucloxacillin, trimethoprim sulfamethoxazole

Sclerosing cholangitis

Strictures of large bile ducts

Intra-arterial floxuridine, intralesional scolicidals

Steatohepatitis

Steatosis, focal necrosis, Mallory’s hyaline, pericellular fibrosis, cirrhosis

Amiodarone, perhexiline, tamoxifen

Fibrosis and cirrhosis

Fibrosis, nodular regeneration (other features such as interface Cyproterone acetate (see also VBDS, chronic hepatitis, hepatitis, steatohepatitis, paucity of bile ducts, and steatohepatitis), methotrexate cholestasis depend on etiology)

Vascular disorders

Nodular regenerative hyperplasia, sinusoidal obstruction syndrome, others

Many (see Table 88.10)

Tumors

HCC, adenoma, angiosarcoma, others

Many (see Chapter 96)

AP, alkaline phosphatase; ART, antiretroviral therapy; VBDS, vanishing bile duct syndrome.

pancreatitis. These features tend to occur in genetically predisposed persons who have been exposed to drug metabolites that act as haptens to initiate an immunodestructive tissue reaction, termed the DRESS syndrome (see earlier). Viral reactivation (notably human herpes virus-6 and 7 and EBV infections) are also implicated in the pathogenesis.78 DRESS Syndrome Drugs implicated as a cause of DRESS include sulfonamides, aminopenicillins, fluoroquinolones, clozapine, anticonvulsants (phenytoin, lamotrigine, phenobarbital, carbamazepine, valproic acid, minocycline), antiretrovirals (nevirapine, abacavir), pentoxifylline, some NSAIDs, and Chinese herbal medicines.78 Risk factors include a history of an affected first-degree relative (which increases the risk to 1 in 4) and a personal history of drug allergy, including to aspirin. Using drugs such as glucocorticoids or valproic acid at the time the new agent is started increases the risk 4- to 10-fold. Immune disorders such as SLE and HIV/AIDS increase the risk 10-fold and 100-fold, respectively. The illness characteristically begins between 1 and 12 weeks (typically 2 to 4 weeks) after the drug is started; “sentinel symptoms” include fever, pharyngitis, malaise, periorbital edema, headache or otalgia, rhinorrhea, and mouth ulcers. A severe rash is an essential feature. Erythematous reactions are usual

and may evolve to toxic epidermal necrolysis or erythema multiforme, often with mucositis (Stevens-Johnson syndrome). Early changes include neutrophilia and elevated levels of acute-phase reactants; atypical lymphocytosis and eosinophilia may be noted later. Hepatic reactions are found in about 13% of cases. Findings include cholestasis, acute hepatitis, and granulomas. Other features include lymphadenopathy (16%), nephritis (6%), pneumonitis (6%), and more severe hematologic abnormalities (5%). In a 12-year review of 172 cases reported as DRESS or drug hypersensitivity reactions, all affected persons had cutaneous changes, but the features most often associated with “probable” or “definite” cases of DRESS syndrome were eosinophilia, liver involvement (abnormal liver biochemical test results in 59%, hepatomegaly in 12%), fever, and lymphadenopathy.79  Latent Period to Onset For idiosyncratic reactions, a latent period occurs between starting the drug and the onset of clinical and laboratory abnormalities. This period is usually 2 to 8 weeks for immunoallergic hepatitis (e.g., DRESS syndrome) and 6 to 20 weeks or longer for agents such as isoniazid, dantrolene, and troglitazone. Occasionally, liver injury may become evident well after the offending drug is stopped, even as long as 2 weeks for oxypenicillins and amoxicillin-clavulanate. In other cases, hepatotoxicity is rare after the

CHAPTER 88  Liver Disease Caused by Drugs

first exposure to a drug but more frequent and more severe after subsequent courses. Examples include halothane, nitrofurantoin, and dacarbazine. Therefore, a history of a previous reaction to the drug in question (inadvertent rechallenge) is an important key to the diagnosis of DILI.  Dechallenge and Rechallenge Another aspect of the temporal relationship between ingestion of a drug and hepatotoxicity is the response to discontinuation of the drug, or dechallenge. Dechallenge should be accompanied by discernible and progressive improvement within days to weeks of stopping the incriminated agent. Exceptions occur with ketoconazole, troglitazone, etretinate, and amiodarone; with these agents, reactions may be severe, and clinical recovery may be delayed for months. Although some types of drug-induced cholestasis also can be prolonged, failure of jaundice to resolve in a suspected drug reaction often indicates an alternative diagnosis. Rarely, deliberate rechallenge may be used to confirm the diagnosis of drug-induced liver disease or prove involvement of one particular agent when the patient has been exposed to several drugs or the benefits outweigh the risks, particularly if safer alternatives are unavailable.80 However, this approach is potentially hazardous, with one study reporting that severe hepatocellular injury developed in 18% of rechallenged persons, and 2 died.81 Therefore, rechallenge should be undertaken only with fully informed written consent and preferably the approval of an institutional ethics committee. 

Diagnosis In the absence of specific diagnostic tests, the diagnosis requires clinical suspicion, a thorough drug history, consideration of the temporal relationships between drug ingestion and liver disease, and exclusion of other disorders. The objective weighing of evidence for and against an individual agent—causality assessment— is a probabilistic form of diagnosis.81 Several clinical scales that assess causality have been described.25,81,82 A liver biopsy may be necessary to exclude other diseases and to provide further clues to a drug etiology. Rechallenge is the standard test for drug-induced liver disease but is hardly ever used in practice. Future strategies include in vitro tests to provide confirmatory evidence for particular drugs69,81 and toxicogenomic methods, which encompass transcriptomics, metabolomics, and proteomics (measuring circulating mRNA/microRNA, changes in metabolites, and cellular proteins, respectively).83 In some studies, toxicogenomic changes preceded alterations in serum aminotransferase levels, thereby raising the hope that these changes could serve as biomarkers of early DILI.84

Physician Awareness Physicians should be aware of the many sources of potential hepatotoxins, including prescribed and over-the-counter drugs (e.g., ibuprofen), CAM preparations (see Chapter 89), recreational drugs (e.g., cocaine, ecstasy), self-poisoning, and environmental contaminants in food and water supplies, the home, the workplace, and the community. Unfortunately, patients and physicians do not always heed early nonspecific symptoms of hepatic drug reactions. For example, preventable deaths from liver failure still occur from isoniazid hepatotoxicity.85 Although ongoing education about potentially hepatotoxic drugs is important, physicians have a professional and legal obligation to inform patients about possible adverse drug reactions. Drug toxicity should be considered in cases of obscure or poorly explained liver disease, particularly in cases with mixed or atypical patterns of cholestasis and hepatitis; cholestasis in which common causes have been excluded, especially in older adults; and when histologic features suggest a drug etiology. In such cases,

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the drug history must be addressed as a special investigation, with attention paid to additional sources of information (household members, primary care providers), household drugs, nonprescribed medications, and environmental toxins (see Chapter 89). LiverTox is a web-based searchable database of information relating to liver injury resulting from the use of prescription and nonprescription drugs (see http://www.livertox.nih.gov/). 

Exclusion of Other Disorders Before a diagnosis of DILI is considered, other liver diseases such as viral hepatitis (including hepatitis E),86 AIH, and vascular and metabolic disorders should be excluded. Some types of druginduced chronic hepatitis are associated with autoantibodies and superficially resemble AIH. An approach to the correct diagnosis is described later (see nitrofurantoin). Drug-induced cholestasis should be considered if biliary obstruction has been excluded, and a liver biopsy may be necessary. 

Extrahepatic Features The constellation of rash, eosinophilia, and other organ involvement supports a diagnosis of a hepatic adverse drug reaction (DRESS, see earlier). Because these findings are infrequent, especially with drugs that cause nonimmune idiosyncratic liver injury, their absence is not helpful in excluding DILI. Specific diagnostic tests for individual drug-induced liver diseases have been described69 but are not generally accepted or available. With dose-dependent hepatotoxins (e.g., acetaminophen), blood levels may be helpful. 

Chronologic Relationships For most drugs, the chronologic relationship among drug ingestion, onset, and resolution of liver injury remains the main consideration in diagnosis. The criteria for temporal eligibility include the relationship of drug ingestion to onset, course of the reaction after stopping the drug, and response to drug readministration.1,22-25 Inadvertent rechallenge may have already occurred. The rechallenge is regarded as positive if the serum ALT or alkaline phosphatase level increases at least 2-fold.18,22-25 Deliberate rechallenge (discussed earlier) may be considered in selected cases. 

Which Drug? New and nonproprietary compounds should arouse particular suspicion. For patients who are taking multiple drugs, the most recently introduced drug preceding the onset of liver injury is often responsible. If that agent is an unlikely cause and another well-known hepatotoxin is being taken, the latter is the more likely culprit. When possible, the most likely hepatotoxin or all therapeutic agents should be discontinued. If the patient improves, the drugs that are unlikely to be responsible can be carefully reintroduced. 

Indications for Liver Biopsy Liver biopsy may be helpful in difficult cases, especially when the temporal relationship between the ingestion of a known hepatotoxic agent and the onset of liver injury is unclear. In practice, for example, the onset of jaundice within 2 to 6 weeks of starting an agent such as amoxicillin-clavulanic acid or of acute hepatitis with other features of DRESS syndrome in a person taking nevirapine as part of ART strongly suggests a drug etiology, and liver biopsy is usually unnecessary. Conversely, substantially abnormal liver biochemical test levels (e.g., a serum ALT level elevated more than 5-fold) in a person who has serologic evidence suggestive of

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AIH and has been taking a statin for 3 to 6 months is a clinical challenge that often can be resolved only by liver biopsy. The medical community may benefit when new instances or patterns of drug-induced liver disease are adequately defined; this benefit may persuade the clinician (but not always the informed patient) to proceed with a liver biopsy in equivocal cases. 

Considerations in Patients with Viral Hepatitis Patients with chronic hepatitis B or C may be at higher risk of liver injury from antituberculous chemotherapy, ibuprofen and possibly other NSAIDs, anticancer drugs, and ART compared with persons without viral hepatitis. A more common clinical problem is the finding of a high serum ALT level (>300 U/L) at a routine office visit in a patient with previous levels less than 150 U/L. In patients with hepatitis C, the rise in serum ALT is more likely the result of DILI than a spontaneous change in the activity of the hepatitis C, particularly when the ALT level is greater than 1000 U/L. The most commonly implicated agents are acetaminophen taken in moderate doses under conditions of increased risk (e.g., fasting, alcohol excess, use of other medication) and CAM preparations (see Chapter 89). Clinical suspicion is essential for recognizing DILI so that appropriate advice can be given. Determination of serum acetaminophen levels may be useful in difficult cases, but the results can be difficult to interpret in the context of regular ingestion, as opposed to a single episode of self-poisoning. 

Prevention and Management With the exception of acetaminophen hepatotoxicity, little effective treatment for drug-induced liver disease is available, other than LT for liver failure. Special emphasis, therefore, must be placed on prevention and early detection of liver injury as well as on prompt withdrawal of the offending agent. Safe use of overthe-counter agents such as acetaminophen, NSAIDs, and CAM preparations is important. Most drugs associated with drug-induced liver disease are idiosyncratic hepatotoxins, for which liver injury occurs rarely. Avoiding overuse of these drugs can minimize the overall frequency of adverse hepatic reactions; antibiotics such as amoxicillin-clavulanic acid and flucloxacillin are pertinent examples. Similarly, polypharmacy should be avoided when possible. Postmarketing surveillance of new drugs is critical, and all physicians should participate in reporting adverse effects to monitoring agencies. For dose-dependent hepatotoxins, prevention depends on adherence to dosage guidelines or monitoring of blood levels. This approach has virtually abolished some forms of DILI, such as tetracycline-induced fatty liver, aspirin hepatitis, and methotrexate-induced hepatic fibrosis. In cases with specific risk factors, strategies to prevent toxicity are essential (e.g., avoiding valproic acid use with other drugs in the very young; avoiding methotrexate in persons who consume alcohol in excess). Moderate doses of acetaminophen are also contraindicated in heavy drinkers and after fasting,38 and halothane should not be readministered within 28 days or in persons suspected of previous sensitivity to a haloalkane anesthetic. Early detection is also critical. Patients should be warned to report any untoward symptoms, particularly unexplained nausea, malaise, right hypochondrial pain, lethargy, or fever. These nonspecific features may represent the prodrome of drug-induced hepatitis. They are an indication for liver biochemical testing and, if the results suggest liver injury, for cessation of treatment. A more difficult issue is whether regular (protocol) screening with liver biochemical tests should be performed when a drug is prescribed. Although authors and drug manufacturers often recommend such screening, the efficiency and cost-effectiveness

of this approach are unknown. The onset of liver injury is often rapid, rendering once-a-month or every-second-week screening futile. Furthermore, up to 7.5% of persons who receive placebo in clinical trials have persistently raised serum ALT levels. If liver biochemical test levels are monitored, the threshold at which a drug should be discontinued is uncertain, as illustrated by isoniazid, which causes some liver biochemical test abnormality in 30% of exposed subjects. Generally, it is recommended that isoniazid be stopped if serum ALT levels exceed 250 U/L or more than 5 times the ULN, but elevation of the serum bilirubin level, a decrease in the albumin concentration, prolongation of the prothrombin time, or any pertinent symptoms provides a clearer indication to stop the drug. Conversely, a rise in the serum GGTP level or a minor elevation of the serum alkaline phosphatase level usually indicates hepatic adaptation rather than liver injury. We do not routinely recommend protocol screening except for methotrexate, but this approach could be useful for agents such as valproic acid, isoniazid, pyrazinamide, ketoconazole, dantrolene, thiazolidinediones, and synthetic retinoids, either because the liver injury may be delayed and gradual in some cases or because such screening emphasizes the hepatotoxic potential of these drugs to patients and physicians. Evaluation by liver biopsy or by a noninvasive method such as serum biomarkers or elastography (see Chapters 73 and 74) may have a role in the assessment of hepatic fibrosis in patients who take methotrexate (see later). The management of DILI includes removal of the drug and administration of an antidote. In practice, treatment usually is confined to discontinuing the offending drug. Failure to discontinue the offending drug is the single most important factor leading to poor outcomes, such as ALF and chronic liver disease.24,25 For ingested toxins such as metals and acetaminophen, removal of the unabsorbed drug through the aspiration of stomach contents may be appropriate. Methods to remove absorbed toxins (charcoal hemodialysis, forced diuresis) are usually ineffective except in selected circumstances (e.g., acetaminophen). Thiol replacement therapy, usually with N-acetylcysteine (NAC), is indicated as an antidote for acetaminophen poisoning. Beyond discontinuation of the offending agent, the management of DILI is symptomatic and supportive. NAC can be used in ALF, but early referral for LT should be considered (see Chapter 97).23 UDCA may help in managing drug-induced cholestasis. In general, glucocorticoids are ineffective in treating drug-induced liver disease; however, case reports attest to the occasional effectiveness of glucocorticoids in protracted cases of hepatitis caused by etretinate, allopurinol, diclofenac, or ketoconazole.1 Glucocorticoids should be reserved for atypical and refractory cases, particularly those associated with vasculitis. 

DOSE-DEPENDENT HEPATOTOXICITY Few dose-dependent hepatotoxins are clinically relevant today. Examples include acetaminophen, some herbal and dietary supplements, plant and fungal toxins, amodiaquine, hycanthone, vitamin A, methotrexate, cyclophosphamide, anticancer drugs, carbon tetrachloride, phosphorus, and metals (especially iron, copper, and mercury).

Acetaminophen General Nature, Frequency, and Predisposing Factors Acetaminophen (paracetamol) is safe in recommended doses of 1 to 4 g daily, but hepatotoxicity produced by self-poisoning with acetaminophen has been recognized since the 1960s. Despite the effectiveness of thiol-based antidotes, acetaminophen remains the most common cause of DILI in most countries and an important cause of ALF.23,87 Attempted suicide is the usual reason for

CHAPTER 88  Liver Disease Caused by Drugs

TABLE 88.5  Risk Factors for Acetaminophen-Induced Hepatotoxicity Factor

Relevance

Age

Children may be more resistant than adults

Dose

Minimal hepatotoxic dose: 7.5g (≈100 mg/kg) in adults, 150 mg/kg in children Severe toxicity possible with dose >15 g

Blood level of acetaminophen

Influenced by dose, time after ingestion, gastric emptying Best indicator of risk of hepatotoxicity (see text and Fig. 88.2)

Chronic excessive alcohol ingestion

Toxic dose threshold is lowered; worsens prognosis (also related to late presentation); nephrotoxicity common

Fasting

Toxic dose threshold is lowered—therapeutic misadventure (see text)

Concomitant medication

Toxic dose threshold is lowered—therapeutic misadventure; worsens prognosis (e.g., isoniazid, phenytoin, zidovudine)

Time of presentation

Late presentation or delayed treatment (>16 hr) predicts worse outcome

overdose. Although controversial,88 hepatologists and pediatricians see cases of acetaminophen poisoning that have arisen through what Zimmerman and Maddrey termed “therapeutic misadventure.”89 This occurrence is especially common in persons who habitually drink alcohol to excess and has also been recognized after daily ingestion of moderate therapeutic doses (10 to 20 g over 3 days) of acetaminophen in adults and children who are fasting or malnourished38 or who are taking drugs that interact with the metabolism of acetaminophen.89 Single doses of acetaminophen that exceed 7 to 10 g (140 mg/ kg body weight in children) may cause liver injury, but this outcome is not inevitable. Severe liver injury (serum ALT > 1000 U/L) or fatal cases usually involve doses of at least 15 to 25 g, but because of inter-individual variability, survival is possible even after ingestion of a massive single dose of acetaminophen (greater than 50 g).90 Among persons with an untreated acetaminophen overdose, severe liver injury occurred in only 20%, and among those with severe liver injury, the mortality rate was 20%.90 Conversely, among heavy drinkers, daily acetaminophen doses of 2 to 6 g have been associated with fatal hepatotoxicity.88-91 Risk factors for acetaminophen-induced hepatotoxicity are summarized in Table 88.5. Children are relatively resistant to acetaminophen-induced hepatotoxicity,92 possibly because of their tendency to ingest smaller doses, greater likelihood of vomiting, or biological resistance; however, liver injury has been reported with intravenous acetaminophen use in children (usually due to dosing errors).93 Therapeutic misadventure after multiple doses, especially during fasting and when weight-based recommendations have been exceeded, has a high mortality rate.94 By contrast, the presence of underlying liver disease does not predispose to acetaminophen hepatotoxicity. Self-poisoning with acetaminophen is most common in young women, but fatalities are most frequent in men, possibly because of alcoholism and late presentation.87,91,95 The time of presentation is critical because thiol therapy given within 12 hours of acetaminophen poisoning virtually abolishes significant liver injury (see later). Therapeutic misadventure is also associated with a worse outcome.88 Concomitant use of agents such as phenobarbital, phenytoin, isoniazid, and zidovudine increases the risk of hepatotoxicity. These drugs promote the oxidative metabolism of acetaminophen to NAPQI by inducing CYP2E1 (for isoniazid) or CYP3A4 (for phenytoin) or by competing with glucuronidation pathways (for zidovudine). Alcohol and fasting have dual effects by enhancing expression of CYP2E1 and by depleting

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hepatic glutathione. Fasting also may impair acetaminophen conjugation by depleting cofactors for the glucuronidation and sulfation pathways.38 Acetaminophen hepatotoxicity produces zone 3 hepatic necrosis, with extension to submassive (bridging) or panacinar (massive) necrosis in severe cases. Inflammation is minimal, and recovery is associated with complete resolution without fibrosis. The zonal pattern of acetaminophen-induced necrosis is related to the mechanism of hepatotoxicity, particularly the role of CYP2E1, which is expressed in zone 3, and to lower levels of glutathione in zone 3 hepatocytes than in hepatocytes in the other zones. 

Clinical Course, Outcomes, and Prognostic Indicators In the first 2 days after acetaminophen self-poisoning, features of liver injury are not present. Nausea, vomiting, and drowsiness are often caused by concomitant ingestion of alcohol and other drugs. After 48 to 72 hours, serum ALT levels may be elevated, and symptoms such as anorexia, nausea and vomiting, fatigue, and malaise may occur. Hepatic pain may be pronounced. Repeated vomiting, jaundice, hypoglycemia, and other features of ALF, particularly coagulopathy and hepatic encephalopathy, characterize severe cases. The liver may shrink because of severe necrosis. Serum levels of ALT are often between 2000 and 10,000 U/L. These high levels can help confirm the diagnosis in complex settings, as may occur with alcoholic patients and those with viral hepatitis.89 Indicators of a poor outcome87,88,91,95 include grade 4 hepatic encephalopathy, acidosis, severe and sustained impairment of coagulation factor synthesis, renal failure, and a pattern of falling serum ALT levels in conjunction with a worsening prothrombin time (see also Chapter 95). Renal failure reflects acute tubular necrosis or hepatorenal syndrome. Uncommon accompanying features include myocardial injury90 and skin and lung involvement in rare cases of acetaminophen hypersensitivity.96 Death occurs between 4 and 18 days after the overdose and generally results from cerebral edema and sepsis complicating hepatic and multiorgan failure. The majority of patients recover completely. Cases of apparent chronic hepatotoxicity rarely have been attributed to continued ingestion of acetaminophen (2 to 6 g/day), usually by a susceptible host, such as a heavy drinker or a person with preexisting, unrecognized liver disease.1,22 

Treatment In patients who present within 4 hours of an acetaminophen overdose, the stomach should be emptied with a wide-bore NG tube. Oral charcoal is most useful within the first 1 to 2 hours but can be used up to 4 hours in patients who present with a large overdose, after ingestion of a sustained-release preparation, or consumed drugs that impair gastric emptying concurrently. Use of activated charcoal is contraindicated if there is airway compromise. The aim of management is to identify patients who should receive thiol-based antidote therapy and, in those with established severe liver injury, assess the patient’s candidacy for LT. Blood levels of acetaminophen should be measured at the time of presentation. Because of delayed gastric emptying, however, blood levels within 4 hours of ingestion may underestimate the extent of exposure. After 4 hours, acetaminophen blood levels are a reliable indicator of the risk of liver injury in patients with an acute overdose (but not in those with a therapeutic misadventure). The risk of liver injury is then estimated by reference to the Rumack-Matthew acetaminophen toxicity nomogram (Fig. 88.2).90 Indications for antidote therapy include a reliable history of major poisoning (more than 10 g) or blood acetaminophen levels in the moderate- or high-risk bands on the nomogram, or both.90,95 At-risk patients should be hospitalized for monitoring.

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Acetaminophen plasma concentration

µg/mL µmol/L 300

2000

200 150

1300 1000 900 800 700 600 500 400

100 90 80 70 60 50 40 30

300 250 200

Potential for toxicity

20

10 9 8 7 6 5 4 3

Toxicity unlikely

100 90 80 70 60 50 40 30

Treatment is recommended if the level is above the broken line

20

2 10

4

Measure level at least 4 hours postingestion

8

12

16

20

24

28

32

36

Hours postingestion

Fig. 88.2  Rumack-Matthew acetaminophen toxicity nomogram. The risk of hepatotoxicity correlates with the plasma acetaminophen level and the time after ingestion. (From Smilkstein MJ, Knapp GL, Kulig KW, et al. Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. Analysis of the National Multicenter Study [1976-1985]. N Engl J Med 1988;319:1557-62.)

Hepatic necrosis occurs only when glutathione concentrations fall below a critical level, thereby allowing NAPQI to produce liver injury. Administration of cysteine donors stimulates hepatic synthesis of glutathione. Many cysteine precursors or thiol donors can be used, but NAC has become the agent of choice. Oral administration is preferred in the USA,87,90 with a loading dose of 140 mg/kg followed by administration of 70 mg/kg every 4 hours for 72 hours. This regimen is highly effective, despite the theoretical disadvantage that delayed gastric emptying and vomiting may reduce intestinal absorption of NAC. In Europe and Australia, NAC is administered by slow bolus intravenous injection followed by infusion (150 mg/kg over 15 minutes in 200 mL of 5% dextrose, with a second dose of 50 mg/kg 4 hours later, if the blood acetaminophen levels indicate a high risk of hepatoxicity, and a total dose over 24 hours of 300 mg/kg).90 The intravenous regimen, now approved by the FDA, is also used in many US centers.97 The intravenous route may be associated with a higher rate of hypersensitivity reactions because of the higher systemic blood levels achieved. Adverse reactions to NAC are common but are usually mild98; however, they can occasionally be severe, with rash, angioedema, and shock. Therefore, NAC must be administered under close supervision. In patients known to be sensitized to NAC, methionine is probably just as effective but is not available in a commercial preparation; it must be made up fresh and often causes vomiting.90 Other regimens have been explored, including shorter (12-hour) and simpler (2-bag versus 3-bag) schedules.99,100 Although these protocols have been well tolerated, the studies evaluating them were retrospective and

inadequately powered to detect non-inferiority as compared with the standard schedule.99 Cases of acetaminophen-induced severe liver injury are virtually abolished if NAC is administered within 16 hours of acetaminophen ingestion.87,90,95 After 16 hours, thiol donation is unlikely to prevent liver injury because oxidation of acetaminophen to NAPQI with consequent oxidation of thiol groups is complete and mitochondrial injury and activation of cell death pathways are likely to be established. Nevertheless, NAC has been shown to decrease the mortality associated with acetaminophen-induced hepatotoxicity when administered 16 to 36 hours after self-poisoning,87,90,95 possibly because NAC stabilizes vascular reactivity in patients with ALF. Therefore, NAC is used in patients with a late presentation after an acetaminophen overdose. LT is an option for selected patients in whom ALF develops after aceta­ minophen poisoning.101 Case selection relies on the prognostic indicators discussed earlier and is strongly influenced by the prospects for successful psychological rehabilitation (see Chapter 97).95 Poor adherence and self-harm post-transplantation cannot be accurately predicted by pretransplant assessment.101 In several series, about 60% of listed patients have been transplanted, and survival rates have exceeded 70%.95 

Prevention Safe use of acetaminophen involves adherence to the recommended maximum dose and education of the patient about the risk factors that lower the toxic dose threshold. Acetaminophen doses of more than 2 g a day are contraindicated in heavy drinkers, in those taking other medications (particularly phenytoin, zidovudine, and isoniazid), and during fasting. Prolonged use of acetaminophen requires caution in patients with severe cardiorespiratory disease or advanced cirrhosis. Use of acetaminophen for self-poisoning continues despite attempts at public education about the risks involved. The chances of harm from a suicidal gesture may be reduced by the sale of acetaminophen in smaller package sizes, a smaller dose per tablet (325 mg), and use of blister packs, which hamper ready access to the tablets or capsules.102 

Other Causes Some hepatotoxins are not as clearly dose dependent as acetaminophen but cause cytopathic changes, such as extensive hydropic change, diffuse or zonal microvesicular steatosis, and zonal necrosis.1,22 Injury likely represents metabolic idiosyncrasy, in which the drug or one of its metabolites accumulates and interferes with protein synthesis or intermediary metabolism, or both. The mitochondrion is often the main subcellular target, and other metabolically active tissues can be involved. Pancreatitis and renal tubular injury may accompany severe liver injury caused by valproic acid, tetracycline, and ART, and metabolic acidosis with a shock-like state is common. This presentation was first recognized with intravenous high-dose tetracycline (>2 g/day for more than 4 days) in pregnant women, men taking estrogens, and patients in renal failure.22 With appropriate dose limitations, this reaction is entirely preventable.

Niacin (Nicotinic Acid) Niacin is a dose-dependent hepatotoxin; liver injury usually occurs at doses that exceed 2 g/day but also occurs in rare instances with low-dose (500 mg/day) sustained-release niacin.103 The clinicopathologic spectrum encompasses mild and transient increases in serum ALT levels, jaundice, acute hepatitis, cholestasis, and ALF, which can also follow ingestion of a single large dose (20 g) of a native niacin supplement.104 Patients taking sulfonylureas and those with preexisting liver disease, particularly alcohol-associated hepatitis, are at increased risk. The symptoms

CHAPTER 88  Liver Disease Caused by Drugs

can begin as early as one week to as long as 4 years after the drug is started. Complete resolution occurs after the drug is stopped. Liver biopsy specimens show hepatic necrosis and centrilobular cholestasis. Substituting one niacin preparation for another without a dose adjustment should be avoided; switching from immediate- to sustained-release preparations requires a 50% to 70% reduction in the niacin dose.105 

Valproic Acid (Sodium Valproate) Valproic acid-associated hepatic injury occurs almost exclusively in children, particularly those under 3 years of age. Also at risk are persons with a family history of a mitochondrial enzyme deficiency (chiefly involving the urea cycle or long-chain fatty acid metabolism) (see Chapter 77), Friedreich ataxia, Reye syndrome, or a history of valproic acid hepatotoxicity in a sibling. Another risk factor is multiple drug therapy. Adult cases are rare. Mutations within the mitochondrial polymerase γ gene (POLG) were present in nearly one half (8 of 17) of subjects with valproic acid hepatotoxicity, and these mutations carried a > 20-fold risk of liver injury compared with population-matched controls.106 The overall risk of liver injury among valproic acid users varies from 1 per 500 persons exposed among high-risk groups (age < 3, polypharmacy, genetic defects of mitochondrial enzymes) to less than 1 in 37,000 in low-risk groups.107 No relationship exists between valproic acid toxicity and dose, but blood levels of valproic acid tend to be high in one half of affected persons. The metabolite 4-en-valproic acid, produced by CYP-catalyzed metabolism of valproic acid, is a dose-dependent hepatotoxin in animals and in vitro. The concept has emerged that valproic acid is an occult dose-dependent toxin in which accumulation of a hepatotoxic metabolite (favored by co-exposure to CYP-inducing antiepileptic agents) produces mitochondrial injury in a susceptible host (e.g., young children, especially those with partial deficiencies of mitochondrial enzymes).108 Valproic acid also inhibits the synthesis of carnitine, a cofactor in mitochondrial fatty acid beta oxidation. Symptoms begin within 4 to 12 weeks, are often nonspecific, and include lethargy, malaise, poor feeding, somnolence, worsening seizures, muscle weakness, and facial swelling. In typical cases, features of hepatotoxicity follow, including anorexia, nausea, vomiting, RUQ abdominal discomfort, and weight loss.107,108 When jaundice ensues, hypoglycemia, ascites, coagulopathy, and encephalopathy indicate ALF with imminent coma and death. In some cases, a neurologic syndrome characterized by ataxia, mental confusion, and coma predominates, with little evidence of hepatic involvement. In other cases, fever and tender hepatomegaly suggestive of Reye syndrome may be present (see later); such cases tend to have a better prognosis. Additional extrahepatic features include alopecia, hypofibrinogenemia, thrombocytopenia, and pancreatitis. The terminal phase is often indicated by renal failure, hypoglycemia, metabolic acidosis, and severe bacterial infection. Laboratory features include modest elevations of serum bilirubin and aminotransferase levels; the AST level is usually higher than the ALT level. A profound decrease in clotting factor levels, hypoalbuminemia, and hyperammonemia are common. A small echogenic liver suggestive of steatosis or extensive necrosis is seen on hepatic imaging. Histologic examination shows submassive or massive hepatic necrosis in two thirds of cases with either zonal or generalized microvesicular steatosis.108 Ultrastructural studies indicate conspicuous mitochondrial abnormalities. Treatment is supportive. Small nonrandomized studies have shown that intravenous L-carnitine supplementation can reduce hyperammonemia and improve survival in severe cases of liver injury109 and in patients with a psychiatric disorder in whom hyperammonemic encephalopathy develops without liver disease.110 LT has been performed successfully, but poor outcomes

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have been reported, particularly in children.111 The outcome of LT may be good in highly selected adult patients.112 Prevention depends on adherence to guidelines, including avoiding valproic acid in combination with other drugs in children < 3 years of age and in those with mitochondrial enzyme abnormalities. Pretreatment screening for POLG mutations is recommended for highrisk groups.113 Liver biochemical test abnormalities develop in at least 40% of persons on valproic acid and, therefore, are an unreliable predictor of valproic acid hepatotoxicity. Patients and parents need to be educated about the importance of reporting any adverse symptoms during the first 6 months of treatment. 

Antiretroviral Agents Abnormal liver biochemical test levels and clinical evidence of liver disease are common in patients with HIV/AIDS. Potential causes include HBV, HCV and other hepatobiliary infections, lymphoma, and other tumors. The frequency of hepatic injury with ART (which often includes 3 or 4 agents) is at least 10%.40,45 Because HIV coinfection with HBV or HCV increases the risk of hepatotoxicity, all patients should be screened for viral hepatitis before starting ART.114 Nucleos(t)ide Reverse Transcriptase Inhibitors (NRTIs) NRTIs are weak inhibitors of mitochondrial DNA polymerase gamma in vitro; the order of their potency is as follows: zalcitabine > didanosine > stavudine > lamivudine > zidovudine > abacavir.115 Oxidative stress may also cause hepatotoxicity, resulting in further mitochondrial DNA deletion and the consequences of impaired oxidative phosphorylation, fatty acyl beta oxidation, and insulin resistance. Abacavir is associated with liver injury that occurs within 6 weeks as part of a systemic hypersensitivity reaction. This complication is linked to HLA-B*57:01. Excluding patients who carry this polymorphism has practically abolished abacavir hypersensitivity (0% vs. 2.7% in controls).116 Zidovudine, didanosine, and stavudine are the NRTIs that are most often implicated in liver injury.116,117 Risk factors for mitochondrial drug toxicity among persons with HIV infection include obesity, female gender, pregnancy, and co-prescription of didanosine and stavudine.116,117 Hallmarks of mitochondrial hepatotoxicity include extensive microvesicular or macrovesicular steatosis (or both), lactic acidosis, and liver biochemical test abnormalities with progression to ALF. Asymptomatic hyperlactatemia is common (especially with stavudine) among persons treated with ART, but life-threatening lactic acidosis with hepatic steatosis is rare, with an estimated risk of 1.3 per 1000 person-years of antiretroviral use. Onset is within 3 to 17 months (median, 6 months) after treatment is started. Symptoms are often nonspecific and include nausea, vomiting, diarrhea, dyspnea, lethargy, and abdominal pain. Extrahepatic manifestations, such as myopathy or peripheral neuropathy, and, in severe cases, pancreatitis and renal failure, may follow the lactic acidosis and liver injury. Discontinuation of the drug is mandatory but does not prevent fatalities. Nevertheless, the overall mortality rate is low. One suggested approach to prevention is to monitor therapy by coupling serum ALT and AST testing with serial measurements of the HIV load and CD4 count. Any new aminotransferase elevation should trigger immediate measurement of serum lactate, creatine kinase, and pancreatic enzyme levels.117 Over 60 cases of noncirrhotic portal hypertension have been associated with NRTIs.118 Most cases involved didanosine alone or in combination with stavudine.119 Features of portal hypertension such as variceal bleeding, ascites, and splenomegaly are usually present, but hepatic encephalopathy and liver failure are uncommon. The majority of cases (75%) are in men. Typically, they have been on treatment for 1 to 9 years and have achieved virologic suppression. Nodular regenerative hyperplasia (NRH) and portal vein thrombosis are the main histologic lesions.

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Postulated mechanisms include sinusoidal endothelial cell injury and thrombophilia. Discontinuation of didanosine does not lead to reversal of portal hypertension.  Non-nucleoside Reverse Transcriptase Inhibitors Like abacavir, non-nucleotide reverse transcriptase inhibitors can cause acute hepatitis as part of an early (400 cells/mm3 and >250 cells/ mm3 for men and women, respectively). Underlying hepatitis B or C increases the risk of liver injury.123 Of 12 reports to the FDA between 1997 and 2000, over one half of the patients (7 of 12) had acute hepatitis, one patient required LT, and the remainder had asymptomatic elevations of serum aminotransferase levels. The recommended 2-week dose escalation regimen was not adhered to in some of the cases.121 Sequential toxicity with nevirapine followed by efavirenz has been reported in an HIV-HCV coinfected person.124  Protease Inhibitors Elevated serum aminotransferase levels are common in patients taking protease inhibitors, but clinical hepatitis is infrequent. The agents most often implicated are ritonavir, indinavir, and atazanavir. The latter 2 also cause unconjugated hyperbilirubinemia, a finding that is of no clinical consequence.25 Severe acute hepatitis may occur rarely. The association with peripheral or hepatic eosinophilia in some cases suggests an immunoallergic basis for liver injury.125 Acute hepatitis occurs in 2.9% to 30% of persons receiving high-dose ritonavir (>400 mg/d) but generally does not recur with low-dose regimens except when used as part of combination treatment in patients with advanced cirrhosis.126 In general, the course of the illness is mild, and the liver injury responds favorably to drug withdrawal. Rarely, ALF may develop; in these cases, liver histology has shown severe microvesicular steatosis, cholestasis, and extensive fibrosis. Several studies have shown that patients coinfected with HIV and hepatitis B or C have a higher frequency of hepatotoxicity while on a protease inhibitor; however, liver injury is rapidly reversible in most cases, suggesting that the overall effect of protease inhibitors in coinfected persons is not detrimental.127 These drugs also induce or inhibit CYP3A4, thereby causing important drug-drug interactions.128 Furthermore, immune reconstitution during ART may lead to reactivation of chronic HBV infection.

Aspirin On occasion, aspirin can cause major increases in serum ALT levels suggestive of drug hepatitis, but hepatotoxicity occurs only when blood salicylate concentrations exceed 25 mg/100 mL.129 In addition, individual susceptibility factors include hypoalbuminemia, active juvenile RA, and SLE. Most cases of aspirin-induced hepatotoxicity are identified by biochemical testing rather than clinical features. If present, symptoms usually begin within the first few days or weeks of high-dose aspirin therapy. ALF and fatalities have been rare. Resolution occurs rapidly after drug withdrawal, and salicylates can be reintroduced at a lower dose. All salicylates appear to carry hepatotoxic potential, so there is no advantage to replacing aspirin with another salicylate. Liver histology shows a nonspecific focal hepatitis with hepatocellular degeneration and hydropic changes. The absence of steatosis usually distinguishes aspirin hepatotoxicity from Reye syndrome.

Reye syndrome has been linked with use of aspirin in febrile children. Although Reye syndrome is not simply a form of druginduced liver disease, aspirin plays an important role in its multifactorial pathogenesis. Reye syndrome usually occurs between 3 and 4 days after an apparently minor viral infection. It is characterized by acute encephalopathy and hepatic injury, the latter documented by a 3-fold or greater rise in serum aminotransferase levels or hyperammonemia and by characteristic histology. Effective public health campaigns against the use of aspirin in young febrile children have led to a decline in the incidence of Reye syndrome; however, cases still occur. Misdiagnosis of cases that subsequently were diagnosed as inborn errors of metabolism that mimic Reye syndrome may have also contributed to the declining incidence. Patients with juvenile RA (Still disease) or SLE are at particular risk of Reye syndrome. Features of chronic liver disease or drug allergy are not present. Management requires clinical suspicion and reducing the dose of (or discontinuing) aspirin. Recovery is usually rapid. Aspirin can be used again in lower doses, but alternative NSAIDs are generally used instead. 

Others L-asparaginase is an antileukemic drug that often causes hepatotoxicity, which usually is reversible but can occasionally result in liver failure associated with diffuse microvesicular steatosis.22 A GWAS has shown an association between elevated serum aminotransferase levels seen after induction with L-asparaginase and a palatin-like phospholipase domain-containing protein 3 (PNPLA3) variant [rs738409 (C>G) I148M] that is implicated in NAFLD (see Chapter 87).130 Antiparasitic drugs such as amodiaquine and hycanthone have also been linked to severe and fatal dose-dependent liver injury (∼ 1:15,000 exposed).131,132 

DRUG-INDUCED ACUTE HEPATITIS The term acute hepatitis refers to lesions characterized by the presence of hepatic inflammation with conspicuous hepatocyte cell death or degeneration. More severe lesions include zonal and bridging necrosis or massive (panlobular) hepatic necrosis; these lesions may be associated with fulminant or subfulminant ALF.1,22 Acute hepatitis accounts for nearly 50% of hepatic adverse drug reactions,18-21 and causative agents are numerous.1,22,24,133,134 Two broad types of drug hepatitis are recognized based on the presence (immunoallergic reactions) or absence of clinical and laboratory features consistent with drug allergy (Table 88.6). Those lacking characteristics of drug allergy could be the result of metabolic idiosyncrasy, partial dose dependence, a relationship between hepatitis and metabolism of the drug, or chemical toxicity. Nitrofurantoin and isoniazid are examples of immunoallergy and metabolic idiosyncrasy, respectively. Other relatively frequent examples of drug hepatitis include those associated with granulomatous reactions and chronic hepatitis.

Immunoallergic Reactions Nitrofurantoin Nitrofurantoin is a urinary antiseptic that has long been associated with hepatic injury.135 This reaction occurs at a frequency of 0.3 to 3 cases per 100,000 exposed persons.136,137 The risk increases with age (particularly after 65 years of age). Two thirds of acute cases occur in women, and the female-to-male ratio is 8:1 for chronic hepatitis.136,137 The range of liver diseases associated with nitrofurantoin includes acute hepatitis, occasionally with features of cholestasis, hepatic granulomas, chronic hepatitis with autoimmune features, ALF, and cirrhosis.136,137 Causality has been proved by rechallenge, and no relationship to dose has

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TABLE 88.6  Drug-Induced Acute Hepatitis: Immunoallergic Reaction Versus Metabolic Idiosyncrasy Characteristic

Immunoallergic Reaction

Metabolic Idiosyncrasy

Frequency

1 yr

Relationship to dose

None

Usually none, but drugs with daily doses >50 mg/day are overrepresented in cases of DILI

Interactions with other agents

None

Alcohol; occasionally other drugs (e.g., isoniazid with rifampin)

Course after stopping the drug

Prompt improvement (rare exceptions [e.g., minocycline])

Variable; occasionally slow improvement or deterioration (e.g., troglitazone)

Positive rechallenge

Always; often fever within 3 days

Usual (in two thirds of cases), abnormal liver biochemical test levels in 2-21 days

Fever

Usual; often initial symptom, part of prodrome

Infrequent, less prominent

Extrahepatic features (rash, lymphadenopathy)

Common

Rare

Eosinophilia: Blood

33%-67% of cases

3 × ULN), the drug should be discontinued. Symptoms suggestive of hepatitis should be assessed immediately. Persons in whom jaundice developed with troglitazone should not take other thiazolidinediones.242  Other Oral Hypoglycemic Drugs Hepatocellular injury was common with older sulfonylureas, such as carbutamide, metahexamide, and chlorpropamide.243 Currently used drugs (tolbutamide, tolazamide, glimepiride, and glibenclamide) may rarely cause cholestasis or cholestatic hepatitis.244,245 Similar to sulfonamides, with which they share a structural relationship, hypersensitivity phenomena (fever, skin rash, eosinophilia [i.e., DRESS syndrome]) were present in some cases. Most cases resolved after withdrawal of the drug; however, chronic cholestasis progressing to vanishing bile duct syndrome (VBDS) has been described with tolbutamide and tolazamide. Fatal liver failure has been reported in 2 cases, including one with underlying cirrhosis. Gliclazide245 and glibenclamide have also been associated with hepatocellular injury and, with the latter drug, hepatic granulomas.246 Metformin, acarbose, repaglinide, and human insulin rarely have been associated with liver injury. 

Drugs Used for Psychiatric and Neurologic Disorders Several neuroleptic agents have been associated with drug hepatitis. Some reactions appear to be immunoallergic, whereas others are related to metabolic idiosyncrasy, depending on the drug structure. Such reactions have been reported for commonly used antidepressants, such as fluoxetine,247,248 paroxetine,249 venlafaxine,250 trazodone,251 tolcapone,252 and nefazodone. Antidepressants Monoamine Oxidase Inhibitors. Iproniazid was one of the first drugs associated with acute hepatitis. Reactions occurred in 1% of recipients and were often severe, with reports of fatal ALF. The hydrazine substituent (which iproniazid shares in part with isoniazid, ethionamide, pyrazinamide, and niacin) was determined to be the hepatotoxic moiety.253 Phenelzine and isocarboxazid have been associated with occasional instances of hepatocellular injury, but monoamine oxidase inhibitors are now prescribed infrequently.  Tricyclic Antidepressants. Tricyclic antidepressants bear a structural resemblance to the phenothiazines and are occasional causes of cholestatic or, less commonly, hepatocellular injury. Recovery following cessation of the drug is usual, but amitriptyline254 and imipramine255 can cause prolonged cholestasis.  Selective Serotonin Reuptake Inhibitors (SSRIs) and Other Modern Antidepressants. Liver enzyme elevations have been observed in asymptomatic persons taking fluoxetine and paroxetine.247 A few reports of acute and chronic hepatitis have been attributed to the use of SSRIs,247,248 and acute hepatitis with mirtazapine, a tetracyclic antidepressant.256 Nefazodone (now withdrawn) was associated with cases of subacute liver failure.257 Liver histology showed centrilobular, submassive, or massive hepatic necrosis. Trazodone has been implicated in causing acute

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and chronic hepatocellular injury.251,258 The onset can be delayed as long as 18 months or can occur within 5 days of the start of the drug.259 Occasional reports document severe hepatotoxicity with combinations of antidepressants or with antidepressants used in combination with other neuroleptic agents.260,261 Drug regulatory authorities have been alerted about cases of acute hepatocellular injury (including ALF) with atomoxetine, a norepinephrine reuptake inhibitor, but only a few of these have been linked conclusively with the drug.262  Antipsychotic Drugs In addition to chlorpromazine (see later), liver injury can occur with other antipsychotic agents, mainly as hepatocellular or mixed (clozapine, olanzapine, quetiapine) or cholestatic (risperidone) reactions. Rare cases of ALF have been attributed to clozapine. By promoting weight gain, some of these drugs (clozapine, olanzapine) also promote hepatic steatosis.263  Other Neurologic Drugs Tolcapone, a catechol-o-methyl transferase (COMT) inhibitor used in Parkinson disease, has been associated with 4 cases of ALF.264 All were women older than 70 years of age who presented with jaundice and high serum ALT levels. Centrilobular hepatic necrosis was noted at autopsy in one case. Postmarketing surveillance has identified 3 additional patients with acute hepatocellular injury. Overall, tolcapone is considered safe if patients are monitored appropriately. Current FDA guidelines recommend serum ALT testing every 2 to 4 weeks for the first 6 months. Thereafter, the frequency of testing is left to the discretion of the treating doctor. Patients in whom the serum ALT rises (to at least 1 to 2 × ULN) should be monitored closely; persistent serum ALT elevations (>2 × ULN) are an indication to discontinue the drug. Another COMT inhibitor, entacapone, has only rarely been associated with significant liver injury.265 Alpidem,266 zolpidem,267 and bentazepam268 are sedative hypnotics that have been implicated in hepatotoxicity. With bentazepam, the clinicopathologic pattern resembled chronic hepatitis, but without autoantibodies or other immunologic features.268 Tacrine, a reversible choline esterase inhibitor, was formerly used in Alzheimer disease. Elevated serum ALT levels (>3 × ULN, >20 × ULN) are seen in 25% and 2% of patients, respectively, more often in women than in men.269 These liver enzyme changes resolved after stopping the drug. Symptoms were rare; only nausea and vomiting correlated with major serum ALT elevations. Liver biopsy specimens showed steatosis and mild lobular hepatitis. Minor degrees of hepatocellular injury were noted in up to 50% of cases, but tolerance eventually developed.269 There were isolated reports of jaundice, indicating a rare potential for more severe hepatotoxicity. The mechanism of liver injury is unclear, but mitochondrial injury was observed in an animal model of tacrine hepatotoxicity. Dantrolene, a skeletal muscle relaxant, causes hepatitis in about 1% of exposed persons, with a case-fatality rate of approximately 28%.270 Most of those affected have been older than 30 years of age. One third of patients are asymptomatic, and the remainder present with jaundice and symptoms of hepatitis. Liver histology shows hepatocellular necrosis, often submassive or massive.270 Liver biochemical tests are recommended every 2 weeks while a patient is on treatment, and the drug should be discontinued if the levels become elevated. Other idiosyncratic hepatotoxins include tizanidine (a centrally acting muscle relaxant),271 alverine (a smooth muscle relaxant),272 and riluzole.273 Patients with cirrhosis who take tizanidine are at risk of hypotension; levels of this CYP1A2-metabolized drug are increased as a consequence of diminished cytochrome activity (see Table 88.1).274 Riluzole is approved for treating amyotrophic lateral sclerosis and was associated with increased serum ALT levels in 1.3% to 10% of subjects in clinical trials. Two cases

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of acute hepatitis with microvesicular steatosis have since been reported, with onset 4 and 8 weeks, respectively, after the drug was started.273 Rarely, hepatocellular injury may be delayed up to 6 months. Liver biochemical test elevations resolved rapidly after riluzole was discontinued. 

NSAIDs NSAIDs rarely cause DILI, with or without immunoallergic features and with varying degrees of hepatocellular injury and cholestasis. Bromfenac was withdrawn because of hepatotoxicity.275 Although COX-2 inhibitors are less likely than conventional NSAIDs to cause UGI toxicity, they are not necessarily safer with respect to the risk of liver injury.276 A few cases of acute hepatitis (some severe) have been reported with nimesulide and celecoxib, and rofecoxib was associated with cholestatic liver injury.277 On the other hand, lumiracoxib was withdrawn because it was associated with severe hepatotoxicity.276 In clinical trials, celecoxib was associated with rates of liver injury similar to those in placebo-treated patients (0.8% vs. 0.9%, respectively).277 Increases in serum aminotransferase levels were noted with concurrent use of diclofenac. When serious hepatocellular injury was attributed to celecoxib, female gender was a predisposing factor.278 The onset of symptoms has been between 4 days and 4 weeks after the drug was started. Delayed presentations (5 months to 2 years) may occasionally occur. Liver biochemical and histology were mostly consistent with a pattern of hepatocellular or mixed liver injury, with rare cases of biliary ductopenia and periductal fibrosis.277 Some patients had eosinophilia and skin rash suggestive of DRESS syndrome. Most patients recovered within 1 to 4 months after stopping the drug. Of 18 patients with celecoxib-associated liver injury reported to the FDA, the outcomes included resolution in 12 cases, LT in 2, and persistent biochemical abnormalities 6 to 18 months after the onset in 4.279 Celecoxib should not be administered to persons with a documented sulfonamide allergy because of cross-reactivity. Nimesulide, an NSAID with COX-2 selectivity, has been linked to acute hepatitis and fatal hepatic failure,280 especially in women, although the overall risk of liver injury is low.281 The onset is between 1 to 15 weeks (occasionally up to 8 months) after the drug is started. Risk factors for liver injury include increased treatment duration (>30 days) and higher doses.282 Hypersensitivity features with peripheral eosinophilia may occur. Liver histology shows centrilobular or bridging necrosis and occasionally bland cholestasis. Resolution usually occurred within 2 to 17 months after nimesulide is stopped. 

DRUG-INDUCED GRANULOMATOUS HEPATITIS Drugs account for 2% to 29% of cases of granulomatous hepatitis (see Chapter 37).150,246,283-285 Over 40 drugs and foreign compounds are associated with hepatic granulomas (Table 88.7); not all these agents are associated with systemic inflammation or with persuasive evidence of causality. Many (e.g., halothane, methyldopa, nitrofurantoin, troglitazone, amiodarone, amoxicillin-clavulanic acid) are more commonly associated with other patterns of liver injury. Some of these associations may be fortuitous. The clinical picture is heralded by fever and systemic symptoms (e.g., malaise, headache, myalgia) from 10 days to 4 months after the start of treatment. Hepatomegaly and hepatic tenderness are common; splenomegaly is present in 25% of patients. Extrahepatic features of drug hypersensitivity are common, as is eosinophilia (30%). Liver biochemical test levels are typically mixed because of the infiltrative nature of hepatic granulomas and the frequent presence of some hepatocellular necrosis or cholestasis. For several drugs that cause granulomatous hepatitis, continued exposure leads to more severe types of liver disease, such as cholestatic hepatitis with or without bile duct injury

and hepatic necrosis (see Table 88.7). Small-vessel vasculitis is another potential complication and may involve the kidneys, bone marrow, skin, and lungs; the mortality rate is high. 

DRUG-INDUCED CHRONIC HEPATITIS Chronic hepatitis is defined as hepatitis that continues for more than 6 months. For drug reactions, however, the definition often has been made inappropriately on hepatic histologic features alone. The histologic features include interface hepatitis, bridging necrosis, and fibrosis. Because these features may be present as early as 6 weeks after the onset of severe reactions, they do not confirm chronicity. The diagnosis of chronic hepatitis is more convincing when clinical or biochemical evidence of hepatitis has been present for more than 3 months and when clinical and laboratory features of chronic liver disease or histologic evidence of established hepatic fibrosis are present. Drugs are an uncommon cause of chronic hepatitis (Table 88.8) because the implicated agents such as methyldopa are now rarely used. Nevertheless, recognition of a drug cause remains important for preventing a poor outcome by timely withdrawal of the drug. Chronic hepatitis is more common in women (∼4-fold) and in older patients (as illustrated by nitrofurantoin) but is rare in children. Drugs associated with chronic hepatitis more commonly cause acute hepatitis, and the latent period to recognition tends to be longer in cases of chronic hepatitis; therefore, the duration of drug ingestion may be a risk factor for chronic hepatitis. In one study, the mean duration of use of a drug in patients in whom chronic hepatitis or liver-related morbidity and mortality developed after an episode of DILI was significantly greater than the duration in those in whom an adverse outcome did not occur (153 vs. 53 days).286 Two syndromes of drug-induced chronic hepatitis occur. In the first, cases are identical to acute hepatitis but more severe, more prolonged, or later in onset, perhaps due to failure of recognition. These cases may appropriately be termed chronic toxicity. Clinical and laboratory features of chronic liver disease are rare, and hallmarks of autoimmunity are absent. Management consists of withdrawal of the drug and treatment of liver failure (see Table 88.8). The second syndrome more closely resembles AIH based on the presence of stigmata of chronic liver disease such as spider telangiectasias, a firm liver edge, splenomegaly, bruising, ascites, and other complications related to portal hypertension and liver failure. In addition to raised serum ALT and bilirubin levels, hypoalbuminemia and hyperglobulinemia are usual. The prothrombin time is prolonged in severe cases. ANA and/or smooth muscle antibodies are often present, but, unlike idiopathic AIH, other hallmarks of autoimmunity, such as a history of other autoimmune diseases and genetic predisposition indicated by HLA-B8 and -DRw3 alleles, are absent. Immunosuppressive treatment is not indicated; the clinical condition improves spontaneously after withdrawal of the causative drug. In individual cases, however, glucocorticoids occasionally appear to hasten recovery; nevertheless, immunosuppressive therapy can usually be discontinued, in contrast to most cases (65%) of AIH, in whom discontinuation is followed eventually by relapse.140

Diclofenac Diclofenac is widely prescribed and is considered at least as safe as comparable NSAIDs. Among reports to the U.S. Drug-Induced Liver Injury Network, however, diclofenac was the most frequently implicated NSAID.287 Also, the frequency of diclofenac hepatotoxicity is much higher (11 per 100,000) than previous reports suggested (1 to 5 per 100,000).288 In clinical trials, elevations in serum aminotransferase levels (>3 × ULN and >10 × ULN) were noted in 3.1% and 0.5%, respectively, but liver-disease–related

CHAPTER 88  Liver Disease Caused by Drugs

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TABLE 88.7  Drug-Induced Granulomatous Hepatitis: Major Causative Agents, Frequency, Risk Factors, Clinicopathologic Features, and Outcomes Causative Agent*

Frequency

Risk Factors

Clinicopathologic Features

Outcome

Carbamazepine

16:100,000 treatmentyears

Age >40 yrs, no gender predilection

Two thirds of cases show granulomatous hepatitis; the remainder show acute hepatitis, cholangitis; no drug allergy features

No reported fatalities, rapid recovery

Phenylbutazone

1:5000 exposed

No age or gender predilection

Severe acute hepatitis, cholestasis and bile duct injury also reported; features of drug allergy are common; occasionally vasculitis

Mortality rate 25%, particularly in cases with hepatocellular necrosis

Allopurinol

Rare (40 yr; 90% of cases occur in women; continued ingestion of drug after onset

Clinical features of chronic hepatitis, liver failure; some cases with cholestasis; 20% with pneumonitis; hyperglobulinemia is usual, ANA, SMA

Mortality rate 10%

Methyldopa

Age >50 yr; 80% of cases occur in Jaundice, diarrhea, liver failure; women; repeated courses, continued hyperglobulinemia, ANA, SMA; protracted ingestion of drug in a sensitized patient course

High mortality rate

Diclofenac

Age >65 yr; most cases occur in women

Clinical features of chronic hepatitis, liver failure; hyperglobulinemia, ANA, SMA

Response to glucocorticoids in a few cases

Minocycline

Young women; prolonged use of drug

Often part of drug-induced SLE syndrome (arthritis, rash, nephritis); hyperglobulinemia, ANA

Cases may be severe, with a fatal outcome or need for LT; glucocorticoid treatment may be indicated

Isoniazid

Age >50 yr; continued ingestion of drug after onset; duration of therapy

Severe and fatal cases with cirrhosis; no immune phenomena

High mortality rate or need for liver transplantation

Dantrolene

Age >30 yr; dose, duration of therapy

Jaundice, liver failure; no immune phenomena

High mortality rate

Etretinate

Age >50 yr; two thirds of cases occur in women

Jaundice, weight loss, liver failure; deterioration after drug is stopped

Response to glucocorticoids in 2 reported cases

Acetaminophen

Regular intake at moderate doses (2-6 g/ day); alcohol, fasting, other drugs

No features of chronic liver disease, no autoimmune phenomena; these are cases of chronic toxicity

Rapid normalization of liver biochemical test levels after drug is stopped

*Several other agents, including aspirin, cimetidine, fenofibrate, fluoxetine, germander, halothane, methotrexate, sulfonamides, trazodone have been mentioned as associated with chronic hepatitis, but evidence of causation is not necessarily convincing. Other causes, including oxyphenisatin and tienilic acid, are now of historical interest. SMA, smooth muscle antibodies.

hospitalizations were infrequent (0.023%).289 More than 200 cases of diclofenac hepatitis have been reported,290 including several proven by inadvertent rechallenge. Only 4 cases have been fatal, and 5 cases can reasonably be regarded as chronic hepatitis. Genetic susceptibility to diclofenac hepatotoxicity has been documented.291 In these cases, polymorphisms have been observed in genes that affect metabolic pathways that lead to formation of reactive metabolites of the drug and affect biliary excretion. Immune responses to drug metabolite-protein adducts have been identified.291 The risk of hepatitis is increased in women and with aging. A prodromal illness characterized by anorexia, nausea, vomiting, and malaise heralds the onset of liver injury, which usually

occurs within 3 months (range 1 to 11 months). Fever and rash occur in 25% of patients.290 Liver biochemical test results reflect acute hepatitis with or without cholestasis. Reactions tend to be severe, with jaundice occurring in 50% of cases. Liver histology shows acute lobular hepatitis, and, in severe cases, bridging or confluent necrosis, interface hepatitis, and fibrous expansion of the portal tracts. The prognosis is usually good; resolution occurs after discontinuation of the drug. Cases of drug-induced chronic hepatitis have been described in which the clinical and laboratory features (ascites, hypoalbuminemia, hyperglobulinemia, jaundice) suggested AIH, although the frequency of autoantibodies is unclear. These cases usually improve spontaneously after discontinuation of the drug, but glucocorticoids

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have been used successfully in a few protracted cases.292 Crosssensitivity with other NSAIDs seems to be rare but has been reported with ibuprofen.292 The rarity of severe diclofenacinduced hepatotoxicity makes liver biochemical monitoring unrealistic. Patients should be advised to report adverse effects, and clinicians must be aware that diclofenac can cause both acute and chronic hepatitis.

Minocycline Minocycline has been associated with rare cases of druginduced SLE (rash, polyarthritis, hyperglobulinemia, and ANA), chronic hepatitis with autoimmune features, and both syndromes in the same patient.293 Carriers of the HLA B*35:02 allele have a nearly 30-fold increased risk of DILI as compared with population controls.294 The onset is often well beyond 6 months (median latency, 318 days) after treatment is started. Young women appear to be particularly affected. In the USA, minocycline was the most common drug associated with idiosyncratic drug hepatotoxicity in children.295 The reactions are severe; some patients have died or required LT. Progression to cirrhosis has been reported.296 The course may be prolonged after drug withdrawal; several patients have been treated with glucocorticoids.294

DRUG-INDUCED ACUTE CHOLESTASIS Importance, Types of Reactions, and Diagnosis Cholestatic drug reactions include acute cholestasis with or without hepatitis, cholestatic hepatitis with cholangitis, and chronic cholestasis, either with VBDS resembling PBC (see Chapter 91) or with biliary strictures reminiscent of sclerosing cholangitis (see Chapter 68).297,298 The clinical and biochemical features of druginduced cholestasis resemble other hepatobiliary disorders, and clinicians must elicit a thorough drug history from all patients with cholestasis. The timely cessation of a causative drug prevents an adverse outcome and avoids unnecessary invasive investigations or surgery. Clinical features include pruritus, dark urine, pale stools, and, in more serious cases, jaundice. Liver biochemical test results show a predominant elevation of serum alkaline phosphatase levels, with lesser increases in serum ALT and GGTP levels and conjugated hyperbilirubinemia. The serum ALT level may be elevated up to 8-fold, as a result of either the toxic effects of acute bile retention on hepatocellular integrity or concomitant “hepatitis.” In such cases, the ratio of the relative increases in serum ALT and alkaline phosphatase levels (based on multiples of the ULN) is typically less than 2:1 in patients with cholestasis.297 Cases of mixed cholestasis and hepatitis are highly suggestive of a drug reaction. Hepatobiliary imaging is critical to exclude biliary obstruction and a hepatic or pancreatic mass lesion. In the absence of such findings, drug-induced cholestasis is more likely, and a liver biopsy is often advisable. Certain histologic features suggest a hepatic drug reaction, whereas others (e.g., edema of the portal tracts) suggest biliary obstruction. When the temporal relationship to drug ingestion indicates a high probability of a drug reaction, the incriminated drug should be discontinued and the patient observed for improvement. Management should focus on symptom relief, with particular attention to pruritus (see Chapter 91).297-299 Pruritus is often ameliorated with cholestyramine. In intractable cases, UCDA can be helpful.299,300 Rifampin, phototherapy, plasmapheresis, and opiate receptor antagonists (e.g., naloxone, naltrexone, nalmefene) have been used as third-line therapies.299 Glucocorticoids have no role, and antihistamines are usually ineffective or cause oversedation. 

Cholestasis without Hepatitis Cholestatic reactions are characterized by bile retention within canaliculi, Kupffer cells, and hepatocytes, with minimal inflammation or hepatocellular necrosis; terms to describe this reaction include pure, canalicular, and bland cholestasis. Cholestasis without hepatitis reflects a primary disturbance in bile flow. Sex steroids are typical causative agents. Other drugs generally associated with cholestatic hepatitis occasionally produce bland cholestasis (e.g., amoxicillin-clavulanic acid, sulfonamides, griseofulvin, ketoconazole, tamoxifen, warfarin, ibuprofen).297,298 Cyclosporine is associated with liver biochemical test abnormalities; the features resemble those of cholestasis, but hyperbilirubinemia usually is predominant.1 The reaction is mild and reverses rapidly with a reduction in dose. Tacrolimus can also cause cholestasis,301 whereas sirolimus has been implicated in cases of mild acute hepatitis.302

Steroids Oral Contraceptive Steroids The frequency of cholestasis with OCS is 2.5 per 10,000 women exposed. OCS-associated cholestasis is partly dose dependent and less likely with low-dose than high-dose estrogen preparations.303 Genetic factors contribute to the high frequency of this complication among women in Chile and Scandinavia.298 Persons with a history of intrahepatic cholestasis of pregnancy are also at risk (50%) (see Chapter 40). The estrogenic component is most likely responsible and impairs functioning of the BSEP or canalicular water transport (or both).304 Polymorphisms within genes relating to canalicular transport (e.g., ABCB4, MDR3, BSEP) also underlie some cases of OCS (see Chapter 64).305,306 Symptoms develop 2 to 3 months, rarely as late as 9 months, after OCS are started. A mild transient prodrome of nausea and malaise may occur and is followed by pruritus and jaundice. Serum alkaline phosphatase levels are moderately elevated, and serum aminotransferase levels are increased transiently, occasionally to levels exceeding 10 times the ULN. The serum GGTP level is often normal. Recovery is usually prompt, within days to weeks after cessation of the drug. Chronic cholestasis is rare.298 Acute hepatitis is also an uncommon complication.307 Hormonal replacement therapy is safe in patients with liver disease, but jaundiced patients may experience an increase in serum bilirubin levels. Liver biochemical tests should be monitored in hormonal replacement therapy users with liver disease.298  Anabolic Steroids At high doses, anabolic steroids often produce reversible bland cholestasis, usually within 1 to 6 months after treatment is started. Recovery usually follows drug withdrawal, but protracted cholestasis with biliary ductopenia can occur. Rarely, anabolic steroids may cause acute hepatocellular injury.308 Both OCS and the 17-alkylated anabolic steroids are associated with cholestasis, vascular lesions, and hepatic neoplasms (see later). The strength of these associations with individual lesions varies. Hepatic adenomas are clearly associated with use of OCS, whereas the association of OCS with HCC is controversial.309 By contrast, HCC is well documented in anabolic steroid users. Likewise, hepatic and portal vein thrombosis is an established adverse effect of OCS but not of anabolic steroids, whereas peliosis hepatis is seen more often with the latter than with OCS. 

Cholestasis with Hepatitis Cholestasis with hepatitis is a common hepatic drug reaction and is characterized by conspicuous cholestasis and hepatocellular necrosis. Liver histology shows lobular and portal tract inflammation, often with neutrophils and eosinophils, as well

CHAPTER 88  Liver Disease Caused by Drugs

as mononuclear cells. This type of reaction overlaps with druginduced acute hepatitis, cholestasis without hepatitis, and cholestasis with bile duct injury. Causative agents include chlorpromazine (see later), antidepressants and other psychotropic agents, erythromycins and other macrolides,310 and related ketolide antibiotics (telithromycin,311 clindamycin,312 sulfonamides, oxypenicillins,313 ketoconazole [see earlier],219 sulfonylureas, sulindac,314 ibuprofen, piroxicam,315 cefazolin,316 captopril,167 flutamide,317 enalapril,168 pravastatin,171 atorvastatin,172 ticlopidine,318 ciprofloxacin and other fluoroquinolones,319 and metformin320).

Chlorpromazine Chlorpromazine hepatitis, the prototypical drug-induced cholestatic hepatitis,321 has been recognized since the 1950s. The range of hepatic reactions includes asymptomatic liver biochemical test abnormalities in 20% to 50% of recipients and rare cases of fulminant hepatic necrosis. The frequency of cholestatic hepatitis varies from 0.2% to 2.0%, depending on the type of study; the lower value probably is representative of the risk in the general population. No relationship to dose or to underlying liver disease has been recognized. Female predominance is evident. Reactions do not appear to be more common with increasing age but are rare in children. The onset is within 1 to 6 weeks after the drug is started but can be delayed by 5 to 14 days after its discontinuation. Accelerated onset occurs with rechallenge. A prodromal illness of fever and nonspecific symptoms is usual and is followed by GI symptoms and jaundice. Pruritus is common and occurs later with chlorpromazine hepatitis than with drug-induced bland cholestasis. In a small proportion of affected patients, RUQ abdominal pain is severe. Rash is infrequent. Serum bilirubin, ALT, and alkaline phosphatase levels are increased. Eosinophilia is present in 10% to 40% of patients. Most patients recover completely: one third within 4 weeks, another third between 4 and 8 weeks, and the remainder after 8 weeks.300,321 In about 7% of cases, full recovery has not occurred by 6 months. 

Amoxicillin-Clavulanic Acid Over 150 cases of cholestatic hepatitis have been attributed to this antibiotic. The overall frequency is 1.7 cases per 10,000 prescriptions; male gender, increasing age (>55 years), and prolonged duration of use are risk factors.322 The clavulanic acid component was previously implicated because similar lesions were noted with ticarcillin-clavulanic acid323; however, a subsequent study reported similar cholestatic or mixed-type DILI with amoxicillin alone, suggesting the amoxicillin component may also be involved.324 The onset of symptoms is within 6 weeks (mean 18 days) but can be delayed up to 6 weeks after the drug is stopped. Features of hypersensitivity such as fever, skin rash, and eosinophilia are seen in 30% to 60% of patients. Liver histology shows cholestasis with mild portal inflammation. Bile duct injury (usually mild) and perivenular cholestasis with lipofuscin deposits are often present. Other histologic features include hepatic granulomas, biliary ductopenia, and cirrhosis.325 Most patients recover in 4 to 16 weeks. Fatalities and the need for LT are rare.324 Elevated serum aminotransferase levels can persist for more than 6 months in 11% of patients and return to normal in most, but not all, cases. The pathogenesis involves innate and/or adaptive immune responses or defects in detoxification, as supported by the strong association of liver injury with certain HLA class II (HLADRB1*15:01-DRB5*01:01-DQB1*06:02) haplotypes and class I antigens 326 and by studies identifying amoxicillin- and clavulanic acid-specific T cells.327 Specific HLA genotypes are linked to variations in clinical presentation (hepatocellular or cholestatic/mixed), severity, and age of onset. “Protective” genotypes

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(HLA-DRB1*07 family) have also been described.328,329 Persons with certain glutathione S-transferase genotypes (the double-null genotype, GSTT1 and GSTM1) are at an increased risk of liver injury by a factor of 2, suggesting that defects in detoxification may contribute to hepatotoxicity.330 

Fluoroquinolones Most fluoroquinolones have been associated with acute hepatocellular, cholestatic, or mixed reactions,331 with the highest frequencies attributed to levofloxacin and moxifloxacin.332 Trovafloxacin was withdrawn due to hepatotoxicity. The onset can be rapid (median 8 days; range 1 to 39 days) or may be delayed for up to 30 days after the antibiotic course is completed. Hypersensitivity features may be present. Resolution usually follows discontinuation of the drug, but instances of ALF, chronic cholestasis, and VBDS have been reported.319 

Cholestatic Hepatitis with Bile Duct Injury Bile duct (cholangiolytic) injury is observed with several drugs that cause cholestatic hepatitis, such as chlorpromazine300 and flucloxacillin.313 The severity of bile duct injury may be a determinant of the VBDS (see later).332 The clinical features resemble those of bacterial cholangitis, with upper abdominal pain, fever, rigors, tender hepatomegaly, jaundice, and cholestasis. Liver biochemical test levels are typical of cholestasis. Compounds associated with this syndrome include carbamazepine,333 dextropropoxyphene,334 and methylenediamine, an industrial toxin responsible for an outbreak of jaundice (Epping Jaundice) associated with intake of bread made from contaminated flour (see Chapter 89).335

Dextropropoxyphene Dextropropoxyphene is an opioid analgesic used alone or in compound analgesics and has been linked to over 25 cases of cholestasis with bile duct injury,334 some proven by inadvertent rechallenge. A female predominance has been recognized. The onset of symptoms is usually within 2 weeks. The illness is often heralded by abdominal pain, which may be severe and simulates other causes of cholangitis. Jaundice is usual. ERCP shows normal bile ducts. Liver biopsy specimens demonstrate cholestasis with expansion of the portal tracts by inflammation and mild fibrosis; portal tract edema also may be present. Other features include irregularity and necrosis of the biliary epithelium, together with an infiltrate of neutrophils and eosinophils on the outer surface of bile ducts. Bile ductular proliferation is universal. Recovery is the rule, with liver biochemical test levels returning to normal within 1 to 3 months.334 

DRUG-INDUCED CHRONIC CHOLESTASIS Drug-induced liver disease is considered to be chronic when typical liver biochemical changes last longer than 3 months298; earlier definitions required the presence of jaundice for more than 6 months or anicteric cholestasis (raised serum alkaline phosphatase and GGTP levels) for more than 12 months after the implicated agent was stopped.297 Drug-induced chronic cholestasis is uncommon but has been ascribed to more than 45 compounds.297-299,321,335-337 Chronicity complicates liver injury with flucloxacillin in 10% to 30%,298 chlorpromazine in 7%,300 and erythromycin in < 5%337 of cases and in only isolated instances of toxicity caused by other agents, such as tetracycline,338 amoxicillin-clavulanic acid,339 ibuprofen,340 trimethoprim-sulfamethoxazole,341 and ciprofloxacin.342 Chronic cholestasis is always preceded by an episode of an often severe acute cholestatic hepatitis that is occasionally

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associated with the Stevens-Johnson syndrome.340 The severity of the bile duct injury during the initial hepatic reaction is a critical determinant of a chronic course.332 Other possible mechanisms include continuing toxic or immunologic destruction of the biliary epithelium.336 Liver histology is characterized by a paucity of smaller (septal, interlobular) bile ducts and ductules, often with residual cholestasis, and portal tract inflammation directed against injured bile ducts. This process may lead to an irreversible loss of biliary patency and the VBDS.343 The clinical features are those of chronic cholestasis. Pruritus is the dominant symptom and is often severe. Continuing jaundice, dark urine, and pale stools are possible but not invariable findings and may resolve despite persistence of liver biochemical abnormalities. In severe cases, intestinal malabsorption, weight loss, and bruising caused by vitamin K deficiency may occur; xanthelasma, tuberous xanthomata, and other complications of severe hypercholesterolemia also have been noted. Firm hepatomegaly may be found on physical examination, but splenomegaly is unusual unless portal hypertension develops. AMA are not usually present. Most cases resolve, but there are rare reports of severe biliary ductopenia and biliary cirrhosis.297,298

Flucloxacillin Flucloxacillin is an important cause of drug-induced hepatitis in Europe, Scandinavia, and Australia.313,344 Flucloxacillin-induced hepatotoxicity is usually severe, and several deaths have resulted from the systemic features and associated cholestatic hepatitis. The course is prolonged, and a high proportion of cases have resulted in chronic cholestasis and VBDS.344 The risk of liver injury is 1 per 12,000 exposed, particularly among patients older than 70 years and those receiving repeated courses (39 and 110 per 100,000, respectively).345 A GWAS showed a strong association (odds ratio, 80.6) between HLA-B*57:01 and the risk of liver injury.346 Other oxypenicillins (cloxacillin and dicloxacillin) are less often associated with cholestasis.313 Acute hepatocellular injury has been reported with oxacillin.347 

Fibrotic Bile Duct Strictures Fibrotic strictures of the larger bile ducts can cause chronic cholestasis. Recognized causes include intralesional formalin therapy of hepatic hydatids and intra-arterial infusion of floxuridine for metastatic colorectal carcinoma. After several months of floxuridine infusion, the frequency of toxic hepatitis or bile duct injury, or both, was as high as 25% to 55% but has declined considerably (to ∼5%) with the advent of current protocols.348 Acalculous cholecystitis also may occur. ERCP shows strictures, typically in the common, left, and right hepatic ducts. Unlike PSC, the common bile duct and the smaller intrahepatic bile ducts are spared. Ischemia has been suspected, and toxicity to biliary epithelial cells is another possibility. Recovery may occur after floxuridine is discontinued. Some patients require dilation or stenting of biliary strictures. 

DRUG-INDUCED STEATOHEPATITIS AND HEPATIC FIBROSIS Steatohepatitis is a form of chronic liver disease in which steatosis is associated with focal liver cell injury, Mallory hyaline, focal inflammation of mixed cellularity, including neutrophils, and progressive hepatic fibrosis in a pericentral (zone 3) and pericellular distribution (see Chapters 86 and 87).349 Alcohol is a common etiologic factor. NASH is associated with insulin resistance, diabetes mellitus, obesity, and several drugs (e.g., perhexiline maleate, amiodarone).349 In addition to causing steatohepatitis or chronic hepatocyte or bile duct injury, some exogenous compounds promote hepatic fibrogenesis directly, through

effects on hepatic nonparenchymal cells, especially stellate cells. Compounds that stimulate hepatic fibrosis include arsenic, vitamin A, and methotrexate.

Amiodarone Amiodarone hepatotoxicity encompasses a spectrum of abnormalities including abnormal liver biochemical test levels in 15% to 80% of patients to clinically significant liver disease, including rare cases of ALF, in 0.6%. ALF (7 cases) has been reported with intravenous amiodarone; the vehicle (polysorbate 80) has been implicated because oral amiodarone could be successfully reinstituted in these cases350-354; however, ALF may occur with intravenous amiodarone formulations lacking polysorbate 80.355 Other investigators have disputed the diagnosis altogether, contending that these cases represent ischemic hepatitis rather than drug toxicity.356 In longer-term users, steatohepatitis can develop; cirrhosis develops in 15% to 50% of patients with hepatoxicity.351,352 A notable feature of amiodarone-induced liver disease is continued progression even after amiodarone is discontinued.352,354 Amiodarone is highly concentrated in the liver, and after a few weeks of treatment, the drug accounts for up to 1% of the wet weight of the liver. The iodine content absorbs radiation, so that the liver appears opaque on CT.354 Although odd, this appearance is not clinically significant. Hepatic storage of amiodarone also produces phospholipidosis, a storage disorder characterized by enlarged lysosomes stuffed with whorled membranous material (myeloid bodies). In animals fed amiodarone, the development of phospholipidosis is time and dose dependent.353 Phospholipidosis may result from the direct inhibition of phospholipase or from the formation of nondegradable drug-phospholipid complexes and has no relationship to the development of NASH and hepatocyte injury. Other occasional hepatic abnormalities include granuloma formation and ALF, apparently caused by severe acute hepatitis or a Reye syndrome-like illness.357 Amiodarone is concentrated in mitochondria and may interrupt mitochondrial electron transport.358 In rodent models, amiodarone produces microvesicular steatosis, augments mitochondrial production of ROS, and causes lipid peroxidation.358,359 Chronic liver disease is detected after a year or more (median, 21 months) of treatment. The treatment duration and possibly the total dose,357,360 but not the incremental dose, are risk factors for chronic liver disease. Cases of cirrhosis with low-dose amiodarone have also been documented.361 The other toxic effects, also likely dose related, are more frequent among patients with liver disease.360 Clinical features include fatigue, nausea and vomiting, malaise, and weight loss. Hepatomegaly, jaundice, ascites, bruising, and other features of chronic liver disease may be present. Laboratory test results include increased serum aminotransferase levels (up to 5 × ULN) and minor increases in serum alkaline phosphatase levels. The ratio of serum AST to ALT levels is close to unity, in contrast to that seen in alcohol-associated hepatitis. In severe cases, jaundice, hypoalbuminemia, and prolongation of the prothrombin time are evident. Determining the cause of abnormal liver biochemical test results and hepatomegaly is often difficult in patients taking amiodarone, and a liver biopsy may be indicated. Liver histologic findings include phospholipidosis, steatosis, focal necrosis with Mallory hyaline, infiltration with neutrophils, and pericellular fibrosis.352 Cirrhosis is often present. Preventing and managing amiodarone-induced liver disease is problematic because abnormal liver biochemical test levels are common in persons taking amiodarone, especially in those with heart failure. Further, patients with and without baseline serum ALT elevations have a similar frequency of amiodarone hepatotoxicity, and amiodarone should not be withheld in patients with an elevated serum ALT level.362 In asymptomatic or less severe cases, resolution occurs in 2 weeks to 4 months after amiodarone

CHAPTER 88  Liver Disease Caused by Drugs

is discontinued. In cases of severe liver disease, the mortality rate is high.352,360 Cessation of amiodarone therapy does not always result in clinical improvement, because of prolonged hepatic storage of amiodarone, and in one study, the outcome was worse (usually from fatal arrhythmias) in patients who discontinued amiodarone than in those who did not.352 Although serial liver biochemical testing is recommended,360 the efficacy of this strategy in reducing liver injury and the overall mortality rate is unknown. 

Tamoxifen and Other Causes of Drug-Induced Steatohepatitis For agents reported to be associated with steatohepatitis during the 1990s, causality has been difficult to prove,363 particularly because NASH is frequent among patients with the metabolic syndrome (see Chapter 87). Calcium channel blockers have rarely been associated with steatohepatitis,364 and methyldopa has been reported to be associated with cirrhosis in obese middle-aged women365; however, these associations may have been fortuitous. Other drugs, including estrogens366 and glucocorticoids,367 may precipitate NASH in predisposed persons because of their metabolic effects on the risk factors that drive NASH. On the other hand, the association between NASH and tamoxifen is much stronger. Several forms of liver injury have been attributed to tamoxifen,368 including cholestasis, hepatocellular carcinoma,369 peliosis hepatis,370 acute hepatitis, massive hepatic necrosis,368 steatosis, and steatohepatitis, occasionally with cirrhosis.371-373 In one series of 66 women with breast cancer who had taken tamoxifen for 3 to 5 years, 24 showed imaging evidence of hepatic steatosis.372 The median time to the development of NAFLD is around 2 years.374 Seven other patients have been diagnosed with NASH after taking tamoxifen for 7 to 33 months.371 The metabolic profile of women with imaging evidence of hepatic steatosis (or histologic proof of steatohepatitis) during tamoxifen therapy appears to be similar to that of most patients with NASH; one half have been obese, and the increase in body mass index has correlated with hepatic steatosis. Tamoxifen can induce hypertriglyceridemia, another risk factor for NASH. Reduction in the severity of hepatic steatosis has been documented with bezafibrate, a peroxisome proliferator-activated receptor-α agonist.375 Therefore, tamoxifen may play a synergistic role with other metabolic factors in causing steatohepatitis. This hypothesis is supported by an Italian study that showed that tamoxifen-associated NAFLD or NASH were mainly observed in overweight or obese women with the metabolic syndrome.376 Clinicians need to be aware of the high frequency (∼30%) of hepatic steatosis and steatohepatitis in women receiving tamoxifen. Tamoxifen recipients should be monitored for this adverse effect by physical examination (to detect hepatomegaly) and liver biochemical testing; some authors also advocate annual hepatic imaging (by ultrasonography or CT).377 Liver biopsy is indicated if the liver biochemical test abnormalities do not resolve after tamoxifen is discontinued, or, in some cases, to exclude metastatic breast cancer. Many patients improve after tamoxifen is discontinued, but the decision to discontinue tamoxifen should be made after discussion with the patient’s oncologist. Optimizing body weight is desirable because there is a 3-fold increased risk of abnormal glucose tolerance.378 Other aromatase inhibitors (anastrozole, letrozole) have also been associated with hepatic steatosis but much less commonly than tamoxifen.379 Toremifene, a tamoxifen analog, is associated with a lower frequency (60 yr, possibly related to reduced renal clearance and/or a biologic effect on fibrogenesis

Care in use of methotrexate in older people

Dose

Alcohol consumption

Incremental dose

5-15 mg/wk is safe

Dose frequency

Weekly bolus (pulse) is safer than a daily schedule

Duration of therapy

Consider liver biopsy every 2 yrs

Cumulative (total) dose

Consider liver biopsy after each 4-5 g of methotrexate

Increased risk with daily alcohol levels >15 g (1-2 drinks)

Avoid methotrexate use if intake not curbed Consider a pretreatment liver biopsy in a patient with a relevant history

Obesity, diabetes mellitus

Increased risk

Consider pretreatment and interval liver biopsies

Preexisting liver disease

Greatly increased risk, particularly related to alcohol, NASH

Pretreatment liver biopsy is mandatory Avoid methotrexate, or schedule interval liver biopsies according to the severity of hepatic fibrosis, total dose, and duration of methotrexate therapy Monitor liver biochemical tests during therapy

Systemic disease

Possibly greater risk with psoriasis than RA (depending on preexisting liver disease, alcohol intake)

None

Impaired renal function

Increased risk because of reduced clearance

Reduce the dose; use methotrexate with caution

Other drugs

Arsenic, NSAIDs, and vitamin A may increase the risk Folate supplementation decreases the risk

Use methotrexate with caution; monitor liver biochemical test levels Concurrent folate therapy is recommended

Genetic factors

Increased risk of hepatotoxicity is associated with SNPs in genes involved in methotrexate transport into and out of red blood cells and in folate metabolism

Future strategies could involve pretreatment genetic screening

SNP, single nucleotide polymorphism.

often is a complicating factor, and in a meta-analysis,385 alcohol consumption was the most important determinant of advanced hepatic fibrosis in patients treated with methotrexate; the risk of progressive hepatic fibrosis was 73% in persons who drank more than 15 g of alcohol daily, compared with 26% in those who did not. The possibility that low-dose (5 to 15 mg) methotrexate given as a single weekly dose can cause hepatic fibrosis has been debated.383-385 The available data are limited by a lack of controlled studies with pretreatment liver histologic data, a particularly serious deficiency in view of the high frequency of liver abnormalities among patients with RA and psoriasis. The conclusion has been reached that, although contemporary regimens can promote hepatic fibrosis, at the ultrastructural level at least, cases of clinically significant liver disease are now virtually unknown. Indeed, repeat liver biopsies in some series have shown a reduction in fibrosis despite continuation of methotrexate in lower doses.386 Therefore, although methotrexate remains a potential cause of liver disease, advanced hepatic fibrosis is in large part preventable. 

Clinicopathologic Features Liver biochemical test abnormalities are common among patients who take methotrexate, but advanced hepatic fibrosis occasionally may develop in their absence. Likewise, nausea, fatigue, and abdominal pain are common adverse effects, but patients with hepatic fibrosis are typically asymptomatic unless complications of liver failure or portal hypertension develop. A firm liver edge, hepatomegaly, splenomegaly, and ascites may be noted. Liver biochemical test levels are either normal or show nonspecific changes, including minor elevations of serum ALT and GGTP levels. In more advanced cases, hypoalbuminemia and

thrombocytopenia are present, but jaundice and coagulation disturbances are rare. Liver histologic findings have been graded according to the system of Roenigk.385 In this system, grades I and II indicate a variable amount of steatosis, nuclear pleomorphism, and necroinflammatory activity, but no fibrosis. Higher grades reflect increasing degrees of fibrosis, as follows: grade IIIa, few septa; grade IIIb, bridging fibrosis; and grade IV, cirrhosis. The pattern of hepatic fibrosis includes pericellular fibrosis, a feature of both alcoholic steatohepatitis and NASH. Cases of hepatic fibrosis with a relative paucity (or complete absence) of portal and lobular inflammation have been reported. 

Outcome and Prevention Serious clinical sequelae (portal hypertension, liver failure, HCC) are now rarely seen. In a meta-analysis of 32 studies involving over 13,000 patients with RA, psoriasis, and IBD, methotrexate was associated with a greater frequency of elevated aminotransferase levels, but there was no increase in the risk of liver failure, cirrhosis, or death.389 Cases that have come to LT generally have been associated with suboptimal supervision of methotrexate therapy.390 Cases of severe hepatic fibrosis (Roenigk grades IIIb and IV) are often associated with lack of progression and even improvement after dose reduction or cessation of methotrexate.386 In less severe cases, a balanced judgment must be made about the appropriateness of continuing or discontinuing methotrexate. An interval liver biopsy after an additional 2 years or 2 g of methotrexate may be judicious in a patient who is found to have minor hepatic fibrosis earlier. Recommendations for preventing methotrexate-induced hepatic fibrosis have been made.384,391 If possible, methotrexate should be avoided when the risk of liver injury is high. Persons treated with methotrexate should abstain

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TABLE 88.10  Types of Drug-Induced Hepatic Vascular Disorders* Disorder

Clinicopathologic Features

Outcome

Implicated Etiologic Agents

Sinusoidal obstruction syndrome (venoocclusive disease)

Abdominal pain, tender hepatomegaly, ascites, liver failure; occasionally chronic liver disease, other signs of portal hypertension

High mortality rate; some cases may evolve into nodular regenerative hyperplasia

Busulfan, 6-thioguanine (especially in bone marrow transplantation); azathioprine, dactinomycin, mitomycin, pyrrolizidine alkaloids

Nodular regenerative hyperplasia

Portal hypertension, encephalopathy—especially after variceal bleeding; diagnosed by histology

Relatively good prognosis

Azathioprine, busulfan, dactinomycin, didanosine, 6-thioguanine

Noncirrhotic portal hypertension

Splenomegaly, varices, hypersplenism; ascites if the patient has associated hepatocellular disease

Prognosis depends on cause and associated liver injury

Anticancer drugs, arsenic, azathioprine, didanosine, methotrexate, vinyl chloride, vitamin A

Peliosis hepatis

May be an incidental finding; hepatomegaly, hepatic rupture, liver failure; diagnosed from appearance at surgery, vascular imaging

Prognosis depends on the cause and complications

Anabolic steroids, azathioprine, 6-thioguanine

Sinusoidal dilatation

Hepatomegaly, abdominal pain

May regress after oral contraceptives are stopped

Oral contraceptive steroids

*See also Chapter 85.

from alcohol, and those drinking more than 100 g of ethanol per week should not be given methotrexate.384,385,390 A pretreatment liver biopsy is indicated only if the liver biochemistry is abnormal or if the history (e.g., alcoholism) and clinical features (e.g., hepatomegaly, risk factors for NASH) indicate possible underlying liver disease.73 The risk of methotrexate hepatotoxicity when used in patients with IBD has been reassuringly low (40 yr Obesity Short duration to onset of jaundice Serum bilirubin level >20 mg/dL Coagulopathy CYP2E1, cytochrome P450 2E1; ULN, upper limit of normal.

of immunoallergy and metabolic idiosyncrasy (see Box 89.1).2 After an initial exposure to halothane, the frequency of this form of toxicity is only about 1 per 10,000,29 but the rate increases to approximately 1 per 1000 after 2 or more exposures, especially when the anesthetic agent is readministered within a few weeks.2 Typically, zone 3 (centrilobular) hepatic necrosis is seen histologically.29 The case-fatality rate ranged from 14% to 71% in the pre-LT era2 and remains high in developing countries where halothane is still used.3,4

Risk Factors Host-related risk factors for halothane hepatitis are listed in Box 89.1. The reaction is rare in childhood21; patients younger than

10 years of age represent only about 3% of the total, and cases in persons younger than 30 years account for less than 10%.21,26 In a 2008 Iranian series, 60% of patients were older than 40, and none were younger than 18.3 The liver injury tends to be more severe in persons older than 40. Two thirds of cases have been in women, and repeat exposure to halothane (especially within a few weeks or months) was documented in as many as 90% of cases.2,30 The time between exposures can be as long as 28 years,31 although after repeat exposure, hepatitis is earlier in onset and more severe. Obesity is another risk factor, possibly because of storage of halothane in body fat. The induction of cytochrome P450 (CYP) enzymes (especially CYP2E1) that metabolize halothane to its toxic intermediate has been produced experimentally with phenobarbital, alcohol, and isoniazid; valproic acid inhibits and phenytoin has no specific effect on halothane hepatotoxicity. 

Pathology In a study of 77 cases of halothane hepatitis reviewed by the Armed Forces Institute of Pathology,30 various degrees of liver injury were seen, depending on the severity of the reaction. Massive or submassive necrosis involving zone 3 was present in all autopsy specimens, whereas biopsy material revealed a broader range of injury—from spotty necrosis in about one third of cases to sharply demarcated zone 3 necrosis in two thirds. The inflammatory response is less severe than in acute viral hepatitis. 

Pathogenesis Approximately one third of halothane is metabolized via oxidative pathways involving CYP2E1 and CYP2A6, while less than 1% is metabolized via reduction.4 Hepatic injury occurs by one or more of 3 potential mechanisms: hypersensitivity, production of hepatotoxic metabolites, and hypoxia, in decreasing order of importance.2 Evidence for the role of hypersensitivity is found in the increased susceptibility and shortened latency after repeat exposure, hallmark symptoms and signs of drug allergy (fever, rash, eosinophilia, and granuloma formation), and detection of neoantigens and antibodies. Halothane oxidation yields TFA, which is generated by the reaction between lysine and halothane metabolites and which acts on hepatocyte proteins to produce neoantigens that are responsible for the major form of injury.4 By contrast, reductive pathways produce free radicals that can act as reactive metabolites that may have a role in causing minor injury.32-34 Zimmerman suggested that halothane injury most likely results from immunologic enhancement of zone 3 necrosis produced by the reductive metabolites.2 Accordingly, the hepatotoxic potential of halothane depends on the susceptibility of the patient and on factors that promote production of hepatotoxic or immunogenic metabolites.2 A murine model of halothane hepatotoxicity demonstrated female susceptibility based on an increase in levels of γ-interferon, possibly mediated through estrogen, and an increase in natural killer cell activity.35,36 A more recent mouse model demonstrated that immune tolerance can be overcome by the TFA halothane protein adducts that are formed in the liver. Hepatic injury was associated with increased levels of interleukin-4 and immunoglobulins G1 and E directed against the halothane protein adducts as well as increased hepatic infiltration by eosinophils and CD4+ T cells that are features of an allergic reaction.37 

Course and Outcome Mortality rates for halothane hepatitis were high in early series; since then, successful treatment has been achieved with LT, when necessary.38 When spontaneous recovery occurs, symptoms usually resolve within 5 to 14 days, and recovery is complete within several weeks.2 Immunosuppressive agents have only rarely been reported to improve the outcome.21 Zimmerman

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TABLE 89.1  Hepatotoxic Anesthetics Other Than Halothane

89

Anesthetic

Percent Metabolized

Incidence of Hepatotoxicity

Cross-Reactivity with Other Haloalkanes

Methoxyflurane

>30

Low

Yes

Nephrotoxicity

Enflurane

2

1 in 800,000

Yes

Similar to halothane

Isoflurane

0.2

Rare

Yes

Similar to halothane

Desflurane

40 yr

Any

Any

Gender

F > M 2:1

F=M

F=M

Body weight

Obese

Any

Any

Hypotension

May or may not be present

Documented in 50%

Absent

Risk factors:

F, female; M, male; ULN, upper limit of normal.

Table 89.2 contrasts the features of halogenated anestheticinduced hepatitis, ischemic hepatitis (shock liver)57 (see Chapter 85), and cholestatic injury in the early postoperative period. Bile cast nephropathy is a relatively newly recognized clinical entity that can contribute to hyperbilirubinemia and the development of hepatorenal syndrome (see Chapter 94) in patients with acute-onchronic liver injury (see Chapter 74), including postoperatively.58 

TABLE 89.3  Chemical Classes Associated with Hepatotoxicity as a Primary Toxic Effect Category

Chemical Name

Other Chemical Name(s)

Aliphatic nitro compounds

2-Nitropropane

Dimethylnitromethane, isoNitropropane

Aromatic amines

4,4′-Methylenedianiline

MDA, diaminodiphenylmethane

CHEMICALS

Aromatic nitro compounds

2,4,6-Trinitrotoluene

TNT, 1-methyl-2,4,6trinitrobenzene

Commercial and Industrial Agents

Chlorinated Hexachloronapthalene hydrocarbons

Halowax

Chlorinated solvents

1,2-Dichloroethane, glycol dichloride

Among the tens of thousands of chemical compounds in commercial and industrial use, several hundred are listed as causing liver injury by the National Institute for Occupational Safety and Health, as published in their Pocket Guide to Chemical Hazards.59 The National Library of Medicine maintains a database of chemical toxins in its Toxicology and Environmental Health Information Program,60 as do other sources.61,62 Table 89.3 lists the various chemical classes associated with hepatotoxicity as a primary toxic effect. Toxic exposure to chemical agents occurs most often from inhalation or absorption by the skin and less often from absorption by the GI tract after oral ingestion or through a parenteral route. Because most chemical toxins are lipid soluble, when absorbed they can easily cross biological membranes to reach their target organ(s), including the liver.5,6,8 Hepatotoxic chemical exposure (as with carbon tetrachloride [CCl4] and phosphorus) usually results in an acute cytotoxic injury that typically consists of 3 distinct phases, similar to those observed after an acetaminophen overdose (see Chapter 88) or ingestion of toxic mushrooms (see later) (Table 89.4).2,5 Less commonly, acute cholestatic injury may occur.63 Many chemicals (e.g., vinyl chloride) are also carcinogenic, and hepatic malignancies have been part of the clinicopathologic spectrum of chemical injury (see Chapter 96) (Box 89.3).2,63 Although liver injury is the dominant toxicity for some agents (see Table 89.3), hepatic damage may be only one facet of more generalized toxicity for other agents.5

Carbon Tetrachloride and Other Chlorinated Aliphatic Hydrocarbons CCl4 is a classic example of a zone 3 hepatotoxin that causes necrosis leading to hepatic failure (see Table 89.4). Injury is

Ethylene dichloride

1,1,2,2-Tetrachloroethane Acetylene tetrachloride Carbon tetrachloride

Tetrachloromethane

Propylene dichloride

1.2-Dichloropropane

Halogenated solvents

Ethylene dibromide

1.2-Dibromoethane, glycol dibromide

Nitrosamines

N-Nitrosodimethylamine

Dimethylnitrosamine, DMNA NDMA

Other solvents

Dimethylformamide

N,N-Dimethylformamide, DMA

Tetrahydrofuran

Diethyl oxide; tetramethylene oxide, THF

Dimethyl acetamide

DMAC, acetic acid, dimethylacetone amide

Adapted from reference Haz-Map, available at www.haz-map.com/­ heptox1.htm; accessed April 7, 2018.

mediated by its metabolism to a toxic trichloromethyl radical catalyzed by CYP2E1.18,64 Alcohol potentiates the injury through induction of this cytochrome.2 Most cases have been the result of industrial or domestic accidents, such as inhalation of CCl4-containing dry cleaning fluids that are used as household reagents or ingestion of these compounds by alcoholics who mistake them for potable beverages.2,65 At the cellular level, direct damage to cellular membranes results in leakage

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TABLE 89.4  Phases of Illness after Ingestion of Various Hepatotoxins

89

Toxin Phase

Acetaminophen

Phosphorus

I (1-24 h) Onset of toxicity

Immediate

Anorexia, nausea, vomiting, diarrhea

+

Shock Neurologic symptoms

Amanita Phalloides

Carbon Tetrachloride

Immediate

Delayed 6-20 hr

Immediate

++++

++++

+

−

+

±

−

−

+

±

−

II (24-72 h) Asymptomatic latent period

+

±

+

+

III (>72 h) Jaundice

+

+

+

+

Hepatic failure

+

+

+

+

Renal failure

+

+

+

+

Maximum serum AST and ALT (×ULN)

1000

1000 U/L).114 Associated features include rhabdomyolysis, hypotension, hyperpyrexia, DIC, and renal failure.2,5 In a series of 39 patients with rhabdomyolysis, 23 had severe hepatotoxicity associated with a high mortality rate.115 Hepatic injury is probably the result of toxic metabolites (e.g., norcocaine nitroxide) formed by CYP2E1 and CYP2A,116 and enhanced hepatotoxicity is seen in persons who regularly consume alcohol.5 In animals, pretreatment with N-acetylcysteine decreases the risk of cocaine hepatotoxicity,117 although the usefulness of N-acetylcysteine for treating human cocaine-induced hepatic injury has not been determined. 

Others “Ecstasy” (3,4-methylenedioxymethamphetamine) is a euphorigenic and psychedelic amphetamine derivative that can lead to hepatic necrosis as part of a heat stroke–like syndrome resulting from exhaustive dancing in hot nightclubs (“raves”).118120 The injury can be fatal and has necessitated LT in some instances.120-122 The role of CYP enzymes in the toxicity of this and other so-called designer drugs may relate to specific genetic polymorphisms of CYP2D6 or other cytochromes.123 Phencyclidine (“angel dust”) is another stimulant that can lead to hepatic injury as part of a syndrome of malignant hyperthermia that produces zone 3 hepatic necrosis, congestion, and collapse, with high serum AST and ALT levels reminiscent of ischemic hepatitis.124 Cannabis (marijuana) has not been associated with acute or chronic liver injury by itself,110 although daily use was associated with progression of fibrosis in patients with untreated chronic hepatitis C.125 Synthetic cannabinoids (known popularly as “Spice,” “K2,” or other street names) have been associated with hepatic steatosis in animals and a few reports of variable liver injury in humans. Although liver failure from hepatic necrosis is mentioned in some case reports, the mechanism is poorly understood and clinical details to confirm causality are often scant.126 Cannabidiol (CBD) oil is one of the major phytocaanbinoids in Cannabis sativa which is being used for the management of several conditions, including chronic pain and seizure activity.127 CBD oil is the main ingredient in Epidiolex, approved in 2018 by FDA for the management of Lennox-Gastaut and Dravet syndromes , two pediatric conditions where epilepsy can be refractory to traditional anticonvulsants.128,129 In human trials, increases in ALT >3X ULN (without any rise in bilirubin) were seen in 10-20% of patients, often within one month of starting Epidiolex . These elevations usually resolved spontaneously or after discontinuation or dose reduction of the CBD oil or of valproic acid (VPA) taken concomitantly. No ALT elevations were seen in subjects not receiving VPA.128,129 In animals, increases in aminotransferases and bilirubin were seen in a dose-related fashion when CBD was administered acutely with doses up to the equivalent of the maximum Epidiolex dose in humans, or when given in lower doses over 10 days. This subacute dosing regimen produced severe toxicity in 75% of mice after 3-4 days.130 These investigators also found that mice given CBD by gavage for 3 days followed by the intraperitoneal administration of acetaminophen (APAP) on day 4 developed overt toxicity with a high mortality (37.5%). In contrast, no mortality was observed when CBD was given concurrently with APAP.131

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TABLE 89.6  Botanical and Environmental Hepatotoxins Agent

Toxic Component

Type of Injury

Comment

Ackee fruit

Hypoglycin

Microvesicular steatosis

Jamaican vomiting sickness

Aspergillus flavus

Aflatoxin B1

Acute hepatitis, portal hypertension

Hepatocarcinogenic

Aspergillus tamari

Cyclopiazonic acid

Acute hepatitis

—

Cycasin

Methylazoxymethanol

Acute hepatitis

—

Khat

?

Chronic hepatitis, fibrosis, cirrhosis

Cases may be confounded by a high frequency of chronic hepatitis B and C among users

Toxic mushrooms

Alpha-amatoxin, phalloidin

ALF

Resembles acetaminophen injury

Greater activation of c-Jun N-terminal kinase (JNK) was seen in the animals given APAP after CBD , and was associated with a sinusoidal obstruction syndrome-like injury on liver histology. The authors suggested that glutathione depletion and oxidative stress from both drugs was heightened in this setting.131 These potentially serious adverse drug-drug interactions between CBD and APAP and VPA led to an FDA warning detailing their safety concerns with a call for additional study regarding CBD oil.132 

BOTANICAL AND ENVIRONMENTAL HEPATOTOXINS Examples of hepatotoxic mushrooms, fruits, and other foodstuffs, including grains and nuts contaminated by fungal mycotoxins or other potentially injurious compounds, including khat, are listed in Table 89.6.

Mushrooms There are approximately 100 poisonous varieties of mushrooms among the more than 5000 species, but only about one third have been associated with fatalities. The amatoxin-containing species belong to 3 genera: Amanita, Galerina, and Lepiota.132 More than 90% of cases of fatal poisoning are caused by Amanita phylloides (death cap) or Amanita verna (destroying angel), found in the Pacific northwest, northern California, and the eastern USA.133,134 A fatal outcome can follow the ingestion of a single 50 g (2 oz.) mushroom, because the toxin is one of the most potent and lethal in nature.135 Alpha-amatoxin is thermostable, can resist drying for years, and is not inactivated by cooking. Rapidly absorbed through the GI tract, the amatoxin reaches hepatocytes through the enterohepatic circulation and inhibits production of messenger RNA and protein synthesis, leading in turn to cell necrosis. A second toxin, phalloidin, is responsible for the severe gastroenteritis that precedes hepatic and CNS injury.136,137 Phalloidin disrupts cell membranes by interfering with polymerization of actin. A latent period of 6 to 20 hours after ingestion of a mushroom precedes the first symptoms of intense abdominal pain, vomiting, and diarrhea. Hepatocellular jaundice and renal failure occur over the next 24 to 48 hours and are followed by confusion, delirium, convulsions, and eventually coma by 72 hours.2,128,129 The characteristic hepatic lesion is steatosis and zone 3 hepatic necrosis, with nucleolar inclusions seen on electron microscopy.5 Towering serum levels of ALT and AST, similar to those in acetaminophen and other chemical poisonings, can be seen.138 In a case series of 8 patients,139 the mean serum AST level was 5488 U/L (range, 1486 to 12,340), ALT 7618 (range, 3065 to 15,210), and bilirubin 10.5 mg/dL (range, 1.8 to 52), with peak levels on days 4 and 5. In another case series of 27 patients from San Francisco,140 median ALT levels were 2185 IU/L (range 554 to 4546 IU/L) and peak AST levels less than 4000 IU/L by 24 to 48 hours after admission. Acute kidney injury, requiring dialysis in some cases, has been observed.139,140 Mortality rates traditionally have been high, especially when the serum ALT level exceeds 1000 U/L, and emergency LT is often required.140,141 In a case

series from Southeast Asia, hepatic involvement was present in 23 of 93 patients (24.7%), and 10 of the 23 (43.5%) died; all deaths were associated with serum bilirubin levels greater than 5 mg/ dL.142 The time from ingestion to symptom onset was about 14 hours in a series from China, in which 4 deaths from ALF were recorded.143 In an Italian series, mycologists were able to identify the responsible species in nearly 90%, thereby aiding in management.144 Several websites, including that of the North American Mycological Association (www.namyco.org/mushrooms_poisoni ng_syndromes.php), contain photographs of the various poisonous species to help identify the type of mushroom ingested. Some patients survive with conservative management, which includes NG lavage with activated charcoal, IV penicillin G, N-acetylcysteine (using a standard oral or IV protocol [see Chapter 88]), along with milk thistle (Silybum marianum) (see Chapter 131).136 However, the use of these therapeutic modalities is not always effective, and in a large review of 2108 cases over a 20-year period in the USA and Europe,132 penicillin G, either alone or in combination with other therapy, demonstrated limited benefit. No role for glucocorticoids has been found, but plasmapheresis or hemoperfusion has been beneficial in some instances.145 In a 2012 study, the addition of IV silibinin (isolated from milk thistle) in a loading dose of 5 mg/kg, followed by 20 mg/kg continuous infusion for 24 hours, given with standard supportive measures, proved effective in reducing mortality to less than 10% in nearly 1500 cases.14 These results prompted the authors to recommend silibinin as the antidote of choice. 

Other Foodstuffs The unripe fruit of the ackee tree (Blighia sapida), native to Jamaica, contains hypoglycin A, a hepatotoxin that produces a clinical syndrome of GI distress and microvesicular steatosis known as Jamaican vomiting sickness, that resembles Reye syndrome (see Chapter 88).146,147 Cholestatic jaundice has been described after chronic ingestion.147 Cycasin is a potent hepatotoxin and hepatocarcinogen found in the fruit of the cycad tree (Cycas circinalis, Cycas revoluta). A small epidemic of acute hepatic injury attributable to the ingestion of cycad nuts was reported from Japan. The purported toxin is methylazoxymethanol, which is normally eliminated or rendered inactive in preparing the nuts before ingestion.5 Aflatoxins are a family of mycotoxins found in Aspergillus flavus and related fungi that are ubiquitous in tropical and subtropical regions. They contaminate peanuts, cashews, soybeans, and grains stored under warm, moist conditions and are well-known hepatotoxins and hepatocarcinogens.2,5 Aflatoxin B1, a potent inhibitor of RNA synthesis, is the most hepatotoxic member of the family. Reactive metabolites are formed by CYP enzymes, and malnutrition is a possible potentiating factor (perhaps because of the depletion of glutathione). When consumed in large quantities, aflatoxin B1 is responsible for a clinical syndrome characterized by fever, malaise, anorexia, and vomiting, followed by jaundice. Portal hypertension with splenomegaly and ascites may develop over the next few weeks. In large epidemics, mortality rates have approached 25% and correlate with

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the dose ingested.5 Zone 3 hepatic necrosis without inflammation is the characteristic lesion. Other histologic findings include cholestasis, microvesicular steatosis, and bile duct proliferation.148 The risk of HCC correlates with the amount of aflatoxin consumed, especially in sub-Saharan Africa and eastern China, where wheat often exceeds rice as a staple in the diet.149 Alcohol and possibly exposure to DDT (see earlier) may play an enhancing role in hepatocarcinogenesis.150 An even more important co­factor may be HBV.151,152 The frequency of a mutation in the TP53 tumor suppressor gene correlates with the development of HCC in these regions, but this mutation is rare in HCC from Western countries (see Chapter 96).151 Chewing fresh khat leaves (Catha edulis), predominantly by men from East Africa and Yemen, has been associated with chronic liver injury, including severe fibrosis and cirrhosis, liver failure, and death.153-156 Injury appears to be dose dependent, but the hepatotoxic moiety has not been identified. Although many patients have other risk factors for chronic liver disease (including hepatitis B and C, alcohol, and schistosomiasis), case-control studies have strongly implicated khat as a growing health hazard.157 

VITAMINS Vitamins, dietary, weight-loss and body-building supplements, herbal remedies, and other nutraceuticals are often the main components of many CAM preparations, and their use continues to increase (see later and Chapter 131).158 According to results of the 2012 National Health Interview Survey, nearly 42 million Americans (18.6% of the population) used herbal or homeopathic therapies in the previous year for a variety of health conditions,158 including chronic liver disorders,10,159 despite the absence of formal controlled clinical trials to assess their safety and efficacy in this setting.158,160-162 In a population-based survey of 1040 patients with a wide array of chronic liver diseases (including 18% with cirrhosis), concurrent use of a CAM preparation was listed by 27.3%.159 The most commonly used products were vitamins and other dietary supplements in 18% and herbal remedies in 16.8%. Interestingly, a CAM preparation had been prescribed by a physician in up to 32% of respondents.159 Many so-called health foods, dietary and weight-loss supplements, body-building compounds, and herbal products are potent hepatotoxins that can lead to ALF and the need for emergency LT.15,16,163,164 Safety concerns involving such dietary supplements persist, despite the enactment of the Dietary Supplement Health and Education Act in 1994.161,165-167

Vitamin A Among vitamin supplements, vitamin A remains the most important hepatotoxin when ingested in supratherapeutic doses. Vitamin A (retinol) is a dose- and duration-dependent hepatotoxin capable of causing injury ranging from asymptomatic elevations in serum aminotransferase levels with minor hepatic histologic changes to perisinusoidal fibrosis leading to noncirrhotic portal hypertension and, in some cases, cirrhosis.168 Approximately one third of the U.S. population is estimated to take vitamin supplements containing vitamin A, with as many as 3% of products providing a daily dose of at least 25,000 IU. Hypervitaminosis A usually is the result of self-ingestion, rather than intentional overdose, and all age groups have been affected.169 The average daily dose of vitamin A in reported cases of liver disease has been nearly 100,000 IU, taken over an average duration of 7.2 years, for a mean cumulative dose of 229 million IU. Liver injury has been described with daily doses of 10,000 to 45,000 IU,170 and cirrhosis has occurred after a daily intake of 25,000 IU for at least 6 years.168,170 By contrast, longterm use of low-dose vitamin A supplements (250 to 5000 retinol equivalents per day) does not appear to be toxic.171 Because of the long half-life of vitamin A in the liver (50 days to 1 year),170,172 the fibrotic process may continue because of the

slow release of hepatic vitamin A stores despite discontinuation of oral intake of the vitamin.173 Genetic factors may play a role, and apparent familial hypervitaminosis A has occurred in 4 siblings who ingested large doses as treatment for congenital ichthyosis.174 Vitamin A toxicity has been reported in native Alaskans who ingest large amounts of fresh polar bear liver,168 which is plentiful in these arctic predators but does not cause them hepatic injury.175 Water-soluble, emulsified, and solid formulations of vitamin A are up to 10 times as toxic as oil-based preparations because of higher peak plasma levels, greater hepatic concentrations, and less fecal loss with the water-miscible formulations.176 Hepatotoxicity from vitamin A has been attributed to activation of hepatic stellate cells, the body’s principal storage site of the vitamin. Resulting hyperplasia and hypertrophy produce sinusoidal obstruction and increased collagen synthesis, leading in turn to portal hypertension.177 Rare cases of peliosis hepatis have also been attributed to hypervitaminosis A. Ethanol interferes with the conversion of beta carotene, a precursor of vitamin A, to retinol, and the combination of ethanol and beta carotene has resulted in hepatotoxicity in various experimental models.178 Liver biopsy specimens show increased storage of vitamin A, seen as characteristic greenish autofluorescence after irradiation with ultraviolet light.168 The excess vitamin A is stored initially in stellate cells that lie in the space of Disse and become hyperplastic and hypertrophic. The enlarged clear stellate cells compress the hepatic sinusoids, giving rise to a “Swiss cheese” or honeycombed appearance.168 Hepatocellular injury is usually minor, with microvesicular steatosis and focal degeneration and without significant necrosis or inflammation. Hepatic fibrosis in a perisinusoidal distribution can arise from activated stellate cells that transform into myofibroblasts. In a widely cited series,168 cirrhosis was present in 59%, chronic hepatitis in 34%, microvesicular steatosis in 21%, perisinusoidal fibrosis in 14%, and peliosis in 3% of cases. In affected persons, hepatomegaly is common, and in severe cases, splenomegaly, ascites, and esophageal variceal bleeding may be features.2,168 Hypervitaminosis A can also involve the skin and CNS.2 Liver biochemical test abnormalities, present in two thirds of cases, are nonspecific, with only modest elevations in serum aminotransferase and alkaline phosphatase levels. The diagnosis of vitamin A toxicity rests on a dietary and medication history and clinical suspicion. Plasma vitamin A levels may be normal, and the diagnosis is supported by the demonstration of increased hepatic stores of vitamin A and characteristic histologic findings.179 The diagnosis may be delayed for several years if hepatotoxicity is not recognized or is misdiagnosed.168,170 Symptoms resolve and liver enzymes gradually normalize after discontinuation of vitamin A ingestion in less severe cases, but deterioration may continue in cases of severe intoxication, particularly when cirrhosis is already present.170 Features of liver failure and cirrhosis at the time of diagnosis indicate a poor prognosis, and LT may be required.2 Alcohol can potentiate hepatotoxicity and should be avoided. Vitamin A supplements generally should be avoided in other types of liver disease because of possible accentuation of hepatic injury and fibrosis.178 Severe liver injury has rarely been reported with the use of acitretin, a vitamin A metabolite.180 

Niacin Nicotinic acid (vitamin B3, niacin) is used primarily to treat dyslipidemia by increasing HDL and reducing triglyceride synthesis and VLDL and LDL secretion, via inhibition of hepatocyte diacylglycerol acyltransferase 2.181 Immediate-release (IR) crystalline preparations given in therapeutic doses have rarely been reported to cause hepatic injury182 but are associated with flushing and other unpleasant side effects.183,184 When taken in massive supratherapeutic doses (e.g., 20,000 mg), the IR form has been associated with ALF requiring LT.185 In contrast to the IR formulations, sustained-release (SR) niacin, developed to reduce the vasodilatory

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TABLE 89.7  Level of Evidence for Hepatotoxicity of Herbal, Dietary, Weight-Loss, and Body-Building Supplements* Adequate Evidence of Hepatotoxicity

Reports of Hepatotoxicity

Insufficient Evidence of Hepatotoxicity

Aloe vera Arrowroot Black cohosh Cascara Celandine Comfrey Germander Gota Kolu Green tea extract Groundsel Impila Jin bu huan Kava kava Pennyroyal Rattlebox Saw palmetto Senna Skullcap Thistle Traditional Chinese medicines Usnic acid Valerian

Anabolic steroids Bakuchi Conjugated linoleic acid Euforia Exilis Green tea extract Herbalife Hydroxycut Limbrel (flavocoxid) LipoKinetix Lipolyz fat burner Niacin OxyELITE Pro ProLean

Artemisinin Bee pollen Cascara Chaso Enzyte Glucosamine-chondroitin Hydroxycut Lipolyz Ma huang (ephedra) Mistletoe Niacin (therapeutic doses) Noni Onshido Red rice yeast SlimQuick Vitamin A (therapeutic doses)

Adapted from reference Brown AC. Liver toxicity related to herbs and dietary supplements: online table of case reports. Part 2 of 5 series. Food Chem Toxicol 2017;107(PtA):472–501. *According to the Department of Complementary and Alternative Medicine at the University of Hawaii.

effects of niacin, appears to be a significant hepatotoxin, with about 20% of patients developing symptomatic elevations in ALT and AST levels.182 Several cases have followed a switch from an IR to an SR formulation. Liver injury has been reported to occur after a widely variable latent period ranging from 1 week to as long as 2 years.182 Symptoms suggesting acute hepatocellular necrosis include nausea, vomiting, and fatigue, followed by jaundice and pruritus, although recovery within 4 to 8 weeks is the rule and ALF is rarely reported.183 Importantly, combining niacin with a statin does not increase the risk of hepatotoxicity.186 The mechanism underlying niacin liver injury is thought to be the formation of formulation- and dose-dependent hepatotoxic pyrimidine metabolites. Although amidation pathways rapidly convert IR formulations into nicotinuric acid, thereby leading to vasodilatation and flushing through prostaglandin formation, SR preparations allow for reduced amounts of nicotinuric acid but promote the conversion of niacin to hepatotoxic pyrimidine intermediates.187 As a result, extended (controlled) and SR formulations are contraindicated in patients with liver disease.188 

HERBAL, DIETARY, WEIGHT-LOSS, AND BODYBUILDING SUPPLEMENTS The increasing use of CAM preparations is well described in patients with liver disease (see Chapter 131).10,159,160 Silymarin (Silybum marianum, milk thistle) is the most commonly used herbal preparation among these patients,10and although it appears to be quite safe,189 if ineffective,190-192 an increasing number of reports of hepatotoxicity from several other classes of herbal, dietary, weight-reduction, and body-building supplements (collectively referred to as HDS) have paralleled the rise in use of CAM therapies in both the USA and other Western nat ions.163,167,193-197 Indeed, the percentage of cases of hepatotoxicity due to HDS in DILI registries has risen steadily in the 2000s, increasing from 7% to 20% of cases in the U.S. DILI Network between 2004 and 2013193 and exceeding 50% in some Chinese and other Asian series.198-200 Several dozen HDS compounds are listed as potentially hepatotoxic, including several that are no longer sold (including germander

and usnic acid-containing products) and others that have undergone reformulations (e.g., Hydroxycut) (Table 89.7).193-197,201 Other implicated agents lack sufficient evidence to support their hepatotoxicity.202 Similarly, the LiverTox database compiled by the National Institutes of Health and National Library of Medicine reviews 50 of the best known HDS for potential hepatotoxicity and has concluded that nearly 40% have no evidence to implicate them in clinical hepatotoxicity (see Table 89.7). Additionally, although more than 50 traditional Chinese medicines (TCM) have been associated with hepatic injury,203 causality has been established for only about half of these compounds.204 When TCM have been analyzed prospectively for the development of hepatic injury (defined as a serum ALT level > the ULN), fewer than 4% of 21,470 patients without liver disease developed an ALT level greater than 1 time but less than 5 times the ULN, and only 0.12% had an ALT level exceeding 5 times the ULN, with a return to normal after the agent was discontinued.205 Similarly, among nearly 6900 inpatients taking herbal medications in Korean hospitals, 5.1% were diagnosed with liver injury (based on elevated liver biochemical test levels on admission), and 3.1% developed liver injury at the time of discharge.206 Among 354 patients with elevated liver biochemical test levels on admission, only 9 (2.5%) showed a further increase after treatment with an herbal medication, and among nearly 4800 patients with normal liver test levels on admission, only 27 (0.6%) had liver injury at discharge. The authors concluded that herbal medicines rarely aggravate existing liver injury and that de novo injury is uncommon.206 Warnings have been issued for several agents, and, in a few instances, the FDA and other health authorities have requested their removal from the marketplace (e.g., kava kava, ephedra [ma huang], LipoKinetix [usnic acid], and Hydroxycut in the USA201,207 and germander in France208 [see later]) Any patient with liver disease should be questioned about the ingestion of herbal remedies; Estes and colleagues,164 for example, documented the use of several commonly promoted herbal agents (including LipoKinetix, skullcap, ma huang, chaparral, and kava kava) in half of 20 patients with ALF over a 2-year period. Table 89.8 lists the known or potential hepatotoxic component of the most commonly implicated HDS compounds associated with liver injury. The purported hepatotoxicity of many

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TABLE 89.8  Features of Hepatotoxic Herbal, Dietary, Weight-Loss and Body-Building Supplements Agent

Popular Uses

Source

Postulated Hepatotoxic Component Hepatic Injury

Black cohosh

Menopausal symptoms

Cimicifuga racemosa

Uncertain; ?triterpene glycosides

Latency 2-12 wk; acute hepatocellular jaundice, some cases autoimmune hepatitis; resolution in 2-6 mo

Cascara

Laxative

Cascara sagrada

Anthracene glycoside

Cholestatic hepatitis

Chaparral leaf “Liver tonic,” burn (greasewood, salve, weight creosote bush) loss

Larrea tridenta

Nordihydroguaiaretic acid

Acute viral-like; latency 3-12 wk; hepatitis, ALF leading to LT reported; positive rechallenge cases

Chaso/onshido

Weight loss

—

N-nitro-fenfluramine

Acute hepatitis, ALF

Comfrey

Herbal tea

Symphytum spp.

Pyrrolizidine alkaloids

Acute SOS after latency 1-2 mo with acute RUQ pain, nausea, ascites, weight gain, and hepatocellular jaundice that can lead to ALF; a subacute or chronic injury with insidious onset also described

Germander

Weight loss, fever

Teucrium chamaedry, T. capitatum, T. polium

Teucrin A (Diterpenoids, epoxides)

Acute viral-like hepatitis after mean 9 wk. latency with positive rechallenge and rapid recovery, rare reports of ALF; a second form of injury resembles autoimmune hepatitis after 6-9 mo latency presenting with arthralgias and fever

Greater celandine Gallstones, IBS

Chelidonium majus

Uncertain; ?isoquinoline alkaloids

Acute cholestatic hepatitis after 1-6 mo in about 50% of cases, resolution in 2-6 mo

Green tea leaf extract

Multiple

Camellia sinensis

Catechins

Acute viral-like hepatitis within 3 mo (range 0.5-7 mo); biopsies have shown variable necrosis, eosinophilia; no immunoallergic features; most recover

Herbalife

Nutritional supplement, weight loss

—

Various; ?ephedra

Insidious hepatocellular or mixed injury presenting with fatigue, nausea, abdominal pain and jaundice after 2-9 mo latency; no hypersensitivity features; rare instances of ALF

Hydroxycut

Weight loss

Camellia sinensis, among other constituents

Uncertain

Acute hepatitis, ?ALF

Impila

Multiple

Callilepsis laureola

Potassium atractylate

Hepatic necrosis

Kava kava

Anxiolytic

Piper methysticum

?Kava lactone, pipermethystine (vs. other contaminants)

Acute hepatitis or cholestasis after variable latency (2-24 wk) with occasional hypersensitivity features and reports of positive rechallenge; rare cases of ALF leading to LT; most patients recover within 1-3 mo

Kombucha

Weight loss

Lichen alkaloid

Usnic acid

Acute hepatitis (see LipoKinetix)

Limbrel (Flavocoxid)

Osteoarthritis

Plant bioflavonoids

Baicalin, ?epicatechin

Acute mixed hepatocellular-cholestatic injury

LipoKinetix

Weight loss

Lichen alkaloid

Usnic acid

Acute viral-like hepatitis with jaundice; cases of ALF leading to LT

Mistletoe

Asthma, infertility

Viscus album

Uncertain

Hepatitis (in combination with skullcap)

OxyELITE Pro

Weight loss, body building

Multiple ingredients ?Aegeline

Acute hepatocellular viral-like hepatitis with jaundice with marked elevations in ALT; liver biopsy showing severe necrosis; no hypersensitivity features; mortality of 10% in cases with jaundice; second injury pattern with subacute or chronic autoimmune features

Pennyroyal Abortifacient (squawmint oil)

Hedeoma pulegoides, Mentha pulegium

Pulegone, monoterpenes

Produces an acute acetaminophen-like injury within hours of ingestion resulting in cardiovascular collapse, DIC, and multiorgan failure with liver injury likely due to ischemic hepatitis

Prostata

Prostatism

Multiple

Uncertain

Chronic cholestasis

Sassafras

Herbal tea

Sassafras albidum

Safrole

HCC (in animals)

Senna

Laxative

Cassia angustifolia

Sennoside alkaloids; anthrone

Acute hepatitis

Skullcap

Anxiolytic

Scutellaria

Diterpenoids vs. adulterants

Acute hepatocellular jaundice after 6-24 wk with rapid resolution; rare reports of ALF

Traditional Chinese Medicines Jin bu huan

Sleep aid, analgesic

Lycopodium serratum

?Levotetrahydropalmitine

Acute or chronic hepatitis or cholestasis, steatosis

Ma huang

Weight loss

Ephedra spp.

Ephedrine

Acute viral hepatitis-like injury with fatigue, nausea, abdominal pain, jaundice, ALF requiring LT reported; most recover in 1-6 mo

?Anthraquinone

Acute hepatitis or cholestasis

 Shou-wu-pian

Anti-aging, Polygonum neuroprotection, multiflorum laxative (fleeceflower root)

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TABLE 89.8  Features of Hepatotoxic Herbal, Dietary, Weight-Loss and Body-Building Supplements—cont’d Agent

Popular Uses

Source

Postulated Hepatotoxic Component Hepatic Injury

 Sho-saiko-to

Multiple

Scutellaria root

Diterpenoids

Hepatocellular necrosis, cholestasis, steatosis, granulomas

Valerian

Sedative

Valeriana officinalis

Uncertain

Rare instances of mild-moderate hepatocellular or mixed injury with recovery after 2-4 mo; reports of ALF have occurred only when taken with other herbal preparations

SOS, sinusoidal obstruction syndrome.

HDS products has come under increasing scrutiny and criticism by Teschke and colleagues, who have drawn attention to many pitfalls in the causality assessment of these agents.209-214 Although some cases have had well documented hepatic injury, others have been more poorly confirmed and have not considered alternative causes.214 In addition, several herbal formulations are known to have been contaminated by other hepatotoxic substances, an occurrence that is probably more common than currently appreciated.215-217 Indeed, mislabeling of HDS products is not only frequent, but potentially dangerous. In an analysis performed by the National Center for Natural Products Research at the University of Mississippi using ultrahigh performance chromatography coupled with mass spectrometry, Navarro and colleagues studied more than 340 HDS products used by more than 1260 patients of which 272 had labels listing their ingredients. They found serious inaccuracies in the product labels of greater than 50% of the HDS tested.218 These discrepancies included the failure to confirm the true ingredients in 80% of steroidal compounds, more than 50% of nutritional vitamins, and greater than 40% of botanicals. More disturbing was the finding of undisclosed anabolic steroids in half of the body-building supplements and undisclosed potential hepatotoxins (diclofenac and tamoxifen) in other products.218 Similarly, in a study of herbal and Ayurvedic compounds used by traditional healers in India, Philips and colleagues found that several heavy metals (arsenic, lead, mercury, antimony, and cadmium) were present in toxic amounts ranging from 10 to 100 times safe levels.219 Increased mortality was reported in some recipients of these compounds but was not necessarily due to hepatotoxicity. In an earlier study, Navarro and colleagues studied HDS for the presence of catechins, which have been implicated in hepatotoxicity associated with green tea extract (GTE) and other products.220 They found that, when assayed, just over half of 97 products contained at least one catechin. However, nearly 40% of 73 HDS products that contained catechins did not list GTE or catechins on their labels. Weightloss products were most likely to be mislabeled in this manner. Perhaps not surprisingly, the mislabeling was also seen in reverse (i.e., several products that listed catechins as an ingredient contained either no or only negligible amounts of catechins).220 In addition to the potential hepatotoxicity of many HDS products, several investigators have drawn attention to the risk of herbal-drug interactions that may be mediated through the CYP system221 or P-glycoproteins.222 One of the best known interactions is seen with St. John’s wort, a strong inducer of CYP3A4, that can reduce the bioavailability (and subsequent effectiveness) of several drugs, including certain DAA regimens for the treatment of chronic hepatitis C (see Chapter 80).223 Because the production and review standards for herbal products and dietary supplements are not as strict as for pharmaceutical products161 and most HDS are considered to be food products rather than pharmaceuticals (and thus assumed to be safe),167 it should not be surprising that a number of groups have called for increased regulation regarding the manufacture, quality control, safety, and efficacy of these products in the USA and abroad.162,166,224-227 Additionally, improved methods to screen for

the hepatotoxicity of active compounds in TCMs and HDS are being developed167,228,229 and more accurate causality assessments (including the development of novel HDS biomarkers) have been recommended to improve the quality of case presentations.230,231 Two large case series are instructive in defining the presentation and outcome of HDS in Western countries. In an analysis of the Spanish DILI registry,197 HDS cases were younger (mean age 48 versus 55) and more likely to be female (63% vs. 49%) compared with DILI cases. Jaundice was present in 78% and was the most frequent symptom that brought a patient to medical attention. Hypersensitivity hallmarks (fever, rash, eosinophilia) were present in 28%, and a higher percentage of HDS cases progressed to liver failure (6%), compared with 4% of conventional drugs and none of the patients with anabolic steroid injury. In the U.S. DILI Network registry,11 body-building HDS resulted in reversible jaundice in young men, whereas the non‒body-building HDS occurred predominantly in middle-aged women, were hepatocellular in nature, and, as in the Spanish series, more often led to death or LT compared with non-HDS DILI (13% vs. 3%).11

Features of Toxicity The clinicopathologic features of hepatotoxicity caused by the specific HDS and TCM discussed below are derived from the best available evidence.7,11,12,193-197,201-203

Pyrrolizidine Alkaloids Pyrrolizidine alkaloids (PAs) are found in approximately 3% of all flowering plant species throughout the world, and ingestion of such plants, often as medicinal teas or in other formulations, can produce acute and chronic liver disease, including SOS, in humans and livestock.232 SOS was first reported in the 1950s as a disease of Jamaican children, manifesting with acute abdominal distention, marked hepatomegaly, and ascites—a triad that resembles Budd-Chiari syndrome (see Chapter 85).5 The disease was linked to consumption of “bush tea,” made largely from plants of Senecio, Heliotropium, Crotalaria, and Symphytium species. Many were taken as a folk remedy for acute childhood illnesses. The disease was characterized histologically by centrilobular hepatic congestion with occlusion of the hepatic venules, leading to congestive cirrhosis. In Afghanistan, ingestion of PA-contaminated grains and bread led to a large epidemic of SOS, affecting 8000 persons and innumerable sheep.5Although it is a dose-dependent hepatotoxin, comfrey (Symphytum officinale) remains commercially available on numerous internet sites and can be found in toxic amounts in “medicinal” herbal teas around the world.233-235 Hepatotoxic PAs are cyclic diesters, and some forms (e.g., fulvine, monocrotaline) cause both liver and lung injury. The mechanism of injury is postulated to be impairment of nucleic acid synthesis by reactive metabolites of PAs generated by hepatic microsomes, leading in turn to progressive loss of sinusoidal cells and sinusoidal hemorrhage, as well as injury to the endothelium of the terminal hepatic venule, with deposition of fibrin.231,232 alkaloids and dehydroretronecine generated by the action of the

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CYP system bind to cellular proteins to form pyrrole-protein adducts and have been shown to be cytotoxic to hepatic sinusoidal endothelial cells due to depletion of glutathione.236 The ability to test for these pyrrole-protein adducts in patients with PA-associated SOS provides an important diagnostic tool, with a positive predictive value of 95.8% and a negative predictive value of 100%.237 In addition to PAs, PA N-oxides have been found to be hepatotoxic.238 SOS causes acute, subacute, and chronic injury. The acute form is characterized by zone 3 necrosis and sinusoidal dilatation, leading to a Budd-Chiari–like syndrome with abdominal pain and the rapid onset of ascites within 3 to 6 weeks of ingestion.5 In Jamaica, the course was rapidly fatal in 15% to 20% of affected persons. Approximately one half of the patients with the acute form recovered spontaneously; transition to a more chronic form of injury occurred in the remainder.2In the subacute and chronic forms, central fibrosis and bridging between central veins led to a form of cirrhosis similar to that seen with chronic passive hepatic congestion (so-called cardiac cirrhosis). At one time, this form of injury accounted for one third of the cases of cirrhosis seen in Jamaica, with death often resulting from complications of portal hypertension in as few as 1 to 3 years.2Certain PAs, such as comfrey extracts, are also hepatocarcinogenic and, like aflatoxins, induce mutations of the TP53 gene.232 

Germander The blossoms of plants from the Labiatae family (Teucrium chamaedrys) were used for years in herbal teas and in the mid1980s as capsules predominantly for weight reduction in France, until several dozen cases of liver injury, including fatal hepatic failure, forced its withdrawal from the French market in 1992.208,239 Most patients were middle-aged women who had ingested germander for 3 to 18 weeks, with consequent development of acute hepatocellular injury, often with jaundice. The injury usually resolved within 1.5 to 6 months after the germander was discontinued, with prompt recurrence after rechallenge in many persons. The cause of germander hepatotoxicity is an interplay between toxic metabolites and immunoallergic mechanisms. Germander is composed of several compounds, including glycosides, flavonoids, and furan-containing diterpenoids, all of which are converted by the CYP system (especially CYP3A) to reactive metabolites.221 The furanoneoclerodane diterpene teucrin A is thought to be the toxic component.240,241 Covalent binding to cellular proteins, depletion of hepatic glutathione, apoptosis, and cytoskeleton membrane injury (bleb formation) cause cell disruption in animal models. Epoxide hydrolase on plasma membranes is a target of germander antibodies, which have been found in the sera of patients who have consumed germander teas over long periods of time.242 Reports of liver injury have also appeared with other species of Teucrium, including Teucrium capitatum243 and Teucrium polium.244 

Chaparral The dried leaf of the desert shrub chaparral (Larrea tridentata), also known as greasewood or creosote bush, is ground into a tea or used in capsules or tablets for various ailments. Multiple reports of hepatitis have appeared; most cases have occurred within 1 to 12 months of use and resolved within a few weeks to months of discontinuation.245 Among the 13 cases reported to the FDA, acute hepatocellular or cholestatic injury was observed, with 2 cases of ALF requiring LT and 4 cases progressing to cirrhosis. Renal toxicity and rash can accompany liver injury.245 The active ingredient, nordihydroguaiaretic acid, an inhibitor of COX and lipoxygenase pathways, is the likely cause of hepatic injury, although the mechanism may also

involve phytoestrogen-induced effects on the liver.246 A case of recurrence on rechallenge suggests a possible role for immunoallergy.236

Pennyroyal The leaves of pennyroyal (the common name for 2 related plant species, Hedeoma pulegoides and Mentha pulegium) are used to make oils (squawmint oil), tablets, and home-brewed mint teas. The plant contains pulegone and smaller amounts of other monoterpene ketones. Oxidative metabolites of pulegone (e.g., menthofuran) bind to cellular proteins and deplete hepatic glutathione, thereby leading to liver injury.221,247 Cases of hepatocellular injury, including fatal necrosis, were associated with GI and CNS toxicity within a few hours of ingestion. In animals, inhibition of pulegone metabolism by the CYP system with disulfiram and cimetidine has limited pennyroyal hepatotoxicity.248 The use of N-acetylcysteine may protect against pennyroyal toxicity in human cases.248 

Traditional Chinese Herbal Medicines Traditional Chinese medicines in China are derived from more than 800 patent drugs for use by TCM practitioners.249 Most TCM are composed of several different herbal compounds and usually are dominated by one main ingredient referred to as the “king herb.”249 More than 50 different herbs and herbal mixtures were found in a TCM literature review by Teschke and colleagues, although causality was established for only about half of the compounds.204 The traditional preparations discussed later are among the best characterized with respect to hepatotoxicity.203,204 Jin bu huan (Lycopodium serratum) is a traditional herbal remedy that has been used as a sedative and analgesic for more than 1000 years.246 Numerous cases of hepatic injury have appeared,250 with a mean latency of 20 weeks (range, 7 to 52 weeks) after the start of jin bu huan in recommended doses. Associated symptoms and signs included fever, fatigue, nausea, pruritus, abdominal pain, hepatomegaly, and jaundice. Liver biopsy specimens from a small number of patients showed a range of histopathologic changes, including lobular hepatitis with prominent eosinophils, mild hepatitis with microvesicular steatosis, and fibrotic expansion of the portal tracts. The injury resolved within a mean of 8 weeks (range, 2 to 30 weeks) but could recur on rechallenge.251 The only predisposing factor was female gender. Serum ALT levels were increased 20- to 50-fold, with minor increases in the alkaline phosphatase level, except in one patient with cholestasis. Hyperbilirubinemia was prominent in the more severe cases. A case of chronic hepatitis has been described. The mechanism of injury may involve levotetrahydropalmatine, a neuroactive metabolite with structural similarity to PAs. The FDA banned the importation of jin bu huan anodyne tablets into the USA years ago.246 Sho-saiko-to (xiao-chai-hu-tang, dai-saiko-to) contains Scutellaria root (skullcap), which is a postulated hepatotoxin.252 The spectrum of liver injury has included hepatocellular necrosis, microvesicular steatosis, cholestasis, granuloma formation, and a flare of autoimmune hepatitis.252,253 Reversible acute hepatitis or cholestasis has followed the consumption of shou-wu-pian, a product derived from Polygonum multiflorum.254 Ma huang, derived from plants of Ephedra species, has been reported to cause acute, sometimes severe, hepatitis, including ALF.164,249,255,256 The active ingredient, ephedrine, also has been linked to severe adverse cardiovascular and CNS effects, including fatalities, when used as a stimulant and weight-loss aid.257 The FDA issued a ruling in 2004 that ephedra-containing products present an unreasonable risk and should be avoided.258

CHAPTER 89  Liver Disease Caused by Anesthetics, Chemicals, Toxins, and Herbal and Dietary Supplements

Weight-Loss Products Chaso and onshido are Chinese herbal dietary weight-loss supplements that were reported to cause severe liver injury, with a mean serum ALT level of 1978 U/L (range, 283 to 4074 U/L), in 12 patients.259 ALF developed in 2 persons; one died, and the other survived after receiving an LT. The suspected hepatotoxic ingredient was N-nitroso-fenfluramine, a derivative of the appetite suppressant fenfluramine, which was withdrawn from the U.S. market in 1997.260 Another dietary supplement used for weight loss, LipoKinetix (composed of norephedrine, sodium usniate [usnic acid], diiodothyronine, yohimbine, and caffeine) was associated with acute hepatitis, including ALF requiring LT.163,261 In a case series of 7 previously healthy patients (4 women, 3 men; mean age, 27 years), acute hepatitis developed after a latent period of less than 4 weeks in 5 patients and 8 to 12 weeks in the other 2. Mean serum ALT levels were 4501 U/L (range, 438 to 14,150 U/L), and mean serum bilirubin levels were 6.5 mg/dL (range, 2.2 to 14.6 mg/dL). No evidence of immunoallergy was evident. All of the patients recovered spontaneously, with normalization of serum ALT and bilirubin levels within 4 months.261 ALF necessitating emergency LT was reported in a previously healthy 28-year-old nonobese woman who had taken an over-the-counter preparation of usnic acid for weight loss,262 suggesting that this agent is the likely hepatotoxic component of LipoKinetix. Usnic acid also is a component of Kombucha tea, which has been associated with hepatic injury.246 Usnic acid is a potent inhibitor of CYP2C19 and CYP2C9 and may interact with other medications or supplements to produce hepatotoxic drug-drug interactions.263 A number of additional multi-ingredient weight-loss, muscle-building, and nutritional supplements, including Herbalife, SlimQuick, Hydroxycut, and OxyELITE Pro, have received attention in both the scientific and lay press for their association with severe hepatotoxicity. Herbalife was linked to severe liver injury, including the need for LT,264,265 although many different preparations were taken and other causes may have been responsible in most cases, according to an analysis by Teschke and colleagues.213 The weight-loss supplement Hydroxycut has been associated with nearly 2 dozen spontaneous reports of possible hepatotoxicity, with 2 patients requiring LT and one death. It was recalled from the U.S. market in 2009.266,267 Two of its active ingredients, GTE (Camellia sinensis), and ephedra (ma huang), have been implicated in liver injury,268 although the association with GTE has been called into question in some cases.209 Although the FDA did not identify a specific hepatotoxic component, Hydroxycut was reformulated with caffeine as the principal ingredient and reintroduced into the market, with only a single subsequent report of liver injury.269 SlimQuick products contain a variety of vitamins, botanicals, and other ingredients, including GTE. Among the published reports of liver injury, GTE was noted to be the common exposure,270 although the exact mechanism is unclear.197 OxyELITEPro is a body-building, weight-loss, and performance-enhancing supplement that has come under FDA scrutiny for hepatotoxicity. Its unique story reflects many of the regulatory and manufacturing issues the HDS market has faced and is a cautionary tale for the $40 billion supplement industry.271 Beginning in 2012, the FDA received more than 100 adverse drug reports from 33 states, 2 foreign countries, and Puerto Rico linked to OxyELITE Pro dating back to 2010. Nearly 50% of the reports involved liver disease.272 In 2013, the FDA banned the use of the original active ingredient in OxyELITE Pro Advanced Formula, 1,3-dimethylamylamine, in all nutritional supplements,272 This stimulant caused hypertension and was linked to heart attacks, seizures, psychiatric disorders, and death.273 OxyELITE Pro was

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reformulated, replacing 1,3-dimethylamylamine with aegeline, an alkaloid extract from the leaves of the Asian bael tree (Agele marmelos). Following an initial report of cases of severe hepatitis from Hawaii and among the military in 2013,274-276 and the subsequent reporting of more than 50 cases from both within and outside Hawaii by the end of October 2013,271,272 the FDA issued a warning in October 2013 to avoid the use of the reformulated OxyELITE Pro, and the manufacturer was required to cease production and to recall and destroy the retail product.277 Numerous reports have documented the OxyELITE Pro history.271,276-279 The summary by investigators from the Centers for Disease Control and Prevention, FDA, and Department of Military and Emergency Medicine is perhaps the most informative in chronicling the timeline, the involvement of the numerous agencies that sought to identify cases, and the clinical features and outcomes of the patients.274 Nevertheless, an animal study of the subsequent formulation of OxyELITE Pro-NewFormula has documented elevations in serum AST and ALT levels as well as mortality in female mice, suggesting that even this newest version may be hazardous.280 

Kava Kava Kava kava is a natural sedative and antianxiety agent derived from the root of the pepper plant (Piper methysticum). This herbal product has been the subject of an FDA consumer alert246 after it was banned in the European Union and Canada281 because of severe hepatotoxicity, including fatal liver failure.164,282 A review of 78 cases of hepatic injury reported to the FDA included 11 cases of liver failure requiring LT and 4 deaths.283 Other investigators, however, have questioned the validity of the causality assessment used by regulators, and only rare instances of hepatotoxicity have been found when a more accurate liver-specific causality scale was used.211,284 Although kavalactone has been shown to inhibit CYP enzymes, deplete hepatic glutathione, and possibly inhibit COX,283 the hepatotoxic component may be the major kava alkaloid pipermethystine. Contamination of the raw material by molds has been cited as an alternative explanation for hepatotoxicity,216 although no hard evidence for aflatoxicosis was found.285 Induction of apoptosis and mitochondrial toxicity are the suspected hepatotoxic mechanisms.286 

Black Cohosh Black cohosh (Actaea racemosa and Cimicifuga racemosa), which is used for menopausal symptoms, has been implicated in reports of possible hepatic injury,287 including a case with features of autoimmune hepatitis.288 Causality has been questioned,289 bolstered by a meta-analysis that included 5 studies involving more than 1100 women that found no evidence for an adverse effect of the isopropanolic extract of black cohosh on the liver.290 

Greater Celandine Extract Greater celandine (Chelidonium majus) is regarded as hepatotoxic on the basis of both animal studies and human reports subjected to accepted liver-specific causality assessments.291 Its toxic component appears to be isoquinolone alkaloids.292 Clinical features include reversible hepatocellular or cholestatic injury with jaundice, with recovery after about 2 months. A majority of the patients have been women who were taking the agent for various dyspeptic complaints.291 Formal causality assessments undertaken by Teschke and colleagues have confirmed the hepatotoxic potential of the agent.292 

Flavocoxid Flavocoxid (Limbrel), a blend of plant-derived bioflavonoids, is a medical food prescribed for osteoarthritis. It is an uncommon cause of hepatotoxicity among cases contained within the U.S.

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PART IX  Liver

DILI Network registry.293 Four middle-aged women developed acute hepatocellular injury within 1 to 3 months of starting flavocoxid for arthritis-related complaints. Clinical features included abdominal pain, fever, pruritus, and a rash, with a mean peak serum ALT level of 1286 U/L and moderate elevations of alkaline phosphatase (mean peak 510 U/L) with jaundice (mean peak bilirubin 9.4 mg/dL [with a range of 2.0 to 20.8 mg/dL]). The injury was of moderate severity with no sign of ALF, and all 4 individuals started to recover within days of discontinuing the product.293 

Garcinia cambogia Garcinia cambogia (GC) is a tropical fruit whose rind contains hydrocitric acid (HCA) that is used as an appetite suppressant and weight loss supplement. Its active ingredient reduces synthesis of fatty acids and glycogen storage via inhibition of ATP citrate lyase. Several reports of hepatocellular (and less often cholestatic) injury have been published, with a latent period ranging from 1 to several weeks, and a clinical presentation that often includes nausea, vomiting, fatigue and jaundice, and instances of severe injury and acute liver failure have appeared.294-298 Crescioli et al documented four cases of acute liver injury in which causality was established as probable using the Council for International Organization of Medical Sciences (CIOMS) scoring.298 These investigators also applied causality scoring to a literature review, and concluded that GC was a likely cause of HDS.

Kratom Kratom (Mitragna speciosa) leaves have traditionally been used to brew a tea to manage pain and for use as a stimulant, but more

recently has been taken as a non-sanctioned means to ameliorate poioid withdrawal symptoms in the United States and elsewhere.299 Its active components are mitragynine and 7 hydroxymitragynine, which act as partial mu and delta opioid receptor agonists, with the former mediating euphoria, analgesia and respiratory depression.300 However, the CDC estimated a more than 10-fold increase in kratom use linked to oipiod overdoses between 2010 and 2015,301 with an increasing number of reports of cholestatic injury along with seizures and death associated with its use.300,302-304 Liver histologic information, while limited, suggests kratom causes acute zone 3 cholestasis with mild portal inflammation and bile duct injury that has mimicked a form of antimitochondrial antibody negative primary biliary cholangitis.305,306 The FDA has classified kratom as an opioid, citing its potential for abuse, addiction and other potentially deadly risks,307 prompting caution from others.308,309

Hepatoprotection by Herbal Compounds In contrast to the hepatotoxicity seen with the HDS discussed in this chapter, an entire field of study has been devoted to the hepatoprotective properties of nutraceuticals and other phytomedicines against liver injury induced by various chemicals, drugs, and other hepatotoxins, including acetaminophen and CCl4 in animal models. This topic has been reviewed.310-314 Full references for this chapter can be found on www.expertconsult.com.

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Autoimmune Hepatitis Albert J. Czaja

CHAPTER OUTLINE EPIDEMIOLOGY. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1415 Incidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1415 Prevalence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1415 PATHOPHYSIOLOGY. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1416 Genetic Predisposition. . . . . . . . . . . . . . . . . . . . . . . . . . 1416 Epigenetic Factors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1416 Autoantigens and Molecular Mimicry. . . . . . . . . . . . . . . 1417 Lymphocyte Differentiation and Hepatocyte Loss. . . . . . 1418 CLINICAL FEATURES. . . . . . . . . . . . . . . . . . . . . . . . . . . . 1418 Symptoms and Physical Findings . . . . . . . . . . . . . . . . . 1418 Laboratory Findings. . . . . . . . . . . . . . . . . . . . . . . . . . . . 1418 Serology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1418 Histology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1419 Emerging Biomarkers. . . . . . . . . . . . . . . . . . . . . . . . . . 1420 DIAGNOSIS AND CLASSIFICATION. . . . . . . . . . . . . . . . . . 1420 Scoring Systems. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1420 Types . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1420 Presentations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1421 Variant (“Overlap”) Syndromes . . . . . . . . . . . . . . . . . . . 1422 TREATMENT. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1424 Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1424 Regimens. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1424 Responses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1426 Treatment Withdrawal. . . . . . . . . . . . . . . . . . . . . . . . . . 1428 Second-Line Treatments. . . . . . . . . . . . . . . . . . . . . . . . 1428 Changing Therapeutic Paradigm. . . . . . . . . . . . . . . . . . 1431 LT. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1431 PROGNOSIS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1432

Autoimmune hepatitis (AIH) is a disease of unknown cause that is characterized by the presence of autoantibodies, hypergammaglobulinemia, and histologic features of interface hepatitis (Fig. 90.1) and lymphoplasmacytic infiltration (Fig. 90.2).1 Diagnosis requires the exclusion of other chronic liver diseases that have similar features, including Wilson disease, chronic viral hepatitis, drug-induced liver disease, NAFLD, and the immune cholangiopathies (PBC and PSC).1 Centrilobular (Rappaport zone 3) necrosis (Fig. 90.3) may indicate acute severe AIH2-5 or a spontaneous exacerbation of chronic disease.6,7

EPIDEMIOLOGY Incidence AIH has a global distribution, and it affects persons of all ages and both genders.8,9 The annual incidence ranges from 0.67 cases per 100,000 persons in southern Israel10 to 2.0 cases per 100,000 persons in New Zealand.11 Among countries of similar ethnicity and geographic proximity, disparities in occurrence are also

evident. The annual incidence of AIH per 100,000 persons is 0.85 in Sweden,12 1.1 in the Netherlands,13 1.68 in Denmark,14 and 1.9 in Norway.15 The annual incidence of AIH in children ranges from 0.23 cases per 100,000 persons in Canada16 to 0.4 cases per 100,000 persons in the USA.17 The annual incidence per 100,000 persons has been increasing in Spain (0.83 to 1.07 cases from 1990 to 2003),18,19 Denmark (1.37 to 2.33 cases from 1994 to 2012),14 and the Netherlands (rising trend over a 10-year period),13 in contrast to a stable annual incidence in New Zealand (2.0 between 2001 and 2007).11 In the USA, AIH affects 100,000 to 200,000 persons, and it accounts for 2% to 3% of pediatric and 4% to 6% of adult liver transplants performed in Europe and the USA.20 

Prevalence The prevalence of AIH ranges from 4.0 cases per 100,000 persons in Singapore,21 to 42.9 cases per 100,000 persons in the native population of Alaska.22 In Europe, the prevalence ranges from 10.7 cases per 100,000 persons in Sweden 23 to 23.9 cases per 100,000 persons in Denmark.14 A similar range in prevalence is evident from Australia (8.0 cases per 100,000 persons)24 and southern Israel (11.0 cases per 100,000 persons)10 to New Zealand (24.5 cases per 100,000 persons).11 The prevalence of AIH in the non-native children of Canada (2.4 cases per 100,000 persons) contrasts with that in the native children of Canada (9.9 cases per 100,000 persons)25 and is similar to the prevalence in children of the USA (3.0 cases per 100,000 persons).17

Female Predisposition AIH mainly affects females, regardless of age or ethnicity.9 The female gender predilection in children is evident in the USA (66% to 76% are girls),17,26 Canada (60% girls),16 and Great Britain (75% girls),27 and it is similar to that reported in adults. The magnitude of the female predisposition has varied widely among adults, ranging from 91% to 95% in Alaska22 and Southern Israel10 to 71% to 80% in New Zealand,11 Denmark,14 Sweden,12 the Netherlands,13 the USA,28 and Norway.15 The female-to-male ratio in Singapore is 11:1,21and it is 3.5:1 in the USA.29 In Spain, women have a 5-fold greater annual incidence (1.37 cases per 100,000 vs. 0.26 cases per 100,000) and prevalence (19.17 cases per 100,000 vs. 3.66 cases per 100,000) than men.18 

Peak Age of Onset Population-based epidemiologic studies have indicated that AIH is mainly a disease of mid-to-late life and that its peak age of onset varies among countries.9 The median age of onset in the Netherlands is 43 years in men and 48 years in women.13 In Denmark, the peak age of onset is 70 years,14 and in New Zealand, the peak age of onset ranges from 60 to 69 years.11 Earlier studies described AIH mainly in young women,30 indicated a bimodal age distribution between 10 and 30 years and 40 and 60 years,31 or denoted a peak occurrence that varied by gender (late teenage years in males and postmenopausal period in females).12 These studies may have been biased by referral patterns to tertiary medical centers or indicative of a natural history that has since changed. 

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PATHOPHYSIOLOGY

Fig. 90.1  Histopathology of interface hepatitis.  The limiting plate of the portal tract is disrupted by a lymphoplasmacytic infiltrate. This histologic pattern is the hallmark of autoimmune hepatitis, but it is not disease specific. (H&E, ×200.)

AIH is a consequence of perturbations in homeostatic mechanisms that maintain immune tolerance of self-antigens (Fig. 90.4).32 Genes within the MHC may favor presentation of triggering antigens that differ among age groups, geographic regions, and ethnicities, and genetic polymorphisms outside the MHC may influence the clinical phenotype and outcome.33 Molecular mimicry between foreign and self-antigens,34,35 dysregulated cytokine pathways that favor the differentiation and proliferation of liver-infiltrating cytotoxic CD8+ T lymphocytes,36 deficiencies in the number and function of regulatory T cells (Tregs),37-40 and counter-regulatory molecules, such as micro-RNAs (miRNAs),41 the programmed death-1 (PD-1) protein and its ligands,42-46 soluble CD163,47, 48 macrophage migration inhibitory factor,49,50 and B-cell activating factor (BAFF)51,52 may contribute to the homeostatic imbalance. Apoptosis, mediated mainly by the ligation of Fas ligand (FasL/ CD95L) on the surface of activated CD8+ T cells with the Fas death receptor (CD95/APO-1) on hepatocytes, is the principal method of hepatocyte loss,53 and reactive oxygen species (ROS) generated mainly by Kupffer cells can induce mitochondrial dysfunction, apoptosis of hepatocytes, activation of hepatic stellate cells, and progressive hepatic fibrosis (see Fig. 90.4).54

Genetic Predisposition

Fig. 90.2  Histopathology of lymphoplasmacytic infiltration.  Plasma cells denoted by perinuclear halos are present in the portal tract and extend into the liver parenchyma with the interface hepatitis. (H&E, ×400.)

Fig. 90.3  Histopathology of centrilobular zone 3 necrosis with hepatocyte rosettes.  Mononuclear inflammatory cells surround the terminal hepatic venule and are distributed diffusely in the hepatic parenchyma. The hepatic architecture is disorganized, and hepatocyte rosettes are in the perivenular area. (H&E, ×100.)

The susceptibility alleles of AIH in white North Americans and northern Europeans are DRB1*03:01 and DRB1*04:01.55,56 DRB1*04:04 and DRB1*04:05 are the susceptibility alleles in Mexican,57 Japanese,58,59 mainland Chinese,60 and Argentinian adults,61 and DRB1*04:05 and DQB1*04:01 are the susceptibility alleles in South Korea.62 The susceptibility alleles on the DRB1 gene encode the antigen binding groove of the class II molecules of the MHC, and they differ mainly by amino acid substitutions encoded within this groove.33 AIH associated with DRB1 alleles that encode similar antigen presenting grooves may have triggering antigens with shared epitopes. DRB1*13:01 is associated with AIH in the children of Argentina61 and Brazil,63,64 and DRB1*13:01 and DRB1*03:01 are the susceptibility alleles in Venezuela.65 DRB1*13:01, DRB1*04:05, DQB1*02, and DQB1*06:03 have been implicated as the principal susceptibility alleles in South America by meta-analysis.66 DRB1*13:01 encodes an antigen binding groove on the class II MHC molecule that is dissimilar to that encoded by the DRB1*03 and DRB1*04 alleles, and it may identify individuals in whom the disease has different triggering antigens. The genetic predisposition of a subgroup of patients characterized by antibodies to liver/kidney microsome type 1 (anti-LKM1) is DRB1*07,67,68 and DQB1*02:01, which is in strong linkage disequilibrium with DRB1*07 and DRB1*03, has been proposed as the principal genetic determinant of this type of AIH.69 Multiple polymorphisms outside the MHC have also been associated with AIH,32,33 and they may influence the occurrence and clinical phenotype of the disease.70 These variant alleles have not been consistently found in patient cohorts, and their pathogenic importance is unknown. Variants of the Scr homology 2 adaptor protein 3 gene and the caspase recruitment domain family member 10 (CARD10) gene have been described in northern European patients by genome-wide association studies and warrant further scrutiny.71 

Epigenetic Factors Epigenetic changes can influence the transcriptional activity of genes without altering the sequence of DNA.72,73 They may be induced by environmental factors (pollutants, infections, and diet), transmitted to progeny, and influence the clinical phenotype.74-76 MicroRNAs are gene-silencing mechanisms, and the association of

CHAPTER 90  Autoimmune Hepatitis Molecular mimicry Self

Cytokine-directed differentiation

1417

Epitope spread

90

FasL

TNF- IFN-

Foreign

APC

Class II MHC

Fibrosis

CD4 helper T cell

IL-10

Neoantigens

TGF- IL-6

Hepatic stellate cell Intrinsic apoptosis

CD8+ cytotoxic T cell

Plasma cell

Autoantibodies Extrinsic apoptosis

ROS Apoptotic body

FasL Fas

Mitochondria

Caspases

Apoptosome Kupffer cell

Caspases

Th17 lymphocyte

Regulatory T cell

DNA

DNA Hepatocyte

Positive feedback loops

Hepatocyte

Fig. 90.4  Putative pathogenic mechanisms of autoimmune hepatitis.  APC activate CD4+ helper T cells by presenting homologous foreign and self-antigens (molecular mimicry) in the antigen-binding grooves of class II molecules of the MHC. The activated CD4+ helper T cells can then differentiate along cytokine pathways into liver-infiltrating CD8+ cytotoxic T cells, antibody-producing plasma cells, and Th17 lymphocytes (cytokinedirected differentiation). The differentiation is directed by interferon-γ (IFN-γ), TNF-α, interleukin-10 (IL-10), transforming growth factor-β (TGF-β), and IL-6. The Th17 lymphocytes can inhibit regulatory T cells and limit (red X) their ability to dampen extrinsic apoptosis. The reactivity of the activated lymphocytes spreads (epitope spread) to self-antigens distant from the original antigenic trigger, and the promiscuous activity of the activated lymphocytes can increase inflammatory activity. Liver-infiltrating CD8+ cytotoxic T cells bearing Fas ligand (FasL) can bind with Fas receptors on the surface of hepatocytes, activate caspases, and promote apoptosis of liver cells (extrinsic or receptor-mediated apoptosis). Apoptotic bodies can serve as neoantigens and stimulate the activation of naïve CD4+ helper T cells in a positive feedback loop (red arrows). The apoptotic bodies can also activate Kupffer cells to produce reactive oxygen species (ROS), which in turn can activate hepatic stellate cells, promote hepatic fibrosis, alter mitochondrial membrane permeability, and trigger liver cell apoptosis (intrinsic or mitochondrial apoptosis). The apoptotic bodies produced by these mechanisms constitute another positive feedback loop (blue arrows) that sustains the immune reactivity.

miR-22 and miR-122 with serum ALT levels and histologic grades of liver inflammation in AIH suggest that the mi-RNAs have disrupted the transcriptional activities of anti-inflammatory genes or de-repressed pro-inflammatory genes.41 Vitamin D activates the vitamin D response element in regulatory genes77,78 and may be an epigenetic factor that modulates immune, inflammatory, and fibrotic responses in AIH.79-81 Epigenetic changes are in early stages of study in AIH, but they may help explain the diversity of manifestations of the disease and link environmental factors with its occurrence and outcome.74-76

Autoantigens and Molecular Mimicry The principal autoantigen of AIH that is targeted by anti-LKM1 is cytochrome P450 2D6 (CYP2D6).82 Another autoantigen that

may contribute to the autoreactive response is formiminotransferase cyclodeaminase, which is targeted by antibodies to liver cytosol type 1 (anti-LC1).83,84 Immunization of mice with human CYP2D6 and human formiminotransferase cyclodeaminase85 or infection with an adenovirus expressing human CYP2D686 induces the histologic features of AIH and the expression of antiLKM1. The majority of patients with AIH lack anti-LKM1 (see later), and the principal autoantigen associated with their disease is unknown.87 Protracted or repeated exposure to foreign peptide sequences homologous to self-antigens has induced the loss of self-tolerance in animal models,35,85,88-90 and molecular mimicry has been invoked as a mechanism for generating autoantibodies and sensitizing CD4+ lymphocytes (see Fig. 90.4).91,92 Molecular mimicry may also extend the autoreactive response, because less dominant sequence homologies within the same self-antigen

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induce reactivity during the course of the disease (“epitope spread”).35 Homologies in peptide sequences have been recognized between CYP2D6 and HCV,93 HSV type 1,94 and CMV.95 Alterations in the intestinal microbiome (dysbiosis) have been described in experimental models96 and patients with AIH,97 and gut-derived lipopolysaccharides have been detected in the systemic circulation of patients.97 The translocation of intestinal microbial products and activated immune cells through a permeable intestinal mucosal barrier could be another basis for overcoming the immune tolerance of self-antigens.98 

Lymphocyte Differentiation and Hepatocyte Loss Activated CD4+ T lymphocytes differentiate along cytokinemediated pathways into liver-infiltrating CD8+ cytotoxic T cells, B lymphocytes, plasma cells, and T helper 17 (Th17) lymphocytes (see Fig. 90.4).99 The liver-infiltrating CD8+ cytotoxic lymphocytes induce the apoptosis of hepatocytes by the ligation of FasL with the apoptosis death receptor on hepatocytes (extrinsic apoptosis).53 The B lymphocytes and plasma cells modulate autoantibody production,99 and the Th17 cells sustain and intensify the inflammatory activity by producing the pro-inflammatory interleukin (IL) 17, inducing IL-6 production, promoting proliferation of Th17 cells, and suppressing the function of Tregs.100,101 The phagocytosis of apoptotic bodies by Kupffer cells generates ROS, which induce mitochondrial dysfunction, caspase activation, and the apoptosis of hepatocytes (intrinsic apoptosis).53,54 Hepatic stellate cells transform into myofibroblasts, the extracellular matrix expands, and hepatic fibrosis develops.102 The destructive inflammatory process can be sustained by self-amplification loops that generate apoptotic bodies that serve as neoantigens (see Fig. 90.4).103-105 The principal regulatory defect that may sustain the immune reactivity is uncertain. A reduction in the number and function of Tregs has been proposed37-39 but not confirmed.106 

CLINICAL FEATURES Symptoms and Physical Findings AIH may be asymptomatic,107-109 cause chronic nonspecific symptoms (fatigue, malaise, arthralgias, or amenorrhea),20,110,111 or present with an abrupt onset of symptoms, including jaundice.112-114 An acute severe (fulminant) presentation, defined by the onset of hepatic encephalopathy within 26 weeks of the discovery of the disease,5 occurs in 3% to 6% of British115 and American4 patients. Ready fatigability is the chief complaint in 86% of individuals. Pruritus and hyperpigmentation are cholestatic symptoms that reduce the likelihood of the diagnosis.116 Quality of life, as assessed by a health-related quality of life questionnaire, is commonly decreased in patients with AIH, and symptoms of fatigue, depression, and anxiety are significantly more common than in the general population.117 Depression and anxiety have been associated mainly with a patient’s concern about disease progression, and targeted counselling may be necessary. Persistence or emergence of these symptoms may affect outcome by reducing a patient’s compliance with treatment.118 Physiologic stress has been associated with relapse of AIH,119 possibly by increasing the production of pro-inflammatory cytokines.120,121 At least 25% of adults with AIH have a normal physical examination. Hepatomegaly is the most common physical finding, and splenomegaly may be present. Concurrent extrahepatic immune-mediated diseases are recognized in 14% to 44% of patients,122-126 and the associated autoimmune disease may mask asymptomatic subclinical AIH.109,126 Autoimmune thyroiditis, Graves disease, and RA are the most common concurrent conditions, and celiac disease is present in 2% to 4% of cases.127-129 Patients with multiple endocrine

organ failure, mucocutaneous candidiasis, and ectodermal dystrophy have autoimmune polyendocrinopathy-candidiasisectodermal dystrophy, and 10% to 15% of affected patients also have AIH.130

Laboratory Findings Serum AST, ALT, and γ-globulin elevations reflect the severity of liver inflammation and are the predominant laboratory features of AIH.131 An increased serum immunoglobulin G (IgG) level is a laboratory hallmark of the disease, whereas serum IgM and IgA levels are normal or near-normal.132 Hyperbilirubinemia is present in 83% of patients, but the serum bilirubin level is typically less than 3-fold the upper limit of normal (ULN).133 Similarly, the serum alkaline phosphatase level is commonly increased (81%), but elevations are less than 2-fold ULN in 67% of patients. A serum alkaline phosphatase level exceeding 4-fold ULN is infrequent and challenges the diagnosis of AIH.133 The serum GGTP level can be increased, and its improvement during glucocorticoid therapy is an independent predictor of treatment response.110,134,135 Hyperferritinemia is commonly present in conjunction with other disturbances in iron homeostasis, including a high serum iron concentration and increased transferrin saturation.136 The association of hyperferritinemia and a serum immunoglobulin G level of less than 2-fold ULN has been associated with a complete laboratory response during treatment, and hyperferritinemia is being evaluated as a prognostic biomarker.136 Low serum vitamin D levels are present in 51% to 92% of patients with non-cholestatic chronic liver disease137-140 and 81% of patients with AIH.81 The decrease in circulating 25-hydroxyvitamin D levels probably reflect impaired hepatic conversion of vitamin D3 to its hydroxylated form by the liver. The serum vitamin D level is also emerging as a prognostic biomarker associated with treatment failure, progression to cirrhosis, and increased frequency of death from liver failure or need for LT.141 The serum 25-hydroxyvitamin D level should be assessed at presentation and deficient levels supplemented and monitored. 

Serology The conventional autoantibodies for the diagnosis of AIH are ANA, smooth muscle antibodies (SMA), and anti-LKM1 (Table 90.1).20,110,142 The presence of both SMA and ANA by indirect immunofluorescence (IIF) has a sensitivity of 43%, specificity of 99%, and diagnostic accuracy of 74%.143 Anti-LKM1 are usually detected in the absence of SMA and ANA. They have a specificity of 99% and diagnostic accuracy of 57%.143 Anti-LKM1 are present in only 1% to 4% of North American adults with AIH,87 and most North American patients with AIH have ANA, SMA, or both.143 Autoantibodies are clues to the diagnosis of AIH, but they do not establish its presence. SMA, ANA, and anti-LKM1 can be detected by IIF using rodent tissues or Hep-2 cell lines or by enzyme immunoassay (ELISA) using adsorbed recombinant or highly purified antigens.144 IIF has been the preferred method for diagnosing AIH because the recombinant antigens used in ELISAs may not be the same antigens detected by IIF.144 Other serologic markers of AIH are atypical perinuclear anti-neutrophil cytoplasmic antibodies (pANCA), antibodies to soluble liver antigen (anti-SLA), antibodies to actin (anti-actin), and anti-LC1 (Table 90.1).145,146 Atypical pANCA are common in AIH, PSC, and UC.145-148 They are directed against antigens within the nucleus rather than the cytoplasm of granulocytes, and reactivity localizes to the proteins within the lamina of the nucleus.149 The principal antigen targeted by atypical pANCA is β-tubulin isotype 5, which has homology with an evolutionary bacterial precursor protein that may link the reactivity to the intestinal microbiome.98,150

CHAPTER 90  Autoimmune Hepatitis

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TABLE 90.1  Serologic Markers of Autoimmune Hepatitis Autoantibodies

Antigenic Target

Features

ANA

Multiple nuclear antigens

Present in 80% of patients with type 1 AIH Concurrent with SMA in 43% of patients with type 1 AIH Diagnostic accuracy is 56% as sole marker

SMA

Actin (F and G) Non-actin components (14%)

Present in 63% of patients with type 1 AIH Diagnostic accuracy is 61% as sole marker Diagnostic accuracy is 74% if ANA present

Anti-LKM1

CYP2D6 (main epitope, 193-212 amino acid sequence)

Hallmark of type 2 AIH ANA and SMA usually absent Concurrent with anti-LC1 in 32% of patients with AIH Mainly present in children Associated with HLA DRB1*07

Anti-SLA

Transfer ribonucleoprotein (tRNP(ser)sec); renamed Sep [O-phosphoserine] tRNA::NA::NA:selenocysttRNA synthase (SEPSECS)

High diagnostic specificity for AIH (99%) Associated with HLA DRB1*0301 Commonly concurrent with anti-Ro/SSA (96%) Associated with severe disease and relapse May be sole marker of AIH

Atypical pANCA

β-tubulin isotype 5

Present in 50%-92% of patients with type 1 AIH Absent in type 2 AIH Associated with PSC and UC May be the sole marker of AIH May be the result of gut-derived reactivity

Anti-actin

Actin (F and G)

Present in 86% of SMA-positive patients with AIH Does not detect non–actin-associated SMA Concurrence with anti–α-actinin is associated with severe disease

Anti-LC1

Formiminotransferase cyclodeaminase

Frequently concurrent with anti-LKM1 (32%) Mainly present in young patients (age ≤ 20 yr) Associated with same clinical phenotype as anti-LKM1 Rare in North American patients

AIH, Autoimmune hepatitis; anti-LC1, antibodies to liver cytosol type 1; anti-LKM1, antibodies to liver/kidney microsome type 1; anti-SLA, antibodies to soluble liver antigen; CYP2D6, cytochrome P450 2D6; pANCA, perinuclear anti-neutrophil cytoplasmic antibodies; Ro/SSA, ribonucleoprotein/Sjögren syndrome A protein; SMA, smooth muscle antibodies.

Assessments for atypical pANCA have been useful in diagnosing patients who lack the conventional autoantibodies.20,151 Antibodies to SLA are directed against a transfer ribonucleoprotein (tRNP(ser)sec) involved in the transport of selenocysteine,152 and this antigenic target has been named SEPSECS (Sep [O-phosphoserine] tRNA:Sec [selenocysteine] tRNA synthase) (see Table 90.1).153-155Anti-SLA are closely associated with HLA DRB1*03, and patients with anti-SLA frequently have severe disease and relapse after drug withdrawal.156,157Anti-SLA are present in 15% of patients with AIH in the USA,158 and they almost invariably co-exist with antibodies to ribonucleoprotein/Sjögren syndrome A antigen.159,160 Anti-SLA may be the sole serologic marker of AIH at presentation.161 Anti-actin by ELISA have high sensitivity (74%) and specificity (98%) for AIH, but SMA by IIF have reactivity to actin and non-actin substrates, which may increase their positive predictive value (see Table 90.1).162-164 Fourteen percent of patients with AIH and SMA lack anti-actin.162 An investigational assay assessing reactivity against actin and α-actinin, a component of the actin molecule,165 may characterize patients with severe AIH and poor outcome.166,167 Anti-LC1 target formiminotransferase cyclodeaminase,83,84 and the recombinant human antigen has been used in a murine model of experimental AIH (see Table 90.1).85 Anti-LC1 are commonly detected in patients with anti-LKM1 but may also be the sole serologic marker of AIH.168 Patients with anti-LC1 typically are young at disease onset (mean age, 8 years; range, 2 to 26 years),169 frequently have concurrent immune diseases (vitiligo, diabetes mellitus, SLE),168 have serum ALT levels at presentation that range from 6- to 33-fold the ULN,168 and commonly progress to cirrhosis within 3 years.168,170 The clinical phenotype is

indistinguishable from patients who express only anti-LKM1.168 Antibodies to LC1 are rarely found in North American adult patients with AIH.171 

Histology Interface hepatitis is required for the diagnosis of AIH, but this histologic finding lacks disease-specificity (see Fig. 90.1).20,110,172 Virus-related, drug-induced, hereditary, and metabolic causes of liver injury must be excluded.173 Lymphocytic or lymphoplasmacytic inflammation, hepatocyte rosetting, emperipolesis (penetration of one cell into and through a larger cell), and hepatocyte swelling are other common findings.173,174 Panacinar hepatitis can be seen during an acute onset or relapse after treatment withdrawal.173,175 Bridging necrosis and multi-acinar necrosis are indicative of severe inflammatory activity.173 Plasma cells can be abundant at the interface and throughout the acinus, but only 66% of patients with AIH have plasma cells in groups or sheets in the portal tract (see Fig. 90.2).176 The presence of plasma cells in conjunction with moderate to severe interface hepatitis has a specificity of 81% and positive predictability of 68% for AIH.176 Lymphoid aggregates surround and infiltrate bile ducts in 7% to 9% of liver biopsy specimens, and the bile duct changes do not preclude the diagnosis.177-180 Centrilobular necrosis is found in 29% of patients with AIH and occurs with similar frequency in patients with and without cirrhosis (see Fig. 90.3).7 Interface hepatitis, lymphoplasmacytic infiltration, and hepatocyte rosettes may co-exist with centrilobular necrosis in patients with an acute presentation.2,7,113,181,182 The histologic features of acute severe (fulminant) AIH include centrilobular necrosis with hemorrhage, severe interface

90

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hepatitis, lymphoplasmacytic infiltration around the central vein with hepatocyte drop-out or necrosis (“centrilobular perivenulitis”), lymphoid aggregates (in 50%), and plasma cell infiltration (in 90%).4 Cirrhosis is present in 28% to 33% of patients at presentation12,108,183-185 and is more common in patients 60 years of age or older than in younger adults 30 years of age or younger (33% vs. 10%, P = 0.03).122 These findings suggest that early-stage AIH is underdiagnosed in older adults. 

Emerging Biomarkers Investigative efforts have been ongoing to refine and individualize management strategies by identifying quantifiable biological features (enzymes, gene products, metabolites, cell surface markers, cytokines, or antibodies) that can secure a diagnosis (diagnostic biomarkers), reflect the risk or severity of disease (predictive biomarkers), project disease outcome (prognostic biomarkers), or indicate treatment response (therapeutic biomarkers).141 Serum levels of ferritin, vitamin D, and angiotensin converting enzyme are being evaluated as prognostic biomarkers,81,136,186 and circulating levels of miR-21 and miR-122, PD-1 and its ligands (PDL1 and PD-L2), macrophage migration inhibitory factor, soluble CD163, and BAFF are being assessed as therapeutic biomarkers.141 Patterns of metabolites in blood or urine (metabolomic profiling) promise to reflect metabolic changes that can characterize predominant pathogenic mechanisms and inflammatory activity.187-190 The next generation biomarkers have the potential to individualize management algorithms, secure endpoints of therapy that reduce the frequency of relapse or unnecessarily protracted therapy, and identify pivotal pathogenic mechanisms that can be targeted by pharmacologic and molecular interventions. 

DIAGNOSIS AND CLASSIFICATION The definite diagnosis of AIH requires the presence of ANA, SMA, or anti-LKM1 alone or in various combinations, hypergammaglobulinemia manifested mainly as an increased serum IgG level, histologic features of interface hepatitis, and exclusion of other similar diseases.20,110,116,172 A probable diagnosis is justified when findings are compatible with AIH but insufficient for a definite diagnosis.116 Patients who lack conventional autoantibodies but who have atypical pANCA or antibodies to SLA, actin, or LC1 are classified as having probable disease.116 Liver tissue examination is essential in establishing the diagnosis of AIH20,110,172 because the clinical, laboratory, and serologic features of AIH can be mimicked by other diseases, especially NAFLD191 and drug-induced liver disease.192,193 Furthermore, variant syndromes of AIH with overlapping features of PBC or PSC (see later) can be discovered by liver tissue examination and require adjunctive therapies.194-198 Liver stiffness measured by transient elastography (see Chapters 73 and 80) correlates with histologic grades of inflammatory activity rather than fibrotic stage in untreated patients at presentation.199 Transient elasto­ graphy does not become an accurate assessment of cirrhosis until glucocorticoid treatment has been administered for 6 months or longer.199

Scoring Systems The comprehensive scoring system proposed by the International Autoimmune Hepatitis Group accommodates the diverse manifestations of AIH and renders an aggregate score that reflects the net strength of the diagnosis before and after glucocorticoid treatment (Table 90.2).116 This comprehensive scoring system was developed to ensure the comparability of study populations in clinical trials, and it provides a template for systematically assessing all features of the disease. The comprehensive

scoring system performs better than a simplified scoring system in diagnosing acute-onset AIH (91% vs. 40%)200 and acute severe (fulminant) AIH (40% vs. 24%).201 The comprehensive scoring system should not be used to diagnose variant syndromes.194 A simplified scoring system has been developed to ease clinical application and is based on 4 clinical components that include the presence and level of autoantibody expression by IIF, serum IgG concentration, histologic features, and viral markers (Table 90.3).132 The original scoring system has greater sensitivity for the diagnosis of AIH than the simplified system (100% vs. 95%), but the simplified system has greater specificity (90% vs. 73%) and accuracy (92% vs. 82%).201-204 The scoring systems have not been validated by prospective clinical trials, and the diagnosis by score should never override clinical judgment. Each system renders scores for a “definite” or “probable” diagnosis of AIH. The designations of “definite” and “probable” AIH are arbitrary, and patients with a probable diagnosis typically have valid disease but with less pronounced inflammatory changes.205 The scoring systems are based on antibody determinations by IIF and do not accommodate antibody determinations by ELISA.144 

Types Two types of AIH have distinctive serologic profiles.206 The terms are useful as clinical descriptors and as designations in research studies to ensure homogeneous populations. The designations do not indicate diseases of different cause, severity, or outcome, and each type is managed similarly. Elimination of the designations has been proposed in adults.207

Type 1 Type 1 AIH is characterized by the presence of SMA, ANA, or both.20,110,172 Atypical pANCA are found in as many as 90% of patients with type 1 AIH (often in high titer)147 and are absent in type 2 AIH.208 Type 1 AIH has been described in patients ranging in age from 1 year209 to 90 years,210 and the female-to-male ratio is 3.5:1 in the USA.9,28,29 Autoimmune thyroiditis (in 12% of cases) Graves disease (in 6% of cases), UC (in 6% of cases), RA, pernicious anemia, systemic sclerosis, Coombs-positive hemolytic anemia, celiac disease, autoimmune thrombocytopenic purpura, symptomatic cryoglobulinemia, leukocytoclastic vasculitis, nephritis, erythema nodosum, SLE, or fibrosing alveolitis can occur singly or multiply in patients with type 1 AIH.122-124,126 Patients with AIH who are 60 years of age and older have thyroid and rheumatic diseases more commonly than young adults with AIH 30 years of age and younger (42% vs. 13%), whereas young adults with AIH have UC and autoimmune hemolysis more frequently than patients who are 60 years of age and older (13% vs. 0%).122,211 MRCP or ERCP is warranted to exclude PSC in all patients who have concurrent IBD or prominent features of cholestasis (serum alkaline phosphatase level ≥2-fold ULN or serum GGTP level ≥5-fold ULN), especially if the features do not improve during glucocorticoid therapy.195,198 Type 1 AIH is associated with an abrupt onset of symptoms (fatigue, arthralgia, fever, or jaundice) in 25% to 75% of cases114,212 and may present as an acute severe (fulminant) hepatitis in 3% to 6%.3-5 The frequency of an acute severe presentation in Japan is 7% to 16%.213-216

Type 2 Type 2 AIH is characterized by the presence of anti-LKM1.217 Anti-LC1 and antibodies to liver kidney microsome type 3 can also denote type 2 AIH.218,219 Most patients with type 2 AIH are children (2 to 14 years of age),217 and 14% to 38% of children

CHAPTER 90  Autoimmune Hepatitis

TABLE 90.2  Revised Original Scoring System for the Diagnosis of Autoimmune Hepatitis

TABLE 90.3  Simplified Scoring System for the Diagnosis of Autoimmune Hepatitis

Category

Variable

Score

Category

Variable

Score

Gender

Female

+2

AP/AST

>3

−2

Autoantibodies* ANA or SMA

1:40

+1

2.0 x ULN

+3

Anti-LKM1

≥1:40

+2

1.5-2.0 x ULN

+2

Anti-SLA

Positive

+2

1.0-1.5 x ULN

+1

1 × ULN

+1

>1.1 × ULN

+2

Compatible with AIH

+1

Typical of AIH

+2

No viral markers

+2

Gamma globulin or IgG level

ANA, SMA, or anti-LKM1 titer

>1:80

+3

1:80

+2

1:40

+1

15

Probable diagnosis

10-15

Post-Treatment Score Definite diagnosis

>17

Probable diagnosis

12-17

Anti-LC1, Antibodies to liver cytosol type 1; anti-LKM1, antibodies to liver/kidney microsome type 1; anti-SLA, antibodies to soluble liver antigen; AP/AST (or AP/ALT), ratio of serum alkaline phosphatase level to serum AST (or serum ALT) level; IgG, immunoglobulin G; pANCA, perinuclear antineutrophil cytoplasmic antibodies; SMA, smooth muscle antibodies; ULN, upper limit of normal. Adapted from Alvarez F, Berg PA, Bianchi FB, et al. International Autoimmune Hepatitis Group report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol 1999;31:929-38. Used with permission from Elsevier.

with AIH in Great Britain have anti-LKM1.27,220 In Europe, especially in Germany and France, 20% of adults with AIH have anti-LKM1,217 whereas in the USA, only 4% of patients older than 18 years have anti-LKM1.87 Concurrent autoimmune diseases are present in 18% and include autoimmune thyroiditis,

1421

*Autoantibody titers as determined by indirect immunofluorescence. AIH, autoimmune hepatitis; anti-LKM1, antibodies to liver/kidney microsome type 1; anti-SLA, antibodies to soluble liver antigen; SMA, smooth muscle antibodies; ULN, upper limit of normal. Adapted from Hennes EM, Zeniya M, Czaja AJ, et al. Simplified criteria for the diagnosis of autoimmune hepatitis. Hepatology 2008;48:169-76. Used with permission of John Wiley & Sons.

vitiligo, and type 1 diabetes mellitus.123,217 An acute or fulminant presentation is also possible.5 

Presentations Asymptomatic AIH can be asymptomatic in 29% to 45% of patients.107-109 Histologic findings of moderate to severe interface hepatitis (91% vs. 95%) and fibrosis (41% vs. 44%) are similar in asymptomatic and symptomatic patients. From 26% to 70% of asymptomatic patients become symptomatic.107,108 Asymptomatic patients have lower serum ALT and bilirubin levels at presentation than symptomatic patients, lower histologic grades, and greater frequencies of concurrent autoimmune thyroid (27% vs. 13%) and skin (9% vs. 2%) diseases.109 Disease progression and treatment responses are similar between asymptomatic and symptomatic patients, and therapy is warranted.109 Asymptomatic patients can improve without treatment, but spontaneous improvement is unpredictable, usually incomplete, and slow to evolve.221 Progression to cirrhosis and liver failure are possible, and the 10-year survival of untreated asymptomatic patients with mild AIH is less than that of treated patients with severe symptomatic AIH (67% vs. 98%).221 Inflammatory activity can fluctuate spontaneously, and treatment is preferred over observation in patients with active disease.20,109,110,221 Patients who present with autoimmune thyroid or skin disease should be assessed for asymptomatic subclinical AIH.109 

Acute or Acute Severe (Fulminant) AIH can have an acute or an acute severe (fulminant) presentation that can be mistaken for a viral or drug-induced hepatitis.2-5,222-224 The acute presentation may reflect a spontaneous flare of preexisting chronic disease, an abrupt onset of new disease, chronic

90

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PART IX  Liver

disease with a superimposed infection or toxic injury (“acute-onchronic disease”), or an acute disease that follows previous viral infection or treatment with immune-modifying drugs.5 The acute severe presentation is characterized by marked serum AST and ALT elevations, hepatic encephalopathy, and histologic changes that commonly include centrilobular necrosis with hemorrhage, lymphoid follicles, and plasma cell infiltration.4 Interface hepatitis is present in 78% of patients with centrilobular necrosis,2 but the histologic changes of acute severe hepatitis are mainly in the centrilobular (not periportal) area.4 Difficulties in diagnosis relate mainly to the frequency with which typical laboratory findings are absent. The serum IgG level is normal in 25% to 39% of patients, and ANA are absent or weakly positive (titers ≤1:40) in 29% to 39%.213,215,225 The decision to obtain liver tissue by the transjugular route must be guided by clinical judgment.225 The international comprehensive scoring systems can support the clinical diagnosis in difficult cases.5,200,201 CT or MRI of the liver in patients with an acute presentation may show ascites, splenomegaly, and surface nodularity characteristic of advanced fibrosis and preexisting chronic liver disease.226 Furthermore, a heterogeneous reduction in hepatic attenuation on unenhanced CT may indicate acute severe AIH.227,228 Heterogeneous hypoattenuated areas within the liver are present in 65% of patients with ALF associated with AIH and only 5% of patients with virus-induced ALF.228 Prednisone or prednisolone alone, 0.5-1 mg/kg daily in adults and up to 2 mg/kg in children, has been effective in at least 20% of patients. Glucocorticoid therapy has not been associated with improved overall survival, and survival rates have been lower in treated patients with MELD scores greater than 40. The key to success is to abandon ineffective treatment quickly (within 1-2 weeks depending on the patient’s clinical status and treatment response) and to proceed to LT. Patients with moderate-to-severe hepatic encephalopathy are probably best managed by LT.228a,228b 

Autoantibody-Negative Thirteen percent of adults with chronic hepatitis of undetermined cause satisfy international criteria for the diagnosis of AIH but lack ANA, SMA, and anti-LKM1.229-233 Autoantibody-negative patients are similar in age, gender, frequency of concurrent immunologic diseases, histologic features, and laboratory findings to patients with classic AIH.229,232,233 Furthermore, they have HLA phenotypes and responses to glucocorticoid treatment that are indistinguishable from those of autoantibody-positive patients.229-231 The autoantibodies may be other than those in the conventional testing battery, suppressed, or delayed in expression. Serologic evaluation for atypical pANCA and anti-SLA can support the diagnosis of AIH in 15% to 20% of cases,158,233 and anti-LC1 may be another isolated marker of the disease.168 IgA antibodies to tissue transglutaminase or endomysium may indicate a celiac disease-related liver disease that resembles AIH,234,235 and follow-up assessments may document the late appearance of conventional autoantibodies in some seronegative patients.236 The comprehensive scoring system (see Table 90.2) can be useful in supporting a diagnosis of AIH before and after glucocorticoid therapy, and improvement has occurred in 67% to 87% of seronegative patients during a well-monitored treatment trial.233 

onset is typical (median onset from drug exposure, 42 days; range, 20 to 117 days); and features of hypersensitivity (fever, rash, and eosinophilia) are present in 15% to 20%.193 Histologic features include interface hepatitis with portal and periportal lymphocytes, plasma cells, and eosinophils.174 Findings that especially favor drug-induced injury are portal neutrophils and intercellular cholestasis, whereas portal and intra-acinar plasma cells, hepatocyte rosettes, and emperipolesis (see earlier) favor classic AIH.174 Hepatic fibrosis may be present, but cirrhosis is rare.192,193 Keys to the diagnosis of drug-related AIH are the interval between the drug exposure and onset of disease and the disease behavior after drug withdrawal. Drug-induced autoimmune-like hepatitis typically resolves after discontinuation of the drug, whereas classic AIH persists.192,193 Glucocorticoids are commonly administered after drug withdrawal because the diagnosis is uncertain and the severity of the disease precludes observation alone.192,193 Patients with classic AIH often relapse after laboratory resolution and glucocorticoid withdrawal (50% to 87% of cases),238,239 whereas patients with drug-induced disease do not.192,193 Recurrent disease does not exclude the possibility that drug exposure converted a preexisting “latent” AIH into a fully expressed classic phenotype.240 

Cholestatic Mild cholestatic laboratory or histologic changes within the context of otherwise typical AIH justify consideration of alternative diagnoses, but they do not discount the possibility of AIH. Serum alkaline phosphatase and GGTP elevations are common in AIH, albeit serum abnormalities are typically mild and responsive to glucocorticoid treatment.133-135 AMA are present in as many as 18% of patients with AIH,241 and they have been monitored in patients for as long as 27 years without evolving into PBC.242 Similarly, isolated histologic features of bile duct injury in the presence of typical histologic findings of AIH may be transient and fail to affect treatment response or long-term outcome.177,179,180 Furthermore, the parameters for cholestasis established for white North American and northern European patients with AIH may not apply to patients with AIH from other geographical regions and ethnic backgrounds.8,243-246 Alternatively, laboratory and histologic changes of a cholestatic syndrome within the predominant phenotype of AIH may indicate a variant, or “overlap,” syndrome.195,196,198 

Variant (“Overlap”) Syndromes Patients with AIH who have cholestatic laboratory findings and histologic features of bile injury or loss constitute the variant (“overlap”) syndromes of AIH, which lack an official designation and a rigorously established treatment strategy (Table 90.4).194,195,197,198 The International Autoimmune Hepatitis Group has proposed that patients with AIH and cholestatic manifestations be classified by their predominant diagnosis and not by their overlapping features.194 By this categorization, patients with AIH and cholestatic features constitute variant phenotypes of the classic disease rather than the concurrence of different diseases. Liver tissue examination is the principal diagnostic instrument,203,247 and the diagnostic scoring systems for AIH, which perform poorly in the variant syndromes, should be avoided.194,203,247

Drug-Related

Autoimmune Hepatitis with AMA and Bile Duct Injury or Loss

Nine percent of patients diagnosed with AIH have DILI (see Chapter 88), and this possibility should be excluded in all patients at presentation.192 Minocycline and nitrofurantoin are the principal drugs in current practice that can induce an acute idiosyncratic liver injury that resembles AIH, and these drugs account for 90% of cases.192,237 Most patients with drug-induced autoimmune-like hepatitis are women (80% to 90%); jaundice develops in 69%; the age at presentation is 65 years of age or older in 18%; an acute

Patients with AIH may have AMA133,241,248 and histologic features of bile duct injury or loss (see Table 90.4).249 The frequency of this syndrome is 2% in cohorts of AIH and 19% in cohorts of PBC.195,250,251 Diagnosis requires the presence of moderate to severe interface hepatitis, at least one other feature of AIH, and at least 2 of 3 features of PBC.194,252 The additional required feature of AIH is a serum ALT level at least 5 times the ULN, IgG level at least twice the ULN, or positive test for SMA. The PBC

CHAPTER 90  Autoimmune Hepatitis

1423

TABLE 90.4  Diagnostic Criteria and Therapies for Variant (“Overlap”) Syndromes of Autoimmune Hepatitis AIH Variants

Diagnostic Criteria

Empiric Treatment Regimens

AIH with AMA and bile duct injury or loss similar to PBC

AIH components: Interface hepatitis plus 1 of 2 features: ALT ≥ 5 x ULN IgG ≥ 2 x ULN or SMA present PBC components (2 of 3 features): Alk phos ≥ 2 x ULN or GGTP ≥ 5 x ULN AMA present Florid duct lesions

Combination therapy (endorsed by the EASL): Prednisone or prednisolone (30 mg daily tapered to 10 mg daily) and azathioprine (50 mg daily) plus UDCA (13-15 mg/kg daily) Individualized empiric therapies: Budesonide (9 mg daily) and azathioprine (50 mg daily) plus UDCA (13-15 mg/kg daily) Budesonide (6 mg daily) plus UDCA (10-15 mg/kg daily) Cyclosporine (3 mg/kg daily) Mycophenolate mofetil (1-3 g daily) UDCA only (13-15 mg/kg daily) Prednisone (10 mg daily) plus azathioprine (50 mg daily)

AIH with cholangiographic Typical AIH features changes of PSC AMA absent Focal bile duct strictures and dilations by cholangiography Bile duct loss or damage, portal edema, and fibrous obliterative cholangitis possible on histologic examination

Combination therapy (endorsed by the EASL, AASLD): UDCA (13-15 mg/kg daily) and prednisone or prednisolone (0.5 mg/kg daily tapered to 10-15 mg daily) plus azathioprine (50-75 mg daily) Avoid high-dose UDCA (28-30 mg/kg daily) Individualized empiric therapies: Prednisolone (20-80 mg daily, tapered to 7.5-10- mg daily) plus azathioprine (75-150 mg daily)

AIH with unexplained cholestatic features

Individualized empiric therapies: Prednisone or prednisolone (10 mg daily) and azathioprine (50 mg daily) plus UDCA (13-15 mg/kg daily) Prednisone or prednisolone (10 mg daily) plus azathioprine (50 mg daily) UDCA (13-15 mg/kg daily) Caveats: No regimens have been endorsed Treatment must be modified according to response

Typical AIH features AMA absent Normal cholangiography Bile duct injury or loss on histologic examination Probably small-duct PSC or AMA-negative PBC

AIH, autoimmune hepatitis; alk phos, serum alkaline phosphatase level; ASC, autoimmune sclerosing cholangitis; EASL, European Association for the Study of the Liver; IgG, immunoglobulin G; SMA, smooth muscle antibodies; ULN, upper limit of normal.

component must have 2 of the following features: serum alkaline phosphatase level at least twice the ULN or GGTP level at least 5 times the ULN, positive test for AMA, or histologic findings of destructive cholangitis (florid duct lesion) (see Chapter 91).249 The sensitivity and specificity of these criteria for the variant syndrome of AIH with PBC features are 92% and 97%, respectively, using clinical judgment as the gold standard.253 The recommended treatment of patients who satisfy these criteria is UDCA (13 to 15 mg/kg daily) in combination with glucocorticoids.195,196,254,255 This combination regimen has induced laboratory resolution (67% vs. 27%) and prevented progressive hepatic fibrosis (100% vs. 50%) more commonly than low-dose UDCA or prednisone alone.254 The 5-year liver transplant-free survival rate has been 100%, and the 10-year survival rate has been 92%.253 Budesonide has been used in selected cases as an alternative to prednisone with limited efficacy (see later).255 Patients who have AIH and less severe cholestatic features may fail to satisfy the promulgated criteria for the variant syndrome,194,252 and they commonly respond to standard glucocorticoid therapy.250,251 Biochemical remission is achieved in 75%, and death from liver failure or the need for LT occurs in 8%.250 

Treatment is empiric, and improvements have been reported with conventional glucocorticoid therapy (prednisone or prednisolone alone or in combination with azathioprine)258-260 and with UDCA (13 to 15 mg/kg daily) in conjunction with glucocorticoids alone or with azathioprine.257,261 Immunosuppressive therapy in combination with UDCA has been recommended by the European Association for the Study of the Liver (EASL)252 and the AASLD262 despite the absence of strong clinical evidence. High-dose therapy with UDCA (28 to 30 mg/kg daily) should be avoided because liver toxicity and hepatic failure may occur, possibly because of increased exposure to lithocholic acid (see Chapter 68).263,264 Therapy with UDCA (13 to 15 mg/kg daily) in combination with prednisone (10 mg daily) and azathioprine (50 mg daily) can improve laboratory features261 and maintain survival over a mean follow-up interval of 93 months.257 Hepatic fibrosis progresses during therapy, and cirrhosis develops in 75% during a median observation interval of 12 years.261 Patients with AIH and cholangiographic features of PSC have a lower survival rate than patients with classic AIH or AIH with features of PBC.259

Autoimmune Hepatitis with Cholangiographic Changes of PSC

Autoimmune Hepatitis with Unexplained Cholestatic Features

Patients with AIH may have focal bile duct strictures and dilatations by cholangiography that are typical of PSC, and patients with PSC may have laboratory and histologic features of AIH (see Table 90.4).196,250 The frequency of PSC in cohorts with AIH is 6% to 11%,195,196,198 and the frequency of findings consistent with AIH in cohorts with PSC is 8% to 17%.195,256,257 Children with AIH may also have unsuspected cholangiographic changes (“autoimmune sclerosing cholangitis”).220 Concurrent IBD, unexplained cholestatic laboratory or histologic findings, and failure to respond to conventional glucocorticoid therapy are justifications for MRCP or ERCP.

Eight percent of patients with AIH have histologic features of bile duct injury and laboratory changes of cholestasis in the absence of AMA and cholangiographic changes of PSC (see Table 90.4).178,250 This variant form probably encompasses patients with AMA-negative PBC265-267 and small-duct PSC.260,268-270 Patients with this cholestatic variant are inconsistently responsive to glucocorticoids, UDCA or glucocorticoids in combination with UDCA,178,250,271 and a standard management regimen has not been endorsed. Patients with AIH and findings compatible with AMA-negative PBC have a lower frequency of liver failure (19% vs. 50%) and higher rate of laboratory resolution (90% vs.

90

1424

PART IX  Liver

50%) during treatment with UDCA and glucocorticoids than patients with AIH and AMA.272 Empiric combination therapy with UDCA and glucocorticoids can be considered as the initial regimen with modifications introduced according to the response and tolerance. 

Autoimmune Hepatitis with Liver-infiltrating Immunoglobulin G4-staining Plasma Cells Plasma cells that stain for immunoglobulin G4 (IgG4) may infiltrate the liver in 3% to 35% of patients with AIH and justify the designation of IgG4-associated AIH.273-275 Stringent criteria for this diagnosis requires a definite diagnosis of AIH by international criteria, greater than or equal to 10 IgG4-staining plasma cells per high power field, and a serum IgG4 level greater than or equal to 135 mg/dL.274,276 These criteria are satisfied in only 3.3% of patients with AIH.274 IgG4-associated AIH is within the spectrum of IgG4-related diseases that includes autoimmune pancreatitis and IgG4-associated cholangitis (see Chapters 59 and 68),277 and its presence justifies the assessment of the pancreas and biliary system for dense lymphoplasmacytic infiltrations that may enlarge the pancreas or narrow the bile ducts. Liver injury is recognized in 60% to 70% of patients with autoimmune pancreatitis, and the associated IgG4-hepatopathy must be distinguished from IgG4-associated AIH.278 IgG4-staining plasma cells near the portal vein, portal inflammation, portal sclerosis, bile duct damage, lobular hepatitis, and cholestasis characterize IgG4-hepatopathy,278 and prominent IgG4-staining plasma cells in conjunction with otherwise typical features of AIH characterize IgG4-associated AIH.274,276 The serum IgG4 level is commonly, but not invariably, increased in IgG4-associated AIH, 275 and the increased serum IgG4 level may be accompanied by an increased serum IgE concentration.274 These findings have suggested that the disease may be triggered by antigens that generate an allergic respo nse.274,279,280 IgG4-associated AIH is distinguished from typical AIH by its uniform responsiveness to conventional glucocorticoid

therapy,273-275 absence of relapse after drug withdrawal,275 and possible late consequences of autoimmune pancreatitis281 or IgG4-associated cholangitis.274 IgG4-associated AIH has developed de novo after LT.282 

TREATMENT Indications All patients with AIH are candidates for treatment (Table 90.5).20,109,110,172,221 Fragile patients, especially older adults and pregnant women, require individualized treatment regimens with close monitoring,211,283-287 and asymptomatic patients with mild disease may be observed initially to document disease behavior.110,172,288,289 Untreated patients with mild AIH who become symptomatic or who manifest persistent or increasing laboratory findings of liver inflammation during a well-monitored observation period warrant therapy. Only the absence of laboratory or histologic findings of disease activity is a justification for withholding treatment.110,172 

Regimens Prednisone or prednisolone in combination with azathioprine is the preferred treatment regimen (Fig. 90.5).20,110,172 An induction phase lasting at least 4 weeks introduces the medication. The dose of prednisone or prednisolone is reduced during this phase in a gradual fashion until a maintenance level is achieved. The maintenance phase continues until a treatment endpoint is reached. Within the maintenance phase, doses of medication may be modified according to assessments of disease response and patient tolerance.289,290 Different schedules have been end­ orsed,20,110,172 and surveys have indicated the lack of a uniform practice.291 Head-to-head comparisons between the various endorsed regimens have not been performed, and the recommendations proposed with each new guideline have been based mainly on weak clinical evidence.292,293

TABLE 90.5  First-line Treatment Regimens Endorsed by AASLD, BSG, and EASL AASLD-Endorsed Combination Regimen

AASLD-Endorsed Monotherapy Regimen

BSG/EASL-Endorsed Combination Regimen

Induction phase × 4 wk: Prednisone or prednisolone: 30 mg daily × 1 wk 20 mg daily × 1 wk 15 mg daily × 2 wk Azathioprine: 50 mg daily

Induction phase × 4 wk: Prednisone or prednisolone: 60 mg daily × 1 wk 40 mg daily × 1 wk 30 mg daily × 2 wk

Induction phase × 10 wk: Prednisolone: 0.5-1 mg/kg daily (e.g., patient weighing 60 kg) 60 mg daily × 1 wk 50 mg daily × 1 wk 40 mg daily × 1 wk 30 mg daily × 1 wk 25 mg daily × 1 wk 20 mg daily × 1 wk 15 mg daily × 2 wk 12.5 mg daily × 2 wk Azathioprine: 1-2 mg/kg daily started 2 wk after prednisolone 50 mg daily × 2 wk 100 mg daily thereafter

Maintenance phase: Prednisone or prednisolone: 10 mg daily Azathioprine: 50 mg daily Doses may be adjusted to response and tolerance

Maintenance phase: Prednisone or prednisolone: 20 mg daily Doses may be adjusted to response and tolerance

Maintenance phase: Prednisolone: 10 mg daily Azathioprine: 100 mg daily Doses may be adjusted to response and tolerance

Preferred in all patients with thiopurine Preferred in patients with severe cytopenia, absent methyltransferase activity and azathioprine thiopurine methyltransferase activity, azathioprine tolerance, especially those with obesity, diabetes intolerance, or reluctance to use during pregnancy mellitus, osteopenia, or emotional instability BSG, British Society of Gastroenterology; EASL, European Association for the Study of the Liver.

Preferred in all patients with thiopurine methyltransferase activity and azathioprine tolerance

CHAPTER 90  Autoimmune Hepatitis

1425

First-line treatment

90

Remission

Treatment failure

Incomplete response

Drug intolerance

No symptoms Normal liver enzymes Normal liver tissue

Worsening liver tests Worsening clinical status Worsening liver tissue

Improvement but no laboratory resolution within 6 mo

Intolerable obesity Vertebral compression Intractable nausea Severe cytopenia 1

Discontinuation of therapy

High-dose glucocorticoid therapy

Second-line treatment (see Fig. 90.6)

Dose reduction or drug withdrawal 2

Sustained remission

Relapse

Stable liver function

Worsening liver enzymes and clinical status 1

1 Azathioprine (2 mg/kg daily)

Chronic maintenance therapy

3

Second-line treatment (see Fig. 90.6)

2 Low-dose prednisone (≥10 mg daily)

Continuation of tolerated medication in adjusted dose

Second-line treatment (see Fig. 90.6)

2 LT

Fig. 90.5  Management algorithm for autoimmune hepatitis depending on outcome of first-line regimens.  First-line treatment is continued until the criteria for remission, treatment failure, incomplete response, and drug intolerance are met (light purple boxes). Therapy can then be discontinued, increased in dose, or reduced in dose according to the response (light blue boxes). Responses (tan boxes) to the dose adjustments or drug discontinuation determine the need for other second-line therapies (light green boxes). The bold numbers within the algorithm indicate the recommended sequence of treatments.

Prednisone (30 mg daily tapered over a 4-week induction period to 10 mg daily) in combination with azathioprine (50 mg daily) is the regimen endorsed by the AASLD (see Table 90.5).20 Therapy with prednisone alone (60 mg daily tapered over a 4-week induction period to 20 mg daily) is as effective as the combination regimen but is associated with more glucocorticoid-induced side effects (44% vs. 10%).294-296 Monotherapy with prednisone or prednisolone is warranted mainly in patients with severe cytopenia (leukocyte count 6

Total Numerical Score

Child-Pugh Class

5-6 

A

7-9

B

10-15

C

The probability of mortality following TIPS placement can be calculated with use of an online formula (https://www. mayoclinic.org/medical-professionals/model-end-stage-liverdisease/probability-mortality-following-transjugular-intrahepatic-portosystemic-shunts). Patients with a MELD score of 14 or less have an excellent survival rate after TIPS placement; therefore, TIPS may be carried out routinely in such patients when indicated (see earlier). Patients with a MELD score higher than 24 have reduced survival following TIPS placement, with a mortality rate approaching 30% at 3 months. This high risk should be discussed with the patient before the procedure is undertaken. In the intermediate group with a MELD score ranging from 15 to 24, TIPS placement can be carried out depending on the patient’s preference, physician’s judgment, and likelihood of LT in the future. This approach has been validated independently.198 The predictive accuracy of the MELD-Na score (see Chapter 97) has not been well studied in patients undergoing TIPS placement but is likely to be greater than that of the conventional MELD score in patients with a low MELD score and hyponatremia in whom a TIPS is placed for refractory ascites. 

Balloon-Occluded Retrograde Transvenous Obliteration Balloon-occluded retrograde transvenous obliteration (BRTO) of varices may be used to occlude gastric varices when a large splenorenal shunt is seen on abdominal cross-sectional imaging. The left renal vein is approached via the femoral vein, and the splenorenal shunt is then catheterized. Other approaches are via an existing TIPS or via a transjugular approach to the splenic vein. Following occlusion of the shunt with a balloon, the gastric varices are embolized with coils. Although ascites and splenomegaly can be aggravated following this procedure, these complications are easily managed.199 The long-term durability of the occlusion is uncertain. BRTO has been used for both the prevention and control of gastric variceal bleeding. 

Surgical Therapy Surgical treatment of portal hypertension falls into 3 groups: non-shunt procedures, portosystemic shunt procedures, and LT. Surgical procedures (other than LT) are used as salvage therapy when standard management with pharmacologic and endoscopic therapy fails in patients with noncirrhotic causes of portal hypertension and in patients with Child-Pugh class A cirrhosis. Surgical treatment also may be considered early in the course of portal hypertension in patients who live at a great distance from centers that can manage variceal bleeding adequately or in whom

CHAPTER 92  Portal Hypertension and Variceal Bleeding

1461

92 Short gastric v.

Coronary v. Portal v. R. gastric v.

L. gastroepiploic v. Fig. 92.12  Distal splenorenal shunt. The anatomy following completion of a distal splenorenal shunt is depicted. For this procedure, the splenic vein (v.) is disconnected from the superior mesenteric vein and is separated from the pancreas; all its collaterals are ligated. The portal system is thus disconnected from the azygos system so that all flow from the gastroesophageal junction is through the short gastric veins into the splenic vein. The splenic vein is then anastomosed to the left renal vein in an end-toside fashion. L., left; R., right.

Superior mesenteric v. L. renal v.

Splenic v.

the cross-matching of blood products (in case of bleeding) is difficult. How failure of standard therapy is defined depends on the specific circumstances of the patient’s presentation, availability of surgical expertise, and outcome of conservative management. LT should be considered in all patients with cirrhosis and variceal bleeding (see Chapter 97).

devascularization of the upper two thirds of the lesser curve of the stomach and circumferential devascularization of the lower 7.5 cm of the esophagus. The rate of recurrent bleeding following this procedure is variable but may be as high as 40%, depending on the population being treated and duration of follow-up.

Non-Shunt Procedures

Portosystemic Shunts

Non-shunt procedures include esophageal transection and gastroesophageal devascularization. They are performed infrequently but may be required in selected cases.

With the increasing availability of TIPS, the use of surgical shunts for refractory variceal bleeding has declined markedly. In children, surgical shunts are carried out almost exclusively for refractory bleeding due to noncirrhotic portal hypertension, such as congenital hepatic fibrosis and portal vein thrombosis.126 Surgical portosystemic shunts are categorized as selective shunts such as a distal splenorenal shunt, partial shunts such as a side-to-side calibrated portacaval shunt, and total portosystemic shunts such as a side-toside portacaval shunt or end-to-side portacaval shunt.

Esophageal Transection Esophageal transection, in which the esophagus is stapled and transected, was highly effective in controlling variceal bleeding and was associated with a lower risk of encephalopathy than that for portosystemic shunts. Esophageal transection was considered in the past when 2 sessions of endoscopic therapy had failed to control variceal bleeding within a 24-hour period.79 Mortality rates are not improved over those observed with endoscopic sclerotherapy, however. With the advent of TIPS, esophageal transection is no longer recommended.  Devascularization Procedures Devascularization procedures typically have been used to prevent recurrent variceal bleeding in patients with extensive splenic and portal vein thrombosis when a suitable vein is not available for creation of a portosystemic shunt.200 In the original operation described by Sugiura and Futagawa, both a thoracotomy and a laparotomy were carried out.201 The operation is now carried out through an abdominal approach and combined with a splenectomy. The procedure consists of total devascularization of the greater curve of the stomach combined with

Selective Shunts The most widely used selective shunt is the distal splenorenal shunt, originally described by Warren and colleagues.202 With this shunt, only varices at the gastroesophageal junction and spleen are decompressed, and portal hypertension is maintained in the superior mesenteric vein and portal vein; therefore, variceal bleeding is controlled, but the risk of ascites persists. The shunt procedure involves a portal-azygos disconnection and subsequent anastomosis between the splenic vein and left renal vein in an end-to-side fashion (Fig. 92.12). The entire length of the pancreas must be mobilized, and the left adrenal vein must be ligated. The distal splenorenal shunt has been associated with control of variceal bleeding in approximately 90% of patients and a lower rate of hepatic encephalopathy than that reported for total shunts.203 

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PART IX  Liver

Partial Portosystemic Shunts A partial portosystemic shunt is carried out using a synthetic interposition graft between the portal vein and the inferior vena cava. When the shunt diameter is 8 mm, portal pressure is reduced below 12 mm Hg, and antegrade flow to the liver is maintained in most patients.204 Rates of preventing variceal rebleeding and encephalopathy following this shunt are similar to those seen with a distal splenorenal shunt. As in patients who have had a distal splenorenal shunt, ascites may occur in approximately 20% of patients who have had a partial portosystemic shunt, because hepatic sinusoidal pressure is not reduced.205,206  Portacaval Shunts End-to-side and side-to-side portacaval shunts have been described, but only the side-to-side portacaval shunt is in current use.207 Any portacaval shunt that is greater than 12 mm in diameter is likely to result in a total shunting of portal blood. A shunt with a diameter less than 12 mm is created with an interposition graft, or alternatively a direct vein-to-vein anastomosis may be constructed. Variceal bleeding, as well as ascites, is well controlled because the hepatic sinusoids are decompressed. Variceal rebleeding following a total shunt is seen in less than 10% of patients, but hepatic encephalopathy occurs in 30% to 40% of patients.98 LT in patients who have had a portacaval shunt is associated with increased operative morbidity and intraoperative transfusion requirements. The outcome of LT is not otherwise significantly different, however, from that for patients who have not had a portacaval shunt. Nevertheless, surgical portacaval shunts should be avoided in patients who are potential candidates for LT. Mesenterico–Left Portal Venous Bypass The mesenterico–left portal venous bypass, or Rex shunt, is carried out in patients with extrahepatic portal vein thrombosis if the intrahepatic portion of the left portal vein is patent. With this procedure, portal blood flow is restored to the liver, thereby reducing the risk of hepatic encephalopathy or longterm learning disability in children. A jugular vein graft may be used to bridge the superior mesenteric vein to the intrahepatic portion of the left portal vein in the Rex recessus. (The Rex recessus is the location where the left portal vein divides to supply segments III and IV of the liver.) This surgery is the treatment of choice in children with extrahepatic portal vein thrombosis who have complications related to portal hypertension and in adults in whom portal vein thrombosis has developed late after LT.126 Because of limited data on the efficacy of endoscopic or pharmacologic therapy in children, the Rex bypass is also recommended for primary and secondary prophylaxis of variceal bleeding in patients with extrahepatic portal vein obstruction if surgical expertise is available.208

MANAGEMENT OF SPECIFIC CAUSES OF PORTAL HYPERTENSION-RELATED BLEEDING Esophageal Varices Natural History Esophageal varices are present in approximately 40% of patients with cirrhosis and in as many as 60% of patients with cirrhosis and ascites.98 In cirrhotic patients who do not have esophageal varices at initial endoscopy, new varices will develop at a rate of approximately 5% per year. In patients with small varices at initial endoscopy, progression to large varices occurs at a rate of about 10% per year and is related predominantly to the degree of liver dysfunction.209 On the other hand, improvement in liver function in patients with alcohol-associated liver disease who abstain from

alcohol is associated with a decreased risk, and sometimes even disappearance, of varices.210 Up to 25% of patients with newly diagnosed varices will experience variceal bleeding within 2 years.209 The best clinical predictor of bleeding appears to be variceal size. The risk of bleeding in patients with varices less than 5 mm in diameter is 7% by 2 years, and the risk in patients with varices greater than 5 mm in diameter is 30% by 2 years.209 Even more important, however, is the HVPG, because the risk of bleeding is virtually absent when the HVPG is below 12 mm Hg.88 Nevertheless, measurement of HVPG to assess bleeding risk is not routinely performed in clinical practice. Initial treatment is associated with cessation of bleeding in approximately 80% to 90% of patients.209,211 Approximately half of patients with a variceal bleed stop bleeding spontaneously because hypovolemia leads to splanchnic vasoconstriction, which results in a decrease in portal pressure. Excessive transfusions may, in fact, increase the chance of rebleeding.212 Active bleeding at endoscopy, a lower initial hematocrit value, higher serum aminotransferase levels, higher Child-Pugh class, bacterial infection, an HVPG above 20 mm Hg, and portal vein thrombosis are associated with failure to control bleeding at 5 days.211,213-215 Of patients who have stopped bleeding, approximately one third will rebleed within the next 6 weeks. Of all rebleeding episodes, approximately 40% will take place within 5 days of the initial bleed.216 Predictors of rebleeding include active bleeding at emergency endoscopy, bleeding from gastric varices, hypoalbuminemia, renal insufficiency, and an HVPG greater than 20 mm Hg.209 The risk of death associated with acute variceal bleeding is 5% to 8% at 1 week and about 20% at 6 weeks.209 Patients who rebleed early, have a MELD score over 18, require more than 4 units of packed RBC transfusions,217 and in whom renal failure develops have the highest risk of death. Alcohol as the cause of cirrhosis, a higher serum bilirubin level, a lower serum albumin level, hepatic encephalopathy, and HCC are additional factors associated with an increased 6-week mortality rate. Treatment of esophageal variceal bleeding is classified as either primary prophylaxis (i.e., prevention of variceal hemorrhage in patients who have never bled), control of acute variceal bleeding, or secondary prevention of rebleeding in patients who have survived an initial bleeding episode. Effective treatments to prevent the development of varices and ascites in patients with cirrhosis are not yet available, although beta blockers may slow enlargement of small varices into large varices. 

Prevention of Bleeding Pharmacologic The utility of pre-primary prophylaxis—that is, the efficacy of beta blockers to prevent the formation of varices—has not been demonstrated.79,218 Patients with Child-Pugh class C cirrhosis who have small varices may be considered for treatment with a beta blocker. All patients with large varices (diameter >5 mm) should be considered for prophylactic therapy (primary prophylaxis) to prevent variceal bleeding. The presence of additional endoscopic signs such as red wales does not influence the decision regarding prophylactic therapy. The absolute risk reduction with beta blockers is approximately 10%, and the number needed to treat to prevent 1 variceal bleed is approximately 10 patients. The mortality rate is reduced from 28.4% in control patients to 23.9% in patients taking a beta blocker; the absolute risk reduction is 4.5%. The number of patients needed to be treated to prevent 1 death is approximately 22. In patients who do not bleed during therapy and who do not experience side effects, treatment should be continued indefinitely because withdrawal of a beta blocker can result in an increased risk of bleeding.219,220 Patients who have an initial bleed while on a beta

CHAPTER 92  Portal Hypertension and Variceal Bleeding

EGD

No varices

Large esophageal varices

Small esophageal varices

Repeat EGD in 2-3 yr

Consider HVPG measurement

Repeat EGD in 1-2 yr

Nonselective β-adrenergic blocking agent

Consider HVPG remeasurement

Contraindication to β-adrenergic blocking agents Intolerance to β-adrenergic blocking agents Target HVPG not reached Patient preference

Perform EVL Fig. 92.13  Algorithm for the primary prophylaxis of esophageal variceal bleeding in patients with cirrhosis. The hepatic vein pressure gradient (HVPG) may be measured in patients with large varices before a nonselective β-adrenergic blocking agent (beta blocker) is started and may be remeasured 1 month after the maximum tolerated dose of the beta blocker is reached. The goal of treatment is to reduce the HVPG to 18 and requirement for transfusion of > 4 units of RBCs), TIPS carried out within 72 hours of the control of bleeding is associated with reduced rates of mortality and treatment failure.187 Emergency surgical portosystemic shunts, although extremely effective in controlling variceal bleeding, have been abandoned because of high mortality rates. Esophageal stents may be used to stabilize a patient until definitive treatment can be carried out; balloon tamponade may be carried out only if esophageal stents are not available. 

Prevention of Rebleeding All patients who have had a variceal bleed should receive prophylactic therapy (secondary prophylaxis) to reduce the risk of rebleeding, which otherwise occurs in up to 80% of patients at 2 years. A MELD score at time of bleeding less than 11 is associated with a 5% risk of 6-week mortality, whereas a MELD score greater than 20 is associated with 20% mortality risk.238,239 Patients with cirrhosis should therefore be evaluated for LT (see Chapter 97). Options for preventing variceal rebleeding are pharmacologic therapy, endoscopic therapy, and a portosystemic shunt (surgical or radiologic) or combinations of these therapies. Combined therapy with endoscopic variceal ligation and a nonselective beta blocker is the preferred initial option, and long-acting propranolol or nadolol may be used. Ideally, the hemodynamic response to a beta blocker should be monitored, with the goal of reducing the HVPG by greater than 20% or to less than 12 mm Hg. If these goals are not achieved, isosorbide mononitrate may be added. The extended-release form of isosorbide mononitrate is preferred, with an initial starting dose of 30 mg/day. Unfortunately, hypotension and headaches are common and require discontinuation of isosorbide mononitrate. The beneficial effect of long-term pharmacologic therapy in patients with alcohol-associated cirrhosis is largely restricted to patients who remain abstinent.240 Endoscopic variceal ligation alone may be performed to prevent variceal rebleeding in patients who have poor liver function and may not tolerate a beta blocker (Fig. 92.16). In practice, the first endoscopic session is carried out 7 to 14 days after the initial variceal ligation to control bleeding. One-week ligation intervals may lead to more rapid eradication of varices than 2-week intervals but without a reduced risk of bleeding.241 If the HVPG is monitored, a reduction in HVPG to less than 12 mm Hg or by greater than 20% should obviate the need for variceal ligation. For patients who bleed during pharmacologic treatment, variceal ligation should be carried out. Conversely, for patients who have undergone variceal ligation alone and experience recurrent bleeding, a beta blocker should be started, although in patients with a noncirrhotic cause of portal hypertension the addition of propranolol and isosorbide

1465

mononitrate to endoscopic variceal ligation may not reduce the risk of bleeding compared with variceal ligation alone.242 Compared with a beta blocker alone, variceal ligation plus a beta blocker reduces the risk of rebleeding in Child-Pugh class A but not Child-Pugh class B or C patients. Mortality is not reduced in either group. However, when compared with variceal ligation alone, the combination of a beta blocker and variceal ligation reduces the risk of rebleeding in all patients with cirrhosis and reduces mortality in those with Child-Pugh class B and C cirrhosis.243 These results have not been confirmed in the USA. Patients who have variceal rebleeding despite optimal pharmacologic and endoscopic treatment require a portosystemic shunt. Even in patients with Child-Pugh class A cirrhosis, a TIPS may be as effective as a distal splenorenal shunt, and the choice of therapy depends on local expertise.244 

Gastric Varices The most widely used classification of gastric varices is the Sarin classification.245 According to this classification, type 1 gastroesophageal varices (GOV1) extend 2 to 5 cm below the gastroesophageal junction and are in continuity with esophageal varices; type 2 gastroesophageal varices (GOV2) are in the cardia and fundus of the stomach and in continuity with esophageal varices; varices that occur in the fundus of the stomach in the absence of esophageal varices are called isolated gastric varices type 1 (IGV1), whereas varices that occur in the gastric body, antrum, or pylorus are called isolated gastric varices type 2 (IGV2). Approximately 25% of patients with portal hypertension have gastric varices, most commonly GOV1, which comprise approximately 70% of all gastric varices. Intrahepatic causes of portal hypertension may be associated with both GOV1 and GOV2. Splenic vein thrombosis usually results in IGV1, but the most common cause of fundal gastric varices may be cirrhosis.

Natural History Gastric varices typically occur in association with advanced portal hypertension. Bleeding is thought to be more common in patients with GOV2 and IGV1 than in those with other types of gastric varices; in other words, bleeding is more common from fundal varices than from varices at the gastroesophageal junction. Whereas intraesophageal pressure is negative, intra-abdominal pressure is positive, and the transmural pressure gradient across gastric varices is lower than that across esophageal varices. Gastric varices, however, tend to be larger in diameter than esophageal varices. Gastric varices are supported by gastric mucosa, whereas esophageal varices tend to be unsupported in the lower third of the esophagus. Therefore, gastric varices are likely to bleed only when they are

-Adrenergic blocking agent + EVL

Yes

Yes TIPS

Recurrent bleeding

Patient adherent to -adrenergic blocking agent + EVL

No

No

Continue -adrenergic blocking agent + EVL to obliteration

Add -adrenergic blocking agent or EVL, as required

Fig. 92.16  Algorithm for the prevention of recurrent esophageal variceal bleeding (secondary prophylaxis). EVL, endoscopic variceal ligation.

92

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PART IX  Liver

Acute bleeding from gastric varices Resuscitation Vasoactive agent (e.g., octreotide) Antibiotic (e.g., ciprofloxacin) Transfusion to hematocrit value of 24%

A

B

Yes

Endoscopic therapy possible?

Bleeding controlled

No

Cyanoacrylate available? Yes

Prevention of Bleeding Unfortunately, there is a paucity of studies that have evaluated pharmacologic or endoscopic treatment for primary prophylaxis of gastric variceal hemorrhage, and recommendations are still based primarily on the guidelines for managing esophageal varices. Large gastric varices (>20 mm diameter), especially in patients with a MELD score above 17, are most likely to bleed. Because these gastric varices usually are associated with esophageal varices, pharmacologic treatment with a nonselective beta blocker may be initiated to prevent variceal hemorrhage. Cyanoacrylate glue injection may be more effective than beta blocker therapy in preventing gastric variceal bleeding246 but is not currently recommended until confirmed by larger studies. TIPS is also not recommended for the primary prevention of gastric variceal bleeding. BRTO has been used in uncontrolled studies to prevent bleeding from gastric varices, with some success. 

Control of Acute Bleeding The approach to treating esophageal variceal hemorrhage also applies to acute gastric variceal hemorrhage and includes volume resuscitation, avoidance of overtransfusion, and antibiotic prophylaxis with norfloxacin, 400 mg twice daily, or ciprofloxacin, 500 mg twice daily, for 7 days. EGD is carried out after patients have been volume resuscitated and stabilized and often following endotracheal intubation to protect the airway. The endoscopic diagnosis of gastric variceal bleeding may be difficult because of pooling of blood in the fundus. A diagnosis of gastric variceal hemorrhage should be considered if bleeding is noted from a gastric varix (Fig. 92.17); blood is found to appear at the gastroesophageal junction or the gastric fundus; blood is found in the stomach and gastric varices with a “white nipple sign” (indicating a fibrin-platelet plug) are seen in the absence of other causes of bleeding; or gastric varices are noted in the absence of other lesions in the esophagus and stomach.249

TIPS

Yes

Fig. 92.17  Gastric variceal bleeding. A, Active bleeding from a gastric varix (arrowhead) can be seen. B, Bleeding from the varix (straight arrow) is controlled following injection of sodium tetradecyl sulfate. Pooling of blood in the stomach is indicated by the curved arrow.

large, as demonstrated in a study in which larger gastric varices (>20 mm in diameter) in patients with a MELD score above 17 were more likely than smaller ones to bleed.246 Although gastric varices have been thought to bleed less frequently than esophageal varices, the bleeding rates probably are comparable if patients are matched for the severity of cirrhosis (Child-Turcotte-Pugh score).245 In contrast with esophageal varices, bleeding from gastric varices has been described with an HVPG less than 12 mm Hg.247,248 Gastric varices in continuity with esophageal varices may regress following treatment of the esophageal varices. When gastric varices persist despite obliteration of esophageal varices, the prognosis is poorer, probably because of the severity of liver disease. 

No

Consider obliteration of varices

No TIPS

Fig. 92.18  Algorithm for the management of bleeding gastric varices in patients with portal hypertension.

Because controlled studies evaluating pharmacologic therapy for gastric variceal bleeding are lacking, the agents used are based on extension of the data relating to esophageal varices. Medical management with vasoactive agents should be started as early as possible, preferably at least 30 minutes before endoscopic therapy is carried out. The preferred endoscopic therapy for fundal gastric variceal bleeding is injection of polymers of cyanoacrylate, usually N-butyl-2-cyanoacrylate,250,251 but these tissue adhesives are not currently available in the USA. Obliteration of the varices occurs when the injected cyanoacrylate adhesive hardens on contact with blood. The endoscope may be damaged by the glue, but the risk is minimized if silicone gel is used to cover the tip of the instrument and suction is avoided for 15 to 20 seconds following injection.252 The mucosa overlying the varix injected eventually sloughs, and the hardened polymer is extruded. Fortunately, the resulting ulcers occur late, and the risk of bleeding is lower than that associated with sclerotherapy-related ulcers. Cyanoacrylate injection has been found to be superior to both variceal band ligation and sclerotherapy using alcohol.251 Complications of cyanoacrylate injection include bacteremia and variceal ulceration. Pulmonary and cerebral emboli have been reported on occasion, usually in patients with spontaneous large portosystemic or intrapulmonary shunts. Embolization probably occurs via spontaneous splenorenal shunts. Therefore, a combined approach using interventional radiology to occlude the shunt and endoscopic variceal glue injection is probably a safer strategy.253 For injection of GOV2 or IGV1, a retroflexed endoscopic approach is recommended. Sclerosants such as sodium tetradecyl sulfate, ethanolamine oleate, and sodium morrhuate are not particularly effective for control of gastric variceal bleeding.254 When sclerotherapy is carried out for gastric varices, the volume of sclerosant required is larger than that used for esophageal varices, and fever and retrosternal pain are more common. It is much easier to obliterate GOV1 than GOV2 or IGV1. IGV1 are the most difficult gastric varices to obliterate and, when present, should prompt early consideration of definitive treatment such as portosystemic shunting if cyanoacrylate is not available. Although some investigators recommend ligation of gastric varices up to 20 mm in diameter,255 this recommendation is not supported by our experience. Band ligation of varices greater than 10 mm in diameter is usually unsafe. Ligation is safest if the varices are in the cardia of the stomach. Because gastric fundal varices

CHAPTER 92  Portal Hypertension and Variceal Bleeding

1467

are covered by mucosa, drawing the entire varix into the ligation device is often not possible. Application of bands results in creation of a large ulcer on the varix, sometimes with disastrous results (see Fig. 92.10). If endoscopic and pharmacologic therapies fail to control gastric variceal bleeding, then a Linton-Nachlas tube may be passed as a temporizing measure. Most patients in whom endoscopic and pharmacologic treatment fails to control gastric variceal bleeding will require a TIPS, which can control bleeding in greater than 90% of patients—a rate of efficacy equivalent to that for TIPS in controlling esophageal variceal bleeding (Fig. 92.18).189,256 

92

Prevention of Rebleeding Cyanoacrylate glue injection may be superior to nonselective beta blockers in preventing gastric variceal rebleeding.257 In a small study, the 2-octyl-cyanoacrylate polymer (Dermabond) has been used to prevent gastric variceal rebleeding, with excellent results.258 Patients require an average of 2 or 3 sessions for obturation of gastric varices with cyanoacrylate polymers. Detachable snares or BRTO may also be carried out to prevent gastric variceal bleeding. Limited data are available regarding use of surgical portosystemic shunts for the treatment of gastric varices in patients with cirrhosis. Two studies performed in patients with good liver function, most of whom had extrahepatic portal vein thrombosis, demonstrated excellent results, with a low long-term risk of bleeding and encephalopathy, after creation of a surgical shunt.259,260 TIPS is also effective in preventing gastric variceal rebleeding. Because TIPS for this indication does not always result in a decrease in the size of gastric varices,261 the target HVPG is uncertain in these patients.248 Patients with an HVPG less than 12 mm Hg after TIPS are protected from esophageal variceal bleeding but have been known to bleed from gastric varices. Therefore, if the HVPG is reduced to a level below 12 mm Hg but gastric fundal varices are still prominent when contrast is injected into the portal vein (especially if the patient has bled from gastric fundal varices), the gastric varices may be embolized.

Ectopic Varices Varices that occur at a site other than the esophagus and stomach are termed ectopic varices and account for less than 5% of all varixrelated bleeding episodes. Ectopic varices most commonly manifest with melena or hematemesis. They also may manifest with hemobilia, hematuria, hemoperitoneum, or retroperitoneal bleeding. The duodenum is a common site of ectopic varices, and varices typically are associated with portal vein obstruction, but in the West, the usual cause of duodenal varices is cirrhosis. The common occurrence of duodenal varices in patients with portal vein obstruction probably relates to the formation of collateral vessels around the thrombosed portal vein that connect pancreaticoduodenal veins to retroduodenal veins, which drain into the inferior vena cava.262 In some of those patients with extrahepatic portal vein obstruction, varices form around the gallbladder and bile duct, giving rise to portal hypertensive cholangiopathy and biliary strictures (see Fig. 92.8). The other common site of ectopic varices is peristomal in patients with IBD and PSC who have undergone a proctocolectomy with creation of an ileostomy.263 Varices develop at the level of the mucocutaneous border of the stoma and are termed stomal varices. They are recognized by a bluish halo surrounding the stoma and by a dusky appearance and friable consistency of the stomal tissue; no obvious variceal lesions are seen. Bleeding from stomal varices is readily apparent on presentation. Anorectal varices are reported in 10% to 40% of cirrhotic patients who undergo colonoscopy and must be distinguished from

Fig. 92.19  Endoscopic image of a colonic varix (arrow).

hemorrhoids (Fig. 92.19). Rectal varices are dilated superior and middle hemorrhoidal veins, whereas hemorrhoids are dilated vascular channels above the dentate line. Rectal varices collapse with digital pressure, but hemorrhoids do not. Ectopic variceal bleeding should be considered in all patients with portal hypertension and overt GI bleeding without an obvious bleeding source on endoscopy or a drop in the Hgb level associated with abdominal pain and increasing abdominal girth. CT of the abdomen demonstrates layering of free fluid in the peritoneal cavity in patients who have intraabdominal hemorrhage, typical of fresh blood mixed with ascitic fluid. The diagnosis of intra-abdominal hemorrhage secondary to ectopic variceal bleeding is confirmed by a paracentesis that yields bloody ascitic fluid with clots.

Treatment In patients suspected of having ectopic variceal bleeding, vasoactive drugs may be administered initially to control the bleeding. If the bleeding ectopic varix is visualized at endoscopy, as typically is the case with duodenal or colonic varices, then endoscopic therapy can be carried out.264 Endoscopic glue injection or band ligation is the preferred approach for bleeding duodenal varices. Colonic varices tend to be larger in diameter and may require application of hemostatic clips. Patients with bleeding stomal varices can be trained to compress the site locally if bleeding is obvious. Because bleeding from stomal varices is visible and detected early, the mortality rate for bleeding stomal varices is low.265 Percutaneous sclerotherapy of the stomal varices may be carried out under US guidance. At present, no recommendations support primary prophylaxis to prevent bleeding from ectopic varices. To prevent rebleeding from ectopic varices, pharmacologic treatment with a beta blocker is usually tried, although no studies are available to support this approach. If the portal vein is patent, then transhepatic embolization of stomal varices can be carried out (Fig. 92.20). Embolization of varices using a transhepatic approach can control bleeding in most patients with stomal varices. The rate of rebleeding is high, however, because portal hypertension persists. In patients in whom embolization fails to prevent rebleeding, TIPS placement may be considered.266 A surgical portosystemic shunt is recommended in patients with portal hypertension from extrahepatic portal vein thrombosis in which a vein suitable for a shunt is available and TIPS is not feasible. In the rare situations that a surgical shunt is considered for treatment of stomal varices, only a nonselective portosystemic

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PART IX  Liver

Acute bleeding from ectopic varices Resuscitation Vasoactive agent (e.g., octreotide) Antibiotic (e.g., ciprofloxacin) Transfusion to hematocrit value of 24% Yes

Endoscopic therapy possible?

No

Bleeding successfully controlled

Fig. 92.22  Endoscopic images of severe GAVE (“watermelon stomach”). Yes

Start -adrenergic blocking agent

No

Yes

Patent portal vein?

Transhepatic embolization of varices Yes

Bleeding controlled

shunt, such as a portacaval shunt, mesocaval shunt, or proximal splenorenal shunt, should be carried out. Patients with ectopic varices who present with intraperitoneal hemorrhage have a poor outcome because the diagnosis usually is not considered and is often made at laparotomy. Acute bleeding may be controlled by transhepatic obliteration or surgical ligation of the varices. In patients who are critically ill, a TIPS should be placed, followed by embolization of the bleeding varix. 

No

Surgical ligation of varices No

Start -adrenergic blocking agent

Start -adrenergic blocking agent Portal vein obstruction or Child-Pugh class A

Child-Pugh class B or C

Surgical nonselective portosystemic shunt

TIPS

Fig. 92.20  Algorithm for the management of bleeding from ectopic varices in patients with portal hypertension.

A

Portal Hypertensive Gastropathy and Gastric Vascular Ectasia Mucosal changes in the stomach in patients with portal hypertension include PHG and gastric vascular ectasia (GVE). In all likelihood, these lesions are distinct, as demonstrated by histologic features and differences in the response to a TIPS. An appearance in the colon analogous to PHG is termed portal hypertensive colopathy (see Chapter 38). The diagnosis of PHG is based on the presence of a characteristic mosaic-like pattern of the gastric mucosa on endoscopic examination. This pattern is characterized by small polygonal areas with a depressed border. Superimposed on this mosaiclike pattern may be red point lesions that are usually greater than 2 mm in diameter. PHG is considered mild when only a mosaic-like pattern is present and severe when superimposed discrete red spots are also seen (Fig. 92.21).267 The cause and

B

Fig. 92.21  Endoscopic views of portal hypertensive gastropathy (PHG). A, Mild PHG is characterized by a mosaic appearance without red color signs. B, Severe PHG is characterized by superimposed red spots.

CHAPTER 92  Portal Hypertension and Variceal Bleeding

Chronic bleeding

TABLE 92.5  Comparison of Portal Hypertensive Gastropathy (PHG) and GAVE Feature

PHG

GAVE

Distribution

Proximal stomach

Distal stomach

Mosaic pattern

Present

Absent

Red color signs

Present

Present

Findings on gastric mucosal biopsy:  Thrombi Spindle cell proliferation  Fibrohyalinosis Treatment

No

−

+++

β-Adrenergic blocking agent ?APC TIPS

Endoscopic therapy ?Antrectomy ?LT

Yes No Estrogen/ progesterone therapy

APC, argon plasma coagulation.

No

Iron replacement

Continue iron, β-adrenergic blocking agent; transfusions as required

Yes

Continue therapy

No

Yes

?Antrectomy

Consider LT

β-Adrenergic blocking agent

Patient transfusion dependent?

Bleeding Yes controlled

Is patient a liver transplant candidate?

Chronic bleeding

No

Hemoglobin level stable

GAVE localized Platelet count 45,000/mm3 INR 1.4

+++ ++

Bleeding controlled?

92

Iron replacement

− +

No

1469

Yes

Continue iron replacement Endoscopic thermoablative therapy or cryotherapy No

Bleeding controlled Yes

Continue iron, transfusions as required. Endosopic therapy, as required.

Fig. 92.24  Algorithm for the management of chronic bleeding from GAVE. Yes Continue β-adrenergic blocking agent

TIPS

Fig. 92.23  Algorithm for the management of chronic bleeding from portal hypertensive gastropathy.

pathogenesis of PHG are poorly understood. Development of PHG correlates with the duration of cirrhosis but not necessarily the degree of liver dysfunction. The frequency of detection of PHG is increased following endoscopic treatment of esophageal varices, possibly a result of longer duration of portal hypertension in these patients. In GVE, aggregates of ectatic vessels can be seen on endoscopic examination as red spots without a mosaic background.268 When the aggregates are confined to the antrum of the stomach, the term gastric antral vascular ectasia (GAVE) is used (see Chapters 20 and 38). If aggregates in the antrum are linear, the term watermelon stomach is used to describe the lesion (Fig. 92.22). When the red spots are distributed diffusely, in both the distal and the proximal stomach, the term diffuse gastric vascular ectasia is preferred.269 Distinguishing PHG from GVE is sometimes difficult (Table 92.5). A background mosaic pattern and proximal distribution favor PHG. GVE is less common, occurs in the absence of

a background mosaic pattern, and typically is antral in location, although lesions may be present in the proximal stomach. Mucosal biopsies are recommended when the endoscopic diagnosis is uncertain. GVE appears histologically as dilated mucosal capillaries with focal areas of fibrin thrombi or ectasia in combination with proliferation of spindle cells.270 Similar ectatic lesions may be seen in the small bowel and may cause acute or chronic GI blood loss.

Treatment PHG accounts for approximately one fourth of all cases of GI bleeding (acute and chronic) in patients with portal hypertension, but for less than 10% of all episodes of acute bleeding. The more common presentation is one of chronic, slow bleeding and anemia. Pharmacologic therapy to prevent bleeding (primary prophylaxis) in patients with severe PHG is not currently recommended. Small studies have suggested that octreotide may be useful for controlling acute bleeding.271 Beta blockers are recommended for preventing chronic blood loss in patients who have bled from severe PHG.272,273 When patients are transfusion dependent despite beta blockade and iron supplementation, a TIPS may be inserted (Fig. 92.23). A TIPS decreases transfusion requirements and results in reversal of the mucosal lesions on endoscopic examination.269 Management of GVE is more problematic. Initial treatment involves repletion of iron and RBC transfusions to treat symptomatic anemia. If lesions are localized, the platelet count is greater than approximately 45,000/mm3, and the INR is less than 1.4, thermoablative therapy, as with argon plasma coagulation, may be helpful (Fig. 92.24). The usual settings for argon plasma coagulation are an energy level of 60 to 90 watts and a gas flow rate of 1 to 2 L/min. If the coagulation parameters are suboptimal, thermal

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PART IX  Liver

coagulation is associated with an increase in mucosal bleeding in many patients. Use of the oral thrombopoietin receptor agonist eltrombopag, which increases the platelet count, does not appear to be associated with a decrease in the risk of bleeding associated with procedures.274 When the vascular ectasias are diffuse and extensive in the stomach, cryotherapy using liquid nitrogen or CO2 may be tried.275 If endoscopic treatment fails, therapy with an oral estrogen-progesterone combination (estradiol 35 µg plus norethindrone 1 mg daily) may help reduce transfusion requirements.276 Because the medication is taken daily, no risk of breakthrough vaginal bleeding exists. Rarely, painful gynecomastia may limit use of this combination in men. Bevacizumab may be beneficial in patients who have failed endoscopic and other pharmacologic therapy; surgical antral resection is seldom necessary. TIPS does not reduce the bleeding risk in patients with GVE and is associated with a substantial risk of hepatic encephalopathy269; therefore, TIPS placement is not recommended as therapy for GVE. By contrast, GVE is reversed with LT, even

in the presence of portal hypertension, suggesting that GVE is related to liver failure, rather than to portal hypertension.277,278 

Other Nonvariceal Causes Other causes of GI bleeding include peptic ulcers, Dieulafoy lesions, Mallory-Weiss tears, hemorrhoids, and portal hypertensive colopathy. Mortality during the bleeding episode in patients with cirrhosis is related to degree of liver dysfunction and severity of bleeding rather than the cause of bleeding (i.e., an ulcer or esophageal varices).279 The most common findings reported in patients with cirrhosis and LGI bleeding are portal hypertensive colopathy and hemorrhoids, with diverticulosis a less common cause.280 Patients with cirrhosis, especially alcohol-associated cirrhosis,281 are at increased risk of peptic ulcer bleeding,282 but the risk of ulcer bleeding appears to decline with age.283 Full references for this chapter can be found on www.expertconsult.com.

 ideo 92.1  Esophageal variceal band ligation. https://www.kollaborate. V tv/link?id=5cacde39480bd.

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References1470.e7 246. Mishra SR, Sharma BC, Kumar A, et al. Primary prophylaxis of gastric variceal bleeding comparing cyanoacrylate injection and betablockers: a randomized controlled trial. J Hepatol 2011;54:1161–7. 247. Tripathi D, Therapondos G, Jackson E, et al. The role of the transjugular intrahepatic portosystemic stent shunt (TIPSS) in the management of bleeding gastric varices: clinical and haemodynamic correlations. Gut 2002;51:270–4. 248. Rinella M, Shah D, Vogelzang R, et al. Fundal variceal bleeding after correction of portal hypertension in patients with cirrhosis. Gastrointest Endosc 2003;58:122–7. 249. Siringo S, McCormick P, Mistry P. Prognostic significance of the white nipple sign in variceal bleeding. Gastrointest Endosc 1991;37:51–5. 250. Lo G, Lai K, Cheng J, et al. A prospective, randomized trial of butyl cyanoacrylate injection versus band ligation in the management of bleeding gastric varices. Hepatology 2001;33:1060–4. 251. Sarin S, Jain A, Jain M, et al. A randomized controlled trial of cyanoacrylate versus alcohol injection in patients with isolated fundic varices. Am J Gastroenterol 2002;97:1010–5. 252. Binmoeller K. Glue for gastric varices: some sticky issues. Gastrointest Endosc 2000;52:298–301. 253. Rao AS, Misra S, Buttar NS, et al. Combined endoscopic-interventional radiologic approach for the treatment of bleeding gastric varices in the setting of a large splenorenal shunt. Gastrointest Endosc 2012;76:1064–5. 254. Trudeau W, Prindville T. Endoscopic injection sclerosis in bleeding gastric varices. Gastrointest Endosc 1986;32:264–8. 255. Ryan B, Stockbrugger R, Ryan J. A pathophysiologic, gastroenterologic, and radiologic approach to the management of gastric varices. Gastroenterology 2004;126:1175–89. 256. Chau T, Patch D, Chan Y, et al. “Salvage” transjugular intrahepatic portosystemic shunts: gastric fundal compared with esophageal variceal bleeding. Gastroenterology 1998;114:981–7. 257. Mishra SR, Chander Sharma B, Kumar A, et al. Endoscopic cyanoacrylate injection versus beta-blocker for secondary prophylaxis of gastric variceal bleed: a randomised controlled trial. Gut 2010;59:729–35. 258. Greenwald B, Caldwell S, Hespensheide E, et al. N-2-butyl- cyanoacrylate for bleeding gastric varices: a United States pilot study and cost analysis. Am J Gastroenterol 2003;98:1982–8. 259. Orloff M, Orloff M, Girard B, et al. Bleeding esophagogastric varices from extrahepatic portal hypertension: 40 years’ experience with portal-systemic shunt. J Am Coll Surg 2002;194:717–28. 260. Thomas P, D’Cruz A. Distal splenorenal shunting for bleeding gastric varices. Br J Surg 1994;81:241–4. 261. Sanyal A, Freedman A, Luketic V, et al. The natural history of portal hypertension after transjugular intrahepatic portosystemic shunts. Gastroenterology 1997;112:889–98. 262. Itzchak Y, Glickman M. Duodenal varices in extrahepatic portal obstruction. Radiology 1977;124:619–24. 263. Weisner R, LaRusso N, Dozois R. Peristomal varices after proctocolectomy in patients with primary sclerosing cholangitis. Gastroenterology 1986;90:316–22. 264. Norton I, Andrews J, Kamath P. Management of ectopic varices. Hepatology 1998;28:1154–8. 265. Ackerman N, Graeber G, Fey J. Enterostomal varices secondary to portal hypertension: progression of disease in conservatively managed cases. Arch Surg 1980;115:1454–5.

266. Macedo TA, Andrews JC, Kamath PS. Ectopic varices in the gastrointestinal tract: short- and long-term outcomes of percutaneous therapy. Cardiovasc Intervent Radiol 2005;28:178–84. 267. Primignani M, Materia M, Preatoni P, et al. Natural history of portal hypertensive gastropathy in patients with liver cirrhosis. Gastroenterology 2000;119:181–7. 268. Jabbari M, Cherry R, Lough J. Gastric antral vascular ectasia: the watermelon stomach. Gastroenterology 1984;87:1165–70. 269. Kamath P, Lacerda M, Ahlquist D, et al. Gastric mucosal responses to intrahepatic portosystemic shunting in patients with cirrhosis. Gastroenterology 2000;118:905–11. 270. Payen J, Cales P, Voigt J. Severe portal hypertensive gastropathy and antral vascular ectasia are distinct entities in patients with cirrhosis. Gastroenterology 1995;108:138–44. 271. Zhou Y, Qiao W, Hu H, et al. Control of bleeding in portal hypertensive gastropathy. Comparison of the efficacy of octreotide, vasopressin, and omeprazole in the control of acute bleeding in patients with portal hypertensive gastropathy: a controlled study. J Gastroenterol Hepatol 2002;17:973–9. 272. Perez-Ayuso R, Pique J, Bosch J, et al. Propranolol in prevention of recurrent bleeding from severe portal hypertensive gastropathy in cirrhosis. Lancet 1991;337:1431–4. 273. Panes J, Bordas J, Pique J, et al. Effects of propranolol on gastric mucosal perfusion in cirrhotic patients with portal hypertensive gastropathy. Hepatology 1993;17:213–8. 274. Afdhal NH, Giannini EG, Tayyab G, et al. Eltrombopag before procedures in patients with cirrhosis and thrombocytopenia. N Engl J Med 2012;367:716–24. 275. Cho S, Zanati S, Yong E, et al. Endoscopic cryotherapy for the management of gastric antral vascular ectasia. Gastrointest Endosc 2008;68:895–902. 276. Tran A, Villeneuve J-P, BIlodeau M, et al. Treatment of chronic bleeding from gastric antral vascular ectasia (GAVE) with estrogenprogesterone in cirrhotic patients: an open pilot study. Am J Gastroenterol 1999;94:2909–11. 277. Spahr L, Villeneuve J, Dufresne M, et al. Gastric antral ectasia in cirrhotic patients: absence of relation with portal hypertension. Gut 1999;44:739–42. 278. Vincent C, Pomier-Layrargues G, Dagenais M, et al. Cure of gastric antral vascular ectasia by liver transplantation despite persistent portal hypertension: a clue for pathogenesis. Liver Transpl 2002;8:717–20. 279. Ardevol A, Ibañez-Sanz G, Profitos J, et al. Survival of patients with cirrhosis and acute peptic ulcer bleeding compared with variceal bleeding using current first-line therapies. Hepatology 2018;67:1458–71. 280. Kalafateli M, Triantos CK, Nikolopoulou V, et al. Non-variceal gastrointestinal bleeding in patients with liver cirrhosis: a review. Dig Dis Sci 2012;57:2743–54. 281. Rudler M, Rousseau G, Benosman H, et al. Peptic ulcer bleeding in patients with or without cirrhosis: different diseases but the same prognosis? Aliment Pharmacol Ther 2012;36:166–72. 282. Luo JC, Leu HB, Hou MC, et al. Cirrhotic patients at increased risk of peptic ulcer bleeding: a nationwide population-based cohort study. Aliment Pharmacol Ther 2012;36:542–50. 283. Hsu YC, Lin JT, Chen TT, et al. Long-term risk of recurrent peptic ulcer bleeding in patients with liver cirrhosis: a 10-year nationwide cohort study. Hepatology 2012;56:698–705.

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Ascites and Spontaneous Bacterial Peritonitis Elsa Solà, Pere Ginès

CHAPTER OUTLINE PATHOGENESIS OF ASCITES IN CIRRHOSIS . . . . . . . . . . 1471 Sodium Retention and Extracellular Fluid Volume Expansion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1471 Portal Hypertension. . . . . . . . . . . . . . . . . . . . . . . . . . . . 1472 Systemic Circulatory Dysfunction . . . . . . . . . . . . . . . . . 1473 Systemic Inflammation. . . . . . . . . . . . . . . . . . . . . . . . . 1474 DIAGNOSIS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1474 Laboratory Tests. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1475 Abdominal US. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1475 Ascitic Fluid Analysis. . . . . . . . . . . . . . . . . . . . . . . . . . . 1475 DIFFERENTIAL DIAGNOSIS OF ASCITES . . . . . . . . . . . . . 1476 PROGNOSIS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1477 COMPLICATIONS OF ASCITES. . . . . . . . . . . . . . . . . . . . . 1477 MANAGEMENT OF ASCITES IN CIRRHOSIS. . . . . . . . . . . 1477 Uncomplicated Ascites . . . . . . . . . . . . . . . . . . . . . . . . . 1477 Refractory Ascites. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1479 Hepatic Hydrothorax. . . . . . . . . . . . . . . . . . . . . . . . . . . 1480 Contraindicated Drugs. . . . . . . . . . . . . . . . . . . . . . . . . . 1481 SPONTANEOUS BACTERIAL PERITONITIS. . . . . . . . . . . . 1481 Pathogenesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1481 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1482 Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1482 Prophylaxis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1483 Ascites is defined as the abnormal accumulation of fluid in the peritoneal cavity. In Western countries, cirrhosis is the most common cause of ascites, representing over 80% of cases. In the remaining cases, ascites may be caused by other conditions such as heart failure, malignancies, tuberculosis, or pancreatic disease (Table 93.1).1,2 This chapter focuses on the pathophysiology, evaluation, and management of cirrhotic ascites and its complications. Ascites is the most frequent complication of patients with cirrhosis and will develop in approximately 60% of patients within 10 years of the diagnosis of compensated cirrhosis.3 The development of ascites is associated with impairment of health-related quality of life, an increased risk of developing other complications of the disease such as SBP, hyponatremia, and acute kidney injury (AKI), and diminished survival.3-5 The 5-year survival rate of patients with cirrhosis and ascites is approximately 30%, compared with an 80% survival rate in patients with compensated cirrhosis.2,6

PATHOGENESIS OF ASCITES IN CIRRHOSIS The key mechanism leading to the formation of ascites in patients with cirrhosis is renal sodium retention due to activation of the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system (SNS).2,7-10 Renal sodium retention results in an expansion of the extracellular fluid volume, inducing the formation of ascites and edema. A large body of evidence indicates that the underlying driving force for these renal derangements is

the systemic circulatory disturbance caused by splanchnic arterial vasodilatation.8 The most common functional renal abnormalities in patients with cirrhosis include an impaired ability to excrete sodium, an impaired ability to excrete solute-free water, and a reduction in the glomerular filtration rate (GFR) secondary to renal vasoconstriction. Sodium retention is a key factor in the development of ascites and edema, whereas solute-free water retention is responsible for the development of dilutional hyponatremia and renal vasoconstriction leads to the occurrence of hepatorenal syndrome (HRS) (see Chapter 94). Chronologically, sodium retention is the earliest alteration in kidney function observed in patients with cirrhosis, and dilutional hyponatremia and HRS appear in more advanced stages of the disease.2,7-10 In addition to these hemodynamic alterations, a chronic systemic inflammatory state further impairs circulatory function and may also be involved in kidney and multiorgan failure, particularly in patients with advanced cirrhosis.2,10 Fig. 93.1 summarizes the mechanisms involved in the pathophysiology of ascites in cirrhosis.

Sodium Retention and Extracellular Fluid Volume Expansion Sodium retention is the most frequent and earliest renal abnormality in patients with cirrhosis and is the key factor in the expansion of the extracellular fluid volume and the development of ascites and edema.7,11 Sodium is retained isosmotically together with water, and, therefore, sodium retention is associated with extracellular fluid volume expansion. The amount of sodium retained depends on the balance between sodium in the diet and sodium excreted in the urine. If the sodium excreted in the urine is lower than that ingested, ascites and edema will develop. The central role of sodium retention in the pathogenesis of ascites is supported by the observation that ascites can resolve as a result of either a reduction in dietary sodium intake or enhancement of sodium excretion by diuretics.11,12 In fact, the achievement of a negative sodium balance by increasing urinary sodium excretion is the goal of pharmacologic therapy for ascites in patients with cirrhosis (see later). The degree of sodium retention in patients with cirrhosis and ascites is highly variable from patient to patient. Some patients have relatively high urinary sodium excretion, whereas others have a low urine sodium concentration (Fig. 93.2). Most patients who require hospitalization because of severe or difficult-tocontrol ascites have marked sodium retention (urine sodium excretion 10 mEq/day p < 0.01

0.4

≤ 10 mEq/day

0.2

0 0

1

2

3

4

5 6 Years

7

8

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Fig. 93.3  Prognosis of patients with cirrhosis and ascites according to renal sodium concentration. This figure shows the probability of survival in a series of 204 patients with cirrhosis and ascites categorized according to renal sodium excretion, which is associated with prognosis in patients with cirrhosis and ascites. Patients with marked renal sodium retention (urine sodium concentration ≤10 mEq/L) have a significantly lower probability of survival than those with renal sodium concentration greater than 10 mEq/L. Other prognostic factors in patients with cirrhosis and ascites are arterial pressure, serum sodium concentration, and serum creatinine level. (Adapted from Ginès P, Cárdenas A, Solà E, Schrier RW. Liver disease and the kidney. In: Coffman TM, Falk RJ, Molitoris BA, et al, editors. Schrier´s diseases of the kidney. 9th ed. Philadelphia: Lippincott Williams & Wilkins; 2012).

Assessment of Renal Sodium Excretion

Abdominal US

Assessment of the urinary excretion of sodium is useful for the management of patients with cirrhosis and ascites because it allows the quantification of sodium retention. Ideally, urine should be collected under conditions of controlled sodium intake (a low-sodium diet of approximately 90 mEq/day during the previous 5 to 7 days), because sodium intake may influence sodium excretion. Although the measurement of sodium concentration on a “spot” analysis of urine provides an estimate of sodium excretion, the assessment of sodium excretion in a 24-hour period is preferable because it is more representative of sodium excretion throughout the day. Sodium excretion should be measured without diuretic therapy in patients with a first episode of ascites or with worsening of pre-existing ascites (e.g., a marked increase in ascites despite treatment).1,5,7 The measurement of sodium excretion in patients on diuretic therapy may be useful for monitoring the response to treatment (see later). Measurement of baseline sodium excretion is also useful because it helps predict the response to diuretic treatment and has been associated with prognosis. Patients with moderate sodium retention (urine sodium ≥10 mEq/day) are more likely to respond to lower doses of diuretic treatment than those with marked sodium retention. Finally, the degree of sodium retention also provides prognostic information in patients with cirrhotic ascites. Patients with a baseline urine sodium excretion lower than 10 mEq/day have a median survival time of only 1.5 years, compared with 4.5 years in patients with urine sodium greater than or equal to 10 mEq/ day (Fig. 93.3).66,67

In all patients with a first episode of ascites, abdominal imaging should be performed in order to support the diagnosis of cirrhosis by evaluating the liver parenchyma and to assess the patency of the portal vein and suprahepatic veins and rule out a liver tumor. Abdominal US is the technique of choice because it is simple and cost effective. In addition to all patients with the first presentation of ascites, US should be performed in patients with known ascites who experience unexplained loss of response to treatment.1,5 

Ascitic Fluid Analysis The analysis of ascitic fluid is essential for detecting ascitic fluid infection and excluding causes of ascites other than cirrhosis, in cases in which the diagnosis is not clear. A diagnostic paracentesis with a standard 1.5-inch (longer in obese persons), 22-gauge steel needle should be performed in all patients who present with a first episode of grade 2 or 3 ascites, as well as in those patients with ascites admitted to the hospital for any intercurrent complication. The ascitic absolute polymorphonuclear leukocyte (neutrophil) count and total protein and albumin concentrations should always be assessed, along with an ascitic fluid culture.2,64,65 An ascitic neutrophil count higher than 250/mm3 is diagnostic of SBP (see later). The ascitic fluid protein concentration has been shown to be related to prognosis. Moreover, an ascitic fluid protein less than 1.5 g/dL is also associated with an increased risk of developing SBP (see later).68 Ascitic fluid culture should be performed by inoculating at least 10 mL of ascitic fluid into blood culture bottles immediately after paracentesis.1,2,69 Culture of the fluid will be highly helpful

1476

PART IX  Liver

BOX 93.2 Classification of Ascites by the Serum-Ascites Albumin Gradient HIGH GRADIENT ≥1.1 g/dl (11 g/L) Alcohol-associated hepatitis ALF Budd-Chiari syndrome Cardiac ascites Cirrhosis Fatty liver of pregnancy Massive liver metastases “Mixed” ascites Myxedema Portal vein thrombosis Sinusoidal obstruction syndrome LOW GRADIENT 3.5 *Subsequent modification: arterial pH 3.0 mmol/L after adequate fluid resuscitation.

high levels of viremia and may also be beneficial in patients with acute HBV infection and ALF, even though spontaneous rapid viral clearance from serum is expected (see Chapter 79).36 Penicillin, and possibly silymarin, may be beneficial in patients with Amanita phalloides toxicity, particularly when administered soon after ingestion of the mushrooms (see Chapter 89). D-penicillamine is not effective when encephalopathy develops in patients with Wilson disease but should be considered in patients with an acute presentation in the absence of encephalopathy (see Chapter 76). Similarly, in autoimmune hepatitis, glucocorticoid therapy rarely rescues the patient with established ALF and may complicate the process by predisposing to infection (see ­Chapter 90).37

PROGNOSIS Understanding the prognosis in patients with ALF is pivotal to delivering an optimal management plan, particularly the need to transfer a patient to a liver transplant center and determination of the likelihood that LT will be required. Three important determinants of outcome that are almost immediately apparent on presentation are the underlying etiology of ALF, age of the patient, and grade of encephalopathy. Another early indicator of a poor prognosis is a history of jaundice for more than 7 days before the onset of encephalopathy; most “spontaneous” survivors have the hyperacute category of ALF. The pattern and severity of organ failure as the disease progresses also gives insight into prognosis but at a stage of disease that may be too late to alter the outcome. Prognostication is also supported by a relatively small number of laboratory investigations. Various elements have been combined into prognostic models. The King’s College Hospital criteria, published in 1989, were among the first prognostic models.34 Distinct models were described for acetaminophen-induced and nonacetaminophen ALF (Box 95.1). The criteria have been subjected to meta-analyses that reported an overall specificity of 82% for nonacetaminophen etiologies and 95% for acetaminophen-related ALF.38,39 The analysis of nonacetaminophen etiologies involved 1105 patients in 18 studies and detected a specificity of 93% in patients with more advanced encephalopathy and 88% when the criteria were applied repeatedly in individual patients as the disease progressed.38 The meta-analysis of 1960 acetaminophen-related cases in 14 studies indicated that the high level of specificity was

CHAPTER 95  Acute Liver Failure

counterbalanced by a relatively low sensitivity of 58%,39 due in part to the nondynamic application of the model. The overall sensitivity for nonacetaminophen ALF was 85% prior to 1995, but fell to 58% after 2005 and was lowest in centers not offering LT.38 Serum lactate levels, both at presentation and after initial resuscitation, predict survival in acetaminophen-related ALF but have been shown not to complement the criteria studied in the meta-analysis described earlier.33,39 The Clichy criteria are another set of parameters that have been effective determinants of outcome and continue to be used in France.40 These criteria are based on factor V levels, with threshold values of less than 20% in patients under 30 years of age and less than 30% in older patients. These criteria are applicable once grade 2 encephalopathy has developed but appear to have limited effectiveness in patients with acetaminophen-related ALF.41 The MELD score has been validated for use in prognostication in patients with chronic liver disease and has subsequently been applied to patients with ALF (see Chapter 97).42 The components of the MELD score (bilirubin, INR, serum creatinine) are well-recognized parameters of disease severity, and in unmodified form, the MELD score may show promise as a predictive score in patients with nonacetaminophen etiologies.42 The MELD components have been incorporated into other prognostic models. A hybrid model developed in India combines classic indicators of prognosis (age >50 years, jaundice-to-encephalopathy time >7 days, prothrombin time >35 seconds, and serum creatinine level >1.5 mg/dL) with clinical complications (advanced encephalopathy and cerebral edema) associated with a poor outcome.43 A study from Germany has combined serum bilirubin, serum lactate, and etiology.44 A prognostic model called the Acute Liver Failure Study Group Index combines 3 classes of variables: clinical (coma grade), laboratory (INR, serum bilirubin, serum phosphate), and a marker of apoptosis (M30).45 This model was compared with both the King’s College Hospital criteria and the MELD score and had a higher sensitivity of 86% but a relatively low specificity of 65%. More recently, the U.S. group has presented an alternative model to predict survival for all etiologies of ALF, based on standard clinical variables on admission, including coma grade, etiology, and a requirement for a vasopressor, as well as the serum bilirubin and INR values on admission.46 While yet to be externally validated, the model correctly predicted outcome in 66% of cases. The APACHE II score and Sequential Organ Failure Assessment index correlate well with outcome and may be better predictors in patients with acetaminophen-related ALF than the King’s College criteria and MELD score.47,48 A number of disease-specific prognostic models (for mushroom poisoning and for pregnancy) have also been described.49,50 The contribution of imaging and histologic findings to prognosis is relatively limited. Assessing the volume of viable hepatocytes may have prognostic value, with a critical mass of 25% to 40% suggested as being associated with a good prognosis. This approach is most reliable in hyperacute liver failure in which the histologic changes are homogeneous and viable hepatocytes are likely to have escaped acute liver injury and thereby form the basis for clinical recovery. In the more slowly evolving syndromes, however, a map-like pattern emerges, with areas of regeneration interspersed with areas of collapse. Sampling from the area of regeneration might suggest that the liver is recovering, when in reality the prospects for survival are poor. Assessment of liver volume is valuable in patients with the subacute pattern of ALF, particularly when the degree of encephalopathy and severity of coagulopathy may not be particularly marked.27 

LIVER TRANSPLANTATION LT is one of the main reasons survival rates for ALF have increased from less than 20% in the 1970s to over 70% in the

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2010s (see also Chapter 97).51-53 Data from the Scientific Registry of Transplant Recipients and the European Liver Transplant Registry have indicated that about 8% of overall organ utilization occurs in patients with ALF.53,54 The King’s College Hospital experience of 2095 patients admitted between 1973 and 2008 showed that 19% of patients with ALF and grade 2 or higher encephalopathy underwent LT. Rates of LT for the most recent time period had increased to 53% for nonacetaminophen cases and 35% for acetaminophen cases.5 The application of LT varies with the cause of ALF and in the USA is notably lower, at only 8%, for patients with acetaminophen-related ALF compared with about 40% for other etiologies. Two fundamental approaches are used to select patients with ALF for LT. The first is to use indicators of a poor prognosis (see earlier) to decide which patients to wait-list however, use of these prognostic models creates clinical tensions that reflect the relative strengths and weakness of the models with respect to sensitivity and specificity. This approach relies on having a high level of confidence that an individual patient will benefit from LT in order to justify the use of a limited resource. Failure to list a patient for LT who subsequently dies because the model lacks sensitivity represents a missed opportunity for that patient. The second approach is to list all eligible patients and make the decision to transplant when a suitable donor organ becomes available. This approach favors the individual patient but risks unnecessary transplantation as well as diversion of scarce organs that could have been better used for other patients. The potential for “unnecessary transplantation” is significant and greatest for acetaminophen-related ALF, as illustrated by the French experience in which nearly half of patients initially wait-listed for LT survived to leave the hospital without the need for LT after recovering function in their native livers.41 Donor organ allocation systems prioritize patients with ALF so that most patients receive transplants within 48 to 72 hours of wait-listing. In Europe, the average donor age is 41 years, and nearly all come from brain-dead donors.53 About 70% of organs are ABO blood group identical to the recipient and about 5% are incompatible.53 Waiting times influence policy on the use of ABO-mismatched grafts, steatotic livers, livers from non–heart-beating deceased donors, and other suboptimal potential grafts (see Chapter 97). In Europe, auxiliary transplantation was at its peak from 1994 to 1998, when it accounted for 4% of LT activity; this figure has since fallen to 2%.53 Auxiliary LT is intended to serve as a bridge to transplantfree survival, usually within 3 years of surgery. The outcomes are comparable to those for orthotopic transplants, and about 70% of patients recover enough function in the native liver to allow the graft to involute. Live-donor LT is well established in Asia, where deceased-donor donation is limited, but in Europe less than 1% of transplants have occurred after live donation. The mortality rate on the wait-list is between 19% and 28% and is highest for acetaminophen-related ALF.41,55 In some of these patients, a suitable organ is never allocated, whereas in others a decision is made not to proceed to LT when the opportunity for transplantation arises because the patient has deteriorated to the point of being considered too sick to benefit from LT. The evidence supporting the latter decision is limited, but insight into this issue has emerged from 2 studies—an analysis using the UNOS database of 1457 patients and an analysis of 310 patients listed at King’s College Hospital.56,57 These studies identified 5 clinical factors that correlate with outcome: BMI above 30, serum creatinine level above 2 mg/dL, recipient age older than 45 to 50 years, the need for inotropic support, and use of life support. These individual parameters are not clinically useful in identifying patients too ill to benefit from LT but performed better when grouped, and in the USA study, the survival rate was 81% when none was present but only 42% when 4 were present.56 The decision not to proceed with LT is therefore usually made on the basis of clinical complications. Objective evidence

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of brainstem injury with established fixed and fully dilated pupils should preclude LT. In other patients with cerebral edema, however, no thresholds for cerebral perfusion or intracranial pressure have been validated to automatically exclude a patient from transplantation. With respect to infection, a pragmatic approach is not to contraindicate transplantation on the basis of a bacterial infection after 48 hours of appropriate antibiotic therapy. Confirmed systemic fungal infection, however, should contraindicate LT. A requirement for an inotropic agent is a surrogate marker of disease severity, and both the dose and the dynamics of dose escalation influence the decision to proceed with transplantation. Interpretation of these potential contraindications to transplantation varies with the age of the patient because younger patients are more resilient and more likely to recover following the procedure. The overall one-year patient survival rate following LT for ALF in Europe between 2004 and 2009 was 79%, and the graft survival rate was 73%.53 The one-year patient survival rate in the USA was similar (78.6%) with the use of deceased donors but numerically higher (87%) with the use of live donors.54 After one year, the decline in survival is much less marked than in other patient cohorts undergoing LT, likely because patients with ALF are younger and have a much lower risk of recurrent disease that affects graft function. The etiology of the underlying disease did not correlate with outcome in the overall analysis of the European Liver Transplant Registry data, but patients with acetaminophen-related ALF had a 24% greater risk of death after LT compared with those who underwent LT for nonacetaminophen-related ALF.53 Seronegative hepatitis or ALF without a definable cause was associated with a higher risk of primary graft nonfunction or early graft dysfunction. Survivors of LT for acetaminophen-related ALF received a graft about 2 days sooner than those who succumbed (day 4 vs. day 6 after drug ingestion). 

TREATMENT OF COMPLICATIONS Neurologic Complications Encephalopathy is a consistent clinical feature of ALF but in most patients few treatments are directed specifically to its management. The main exception is in patients with subacute liver failure, who may benefit from the standard measures used in patients with chronic liver disease, including lactulose and nonabsorbable oral antibiotic therapy. Experimental approaches with branched-chain amino acids, the benzodiazepine antagonist flumazenil, and extracorporeal liver support devices (see later) have not resulted in a survival benefit and are not widely used. Therefore, the management of the encephalopathy is essentially that of the underlying liver disease. Protection of the patient’s airway as encephalopathy progresses is important, and endotracheal intubation and mechanical ventilation are indicated once grade 3 encephalopathy develops. At this point, adequate analgesia and sedation are required, and propofol and fentanyl have been suggested as an appropriate combination.58 In addition, propofol decreases the risk of seizure activity, which is frequently unrecognized in these patients. At this point, additional measures to reduce the risk of cerebral edema should be instituted, including measures to control circulating ammonia concentration and treatment of pyrexia.58 Nursing practice includes minimization of tactile stimuli and movement, elevation of the head to 20 to 30 degrees, and avoidance of rotation of the neck. The main neurologic complication amenable to therapy is cerebral edema. Mannitol has been the mainstay of treatment of increased intracranial pressure, but hypertonic saline is now considered to be an alternative first-line therapy. These solutions act in part by increasing serum osmolality and reducing astrocyte swelling in the brain. The rapidity of the response to mannitol,

however, suggests that it also functions by improving cerebral blood flow. A rapidly delivered bolus of 0.25 to 0.5 mg/kg is recommended to obtain the maximal diuretic effect, which in anuric patients is achieved by manipulating the rate of fluid removal through hemofiltration. This process is repeated as determined by the pattern of clinical relapses until the serum osmolality exceeds 320 mOsm.58 Hypertonic saline has the advantage over mannitol of also increasing blood pressure. The induction of hypernatremia (serum sodium 145 to 155 mmol/L) by continuous infusion of hypertonic saline solution has been shown to reduce intracranial pressure in a randomized controlled trial and has a prophylactic role in patients with severe encephalopathy.59 Bolus therapy with hypertonic saline (200 mL of a 2.7% or 20 mL of a 30% solution) is often effective in controlling surges in intracranial pressure. Second-line therapeutic interventions have been described once the osmotic approach ceases to be effective in controlling intracranial pressure. Although little evidence exists that any of these interventions independently improves survival, they can be effective bridges to LT. Hyperventilation to reduce arterial pCO2 and control cerebral hyperemia can limit surges in intracranial pressure, but potentially at the cost of reducing cerebral blood flow, and should probably only be used as an emergency measure.58 Induction of moderate hypothermia (core body temperature reduced to 32°C to 33°C) showed promise in case series but has been shown in a randomized controlled trial to have no advantage above management at 36°C and is reserved for the treatment of elevated intracranial pressure that is refractory to other measures.60 Other more historic measures include phenobarbital (or sodium thiopental) and IV indomethacin.58 Hepatectomy is occasionally considered as a final act of desperation because it predictably secures a period of improvement that lasts up to 18 to 24 hours. This strategy is usually undertaken to buy time when a potential donor organ has been identified for transplantation.58,61 Direct intracranial pressure monitoring is controversial and has not been subjected to clinical trials. The advantages of early detection of increases in intracranial pressure and the eligibility to optimize therapeutic intervention were considered to be significant when the frequency of cerebral edema was as high as 70% and the attendant mortality was also high. This perspective has changed with the dramatic reduction in the frequency of cerebral edema and its now limited contribution to death. The risk of intracranial hemorrhage and the absence of evidence of improved survival were arguments advanced against the routine use of direct intracranial pressure monitoring. Reports of its use in the 2010s have suggested a low rate of hemorrhagic complications but no association with improved survival.62 Refinements in case selection for its use have focused on patients who have evidence of susceptibility to cerebral edema based on noninvasive risk stratification and/or are being considered for LT. Clinical risk factors for cerebral edema include young age, a hyperacute presentation, the requirement for vasopressor support, and the presence of sustained high levels of arterial ammonia.63,64 When intracranial pressure monitors are placed, monitoring should continue for 24 hours after LT, or longer if early graft function is impaired. 

Infection A major consequence of the immunosuppression of ALF is a high frequency of bacterial and fungal infections that often lead to progressive multiorgan failure and death (see earlier).65 The classic clinical indicators of infection may be seen with SIRS, and detection of infection relies on a high level of clinical suspicion and close microbiological surveillance. Encephalopathy at the time of admission and the presence of SIRS are significant predictors of bacteremia. Early clinical trials of prophylactic

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antibiotics demonstrated that systemic antibiotics reduce the frequency of culture-positive bacterial infection by half but at the cost of an increase in detection of highly resistant organisms.66 Furthermore, the reduction in infection rates was not accompanied by a significant improvement in major clinical outcomes, including rates of mortality and LT, or economic benefit (e.g., reduced duration of stay in an ICU or in the hospital). Similarly, small bowel decontamination has not been effective in altering the pattern of infection observed. The standard principles of preventing infection apply to patients with ALF. The sites of infection and the causative organisms are similar to those for other critically ill patients, and the choice of antibiotics should reflect institutional antibiotic policy rather than the cause of the patient’s illness.58 The use of prophylactic systemic antifungal therapy has not been subjected to formal assessment but should be considered in patients with recognized risk factors (e.g., renal failure, severe cholestasis, previous or concomitant immunosuppressive therapy, prior LT). The justification for this recommendation is the difficulty in detecting systemic fungal sepsis and the adverse implications for candidacy for LT if a diagnosis of systemic fungal infection is made. As for bacterial infections, the specific antifungal regimen adopted is generic to critically ill patients. Susceptibility to infection is another complication of ALF that persists after LT, and the treatment plan should be extended into this phase of management. 

Hemodynamic Instability and Hypoxemia Most patients with ALF develop systemic vasodilatation with reduced effective central blood volume. Prompt restoration of circulating volume is the key initial step in addressing hemodynamic instability, although the choice of fluid varies based on the patient’s biochemical status and clinical circumstance. There is no evidence to recommend use of one specific formulation above others, but selection should avoid inducing or worsening hyponatremia from dextrose solutions, hyperchloremia from saline solutions, or elevation of the serum lactate level from lactated Ringer’s solution. In patients who remain hypotensive despite fluid administration, vasopressor or inotropic therapy may be required, guided by invasive hemodynamic monitoring. Norepinephrine is the commonly preferred vasoconstrictor therapy, supported, as required, by concurrent low-dose vasopressin infusion.58 The choice of inotropic therapy is guided by the clinical setting, particularly in patients in whom adrenal insufficiency is identified. In general, epinephrine is not the first choice because it can worsen hyperlactatemia. Some patients with ALF may have a degree of adrenal insufficiency that may contribute to hemodynamic instability. In those patients supplemental hydrocortisone may reduce vasopressor requirements but carries the usual risks from immunosuppression and has not been shown to improve survival.58 The need for airway protection is the usual indication for intubation and initiation of controlled mechanical ventilation. Thereafter, hypoxemia and increasing oxygen requirements are uncommon but may develop secondary to atelectasis, infection, fluid overload, hemorrhage, or any combination of these factors. Early acute respiratory distress syndrome is occasionally seen, particularly in patients with acetaminophen-related ALF, and is associated with preintubation aspiration. SIRS, pancreatitis, or cerebral edema.58,67 Pleural effusions are more typically encountered in patients with subacute liver failure. It has been suggested that raised intra-abdominal pressure frequently compromises pulmonary function in patients with ALF and should be monitored routinely (see Chapter 11). There are a number of potential conflicts between the optimal management of pulmonary complications and the control of intracranial hypertension and cerebral edema. Endotracheal suction may trigger surges in intracranial pressure, but effective airway toilet is a priority in protecting the lungs from infection and

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should be managed by effective sedation. Positive end-expiratory pressure could impair cerebral venous drainage but in practice appears to be well tolerated in patients with severe encephalopathy at risk of cerebral edema. 

Acute Kidney Injury Initial approaches to evolving AKI in patients with ALF do not differ from those applied to other critically ill patients and recognize that these patients often have evidence of a significant reduction in circulatory volume (see Chapter 94). An early fluid challenge is indicated in patients with oliguria or biochemical evidence of renal dysfunction with the aim of rapidly correcting hypotension and restoring renal perfusion. Secondary renal insults are minimized through effective treatment of sepsis, minimization of nephrotoxic medications, and avoidance of imaging procedures that require intravenous contrast. Terlipressin is not indicated in patients with hyperacute ALF, because the pattern of renal injury is acute tubular necrosis; it might in theory be effective for some patients with slowly evolving renal injury in subacute ALF, but no data are available to support this approach. The metabolic complexity of combined liver and renal failure, particularly in relation to hyperlactatemia or hyperammonemia, suggests that early intervention with renal replacement therapy should be considered. Continuous forms of renal replacement are preferred over intermittent hemodialysis because they are associated with less hemodynamic instability and run a lower risk of aggravating latent or established cerebral edema; moreover, high filtration rates may effectively control circulating levels of ammonia.68,69 Established renal failure usually persists after LT, and recovery typically occurs sooner in patients with nonacetaminophen etiologies of ALF than in those with acetaminophen-induced ALF. The coagulopathy of ALF does not provide generally adequate clinical anticoagulation for extracorporeal circuits, and the optimal anticoagulation used for renal replacement therapy is the subject of debate. Few data exist to support particular approaches, and practices vary among centers. Prostacyclin seems to be well tolerated, and some centers report the successful use of regional citrate, the use of which mandates close monitoring of free and total blood calcium levels because patients with profound hepatic insuffiency may have compromised metabolism of the citrate load. Anticoagulation with heparin is often reserved for more stable patients without thrombocytopenia and requires close monitoring of the activated partial thromboplastin time ratio.58 

Coagulopathy Routine prophylactic repletion of coagulation factors seems intuitive but is not indicated.58 Despite often grossly abnormal laboratory tests of coagulation, functional tests may be remarkably normal or even indicate a prothrombotic tendency; spontaneous bleeding is actually uncommon in patients with ALF.32 A balanced, if unstable, picture of hemostasis is often present, resulting from the parallel loss of hepatically synthesized pro- and anticoagulant factors (see Chapter 94).70 An early controlled trial of fresh frozen plasma failed to demonstrate an improvement in survival and was thought to be detrimental in a minority of patients with a consumptive coagulopathy. Administration of fresh frozen plasma interferes with the use of coagulation studies in assessing prognosis and monitoring disease progression and risks inducing fluid overload. Prophylactic coagulation support is used more commonly in anticipation of major invasive procedures (e.g., insertion of intracranial pressure monitors) or LT. Coagulation factor support may also be indicated in patients who are bleeding and is principally targeted at correction of thrombocytopenia or hypofibrinogenemia. It has been suggested that the details of management may

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be assisted by functional coagulation testing such as thromboelastography, but this approach has yet to be fully evaluated (see Chapter 94). Limited data are available on the utility of recombinant factor VIIa in ALF, and its use is not common and may be associated with an increased risk of thrombosis.58 

Metabolic Disorders Hypoglycemia is common in patients with ALF and can be mistaken for the onset of advanced encephalopathy. The symptoms and signs of hypoglycemia are often masked, and regular blood glucose monitoring is required, with administration of glucose as required. Metabolic acidosis is present in 30% of patients with ALF after an acetaminophen overdose and has been associated with a particularly high mortality rate. Fluid resuscitation is first-line therapy, but persistence of acidosis may be an indication to initiate hemofiltration. Metabolic acidosis is found in 5% of patients with other etiologies of ALF, occurs later in the disease process, and is also associated with a poor outcome. Hyperlactatemia may reflect both systemic tissue hypoxia and increased peripheral production in concert with impaired hepatic clearance from the circulation and provides a measure of global illness severity. In spontaneously breathing patients with most etiologies of ALF, alkalosis is the dominant acid-base abnormality and may be associated with hypokalemia. Hyponatremia may reflect sodium depletion in patients with vomiting and therefore responds to administration of IV saline, or it may be dilutional due to excessive antidiuretic hormone secretion or intracellular sodium shifts. If severe, it may be an important cofactor in the development of cerebral edema. Hypophosphatemia is encountered most frequently in acetaminophen-induced ALF when renal function is preserved. Close monitoring and replacement therapy are appropriate management for hypokalemia, hypophosphatemia, and hypomagnesemia. 

Nutritional Deficiencies Although the standard patient with ALF is often well nourished at the onset of the illness, the catabolic process induced by illness can be profound. The catabolic rate increases further in patients with sepsis and those undergoing LT. Numerous theoretical problems, including in tolerance to enteral feeding because of an ileus and the potential adverse hepatic effects of parenteral nutrition, limit nutritional options. In addition, the content of the nutritional supplementation may be influenced by the theoretical role of amino acid ratios in mediating encephalopathy, difficulty in lipid handling, and the desire to minimize protein in the GI tract. Enteral nutrition is desirable to help maintain the integrity of the small intestinal mucosa, and, in practice, feeding is normally commenced within 24 hours of admission to an ICU, with goals of 25 to 30 kcal/kg/day and a protein load of 1 to 1.2 g/kg/ day. Initial administration should be via an NG tube. Pilot studies have shown that parenteral feeding is tolerated considerably better than would be expected from theoretical concerns. Lipid solutions are effectively cleared from serum, and standard amino acid

preparations do not appear to have a clinically relevant impact on encephalopathy. Protein intake is only restricted for short periods of time in selected patients with profound hepatic compromise and hyperammonemia. Continuous renal support systems provide good flexibility with regard to the management of fluid loads, and assiduous attention to the maintenance of feeding lines keeps the infectious complications within the expected frequency. 

EXTRACORPOREAL LIVER SUPPORT Attempts to improve survival in ALF using extracorporeal liver support devices extend back to the 1970s but have failed to provide evidence of a beneficial effect on survival in mostly small studies.71 More recently, a small number of larger randomized controlled trials have been conducted, with mixed outcomes. ALF was the conventional testing ground for these devices. The patient group was attractive because of the rapid progression to either death or recovery. Nevertheless, trials of liver support devices are complicated by the fact that many patients are diverted to LT once a donor organ has been allocated and before the response to therapy with the device as a bridge to transplantfree survival can be evaluated. Therefore, an additional criterion for evaluating the devices evolved in later studies with assessment of the ability of the devices to bridge patients to LT. Additional challenges in designing trials reflect the heterogeneity of ALF, particularly with respect to the capacity for hepatic regeneration. The most practical forms of liver support devices do not rely on biological components, but rather on techniques of filtration, albumin dialysis, or plasma exchange. The most widely used device is the Molecular Adsorbents Recyling System (MARS), which is based on an albumin dialysis circuit. After a case series reported promising effects, a large randomized controlled trial was carried out in France, where 110 patients were recruited over a 3-year period.72 The survival rate was 85% at 6 months in the MARS group compared with 76% in the control group. In the patients with acetaminophen-related ALF, the survival differential was wider at 85% versus 69%, but this difference was not statistically significant. The majority of patients, however, were listed for LT with a median delay of only 16 hours, and 68% of the evaluated cohort received a liver transplant. Although the study was negative, the possibility of benefit from MARS could not be discounted based on trial design and the confounding effect of LT. A randomized controlled trail of high-volume plasma exchange in ALF has also been reported, with encouraging findings. In this study, 182 patients were randomized to standard medical therapy or, in addition, 3 days of high-volume plasma exchange.73 The survival rate was higher, at 59%, in the plasma-exchange group than in controls, who had a survival rate of 48%. The benefit was confined to transplant-free survival; plasma exchange did not improve survival after LT. This study needs to be interpreted with caution, because it was conducted over an 11-year period, and the findings have yet to be reproduced. Full references for this chapter can be found on www.expertconsult.com.

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27. Zabron A, Quaglia A, Peddu P, et al. Clinical and prognostic associations of liver volume determined by computed tomography in acute liver failure. Liver Int 2018;38:1592–601. 28. Oketani M, Ido A, Nakayama N, et al. Etiology and prognosis of fulminant hepatitis and late-onset hepatic failure in Japan: summary of the annual nationwide survey between 2004 and 2009. Hepatol Res 2013;43:97–105. 29. Rolando N, Harvey F, Brahm J, et al. Prospective study of bacterial infection in acute liver failure: an analysis of fifty patients. Hepatology 1990;11:49–53. 30. Karvellas CJ, Cavazos J, Battenhouse H, et al. Effects of antimicrobial prophylaxis and blood stream infections in patients with acute liver failure: a retrospective cohort study. Clin Gastroenterol Hepatol 2014;12:1942–9. 31. Moore JK, Love E, Craig DG, et al. Acute kidney injury in acute liver failure: a review. Expert Rev 2013;7:701–12. 32. Stravitz RT, Ellerbe C, Durkalski V, et al. Bleeding complications in acute liver failure. Hepatology 2018;67:1931–42. 33. Bernal W, Donaldson N, Wyncoll D, Wendon J. Blood lactate as an early predictor of outcome in paracetamol-induced acute liver failure: a cohort study. Lancet 2002;359:558–63. 34. O’Grady JG, Alexander GJ, Hayllar KM, Williams R. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology 1989;97:439–45. 35. Lee WM, Hynan LS, Rossaro L, et al. Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure. Gastroenterology 2009;137:856–64. 36. Yu JW, Sun LJ, Yan BZ, et al. Lamivudine treatment is associated with improved survival in fulminant hepatitis B. Liver Int 2011;31:499–506. 37. Ichai P, Duclos-Vallee J-C, Guettier C, et al. Usefulness of corticosteroids for the treatment of severe and fulminant forms of autoimmune hepatitis. Liver Transpl 2007;13:996–1003. 38. McPhail MJW, Wendon JA, Bernal W. Meta-analysis of performance of King’s College Hospital Criteria in prediction of outcome in nonparacetamol-induced acute liver failure. J Hepatol 2010;53:492–9. 39. Craig DGN, Ford AC, Hayes PC, Simpson KJ. Systematic review: prognostic tests of paracetamol-induced acute liver failure. Aliment Pharmacol Ther 2010;31:1064–76. 40. Bernuau J, Goudau A, Poynard T, et al. Multivariate analysis of prognostic factors in fulminant hepatitis B. Hepatology 1986;6:648–51. 41. Ichai P, Legeai C, Francoz C, et al. Patients with acute liver failure listed for superurgent liver transplantation in France: reevaluation of the Clichy-Villejuif criteria. Liver Transpl 2015;21:512–23. 42. McPhail MJ, Farne H, Senvar N, et al. Ability of King’s College criteria and model for end-stage liver disease scores to predict mortality of patients with acute liver failure: ameta-analysis. Clin Gastroenterol Hepatol 2016;14:516–25. 43. Dhiman RK, Jain S, Maheshwari U, et al. Early indicators of prognosis in fulminant hepatic failure: an assessment of the Model for EndStage Liver Disease (MELD) and King’s College Hospital criteria. Liver Transpl 2007;13:814–21. 44. Hadem J, Stiefel P, Bahr MJ, et al. Prognostic implications of lactate, bilirubin, and etiology in German patients with acute liver failure. Clin Gastroenterol Hepatol 2008;6:339–45. 45. Rutherford A, King LY, Hynan LS, et al. Development of an accurate index for predicting outcomes of patients with acute liver failure. Gastroenterology 2012;143:1237–43. 46. Koch DG, Tillman H, Durkalski V, et al. Development of a model to predict transplant-free survival of patients with acute liver failure. Clin Gastroenterol Hepatol 2016;14:1199–206. 47. Stravitz RT. Critical management decisions in patients with acute liver failure. Chest 2008;134:1092–102. 48. Schmidt LE, Larsen FS. Prognostic implications of hyperlactatemia, multiple organ failure, and systemic inflammatory response syndrome in patients with acetaminophen-induced acute liver failure. Crit Care Med 2006;34:337–43. 49. Westbrook RH, Yeoman AD, Joshi D, et al. Outcomes of severe pregnancy-related liver disease: refining the role of transplantation. Am J Transplant 2010;10:2520–6. 50. Ferreira R, Romaozinho JM, Amaro P, et al. Assessment of emergency liver transplantation criteria in acute liver failure due to Amanita phalloides. Eur J Gastroenterol Hepatol 2011;23:1226–32. 51. Brems JJ, Hiatt JR, Ramming KP, et al. Fulminant hepatic failure: the role of liver transplantation as primary therapy. Am J Surg 1987;154:137–41.

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References

52. O’Grady JG, Alexander GJ, Thick M, et al. Outcome of orthotopic liver transplantation in the aetiological and clinical variants of acute liver failure. Q J Med 1988;68:817–24. 53. Germani G, Theocharidou E, Adam R, et al. Liver transplantation for acute liver failure in Europe: outcomes over 20 years from the ELTR database. J Hepatol 2012;57:288–96. 54. Berg CL, Steffick DE, Edwards EB, et al. Liver and intestine transplantation in the United States 1998-2007. Am J Transpl 2009;9(4 Pt 2):907–31. 55. Reddy KR, Ellerbe C, Schilsky M, et al. Determinants of outcome among patients with acute liver failure listed for liver transplantation in the United States. Liver Transpl 2016;22:505–15. 56. Barshes NR, Lee TC, Balkrishnan R, et al. Risk stratification of adult patients undergoing orthotopic liver transplantation for fulminant hepatic failure. Transplantation 2006;81:195–201. 57. Bernal W, Cross TJS, Auzinger G, et al. Outcome after wait-listing for emergency liver transplantation in acute liver failure: a single centre experience. J Hepatol 2009;50:306–13. 58. European Association for the Study of the Liver. Electronic address: [email protected]. EASL clinical practical guidelines on the management of acute (fulminant) liver failure. J Hepatol 2017;66:1047–81. 59. Murphy N, Auzinger G, Bernal W, Wendon J. The effect of hypertonic sodium chloride on intracranial pressure in patients with acute liver failure. Hepatology 2004;39:464–70. 60. Bernal W, Murphy N, Brown S, et al. A multicentre randomized controlled trial of moderate hypothermia to prevent intracranial hypertension in acute liver failure. J Hepatol 2016;65:273–9. 61. Ringe B, Lubbe N, Kuse E, et al. Total hepatectomy and liver transplantation as two-stage procedure [see comments]. Ann Surg 1993;218:3–9. 62. Karvellas CJ, Fix OK, Battenhouse H, et al. Outcomes and complications of intracranial pressure monitoring in acute liver failure: a retrospective cohort study. Crit Care Med 2014;42:1157–67.

63. Bernal W, Hall C, Karvellas CJ, et al. Arterial ammonia and clinical risk factors for encephalopathy and intracranial hypertension in acute liver failure. Hepatology 2007;46:1844–52. 64. Tofteng F, Hauerberg J, Hansen BA, et al. Persistent arterial hyperammonemia increases the concentration of glutamine and alanine in the brain and correlates with intracranial pressure in patients with fulminant hepatic failure. J Cereb Blood Flow Metab 2006;26:21–7. 65. Antonides C, Berry P, Wendon J, Vergani D. The importance of immune dysfunction in determining outcome in acute liver failure. J Hepatol 2008;49:845–61. 66. Rolando N, Wade JJ, Stangou A, et al. Prospective study comparing the efficacy of prophylactic parenteral antimicrobials, with or without enteral decontamination, in patients with acute liver failure. Liver Transpl Surg 1996;2:8–13. 67. Audimoolam VK, McPhail MJ, Wendon JA, et al. Lung injury and its prognostic significance in acute liver failure. Crit Care Med 2014;42:592–600. 68. Slack A, Auzinger G, Willars C, et al. Ammonia clearance with haemofiltration in adults with liver disease. Liver Int 2014;34:42–8. 69. Cardoso FS, Gottfried M, Tujios S, et al. Continuous renal replacement therapy is associated with reduced serum ammonia levels and mortality in acute liver failure. Hepatology 2018;67:711–20. 70. Habib M, Roberts LN, Patel RK, et al. Evidence of rebalanced coagulation in acute liver injury and acute liver failure as measured by thrombin generation. Liver Int 2014;34:672–8. 71. van de Kerkhove MP, Hoekstra R, Chamuleau RA, van Gulik TM. Clinical applicationof bioartificial liver support systems. Ann Surg 2004;240:216–30. 72. Saliba F, Camus C, Durand F, et al. Albumin dialysis with a noncell artificial liver support device in patients with acute liver failure: a randomized, controlled trial. Ann Intern Med 2013;159:522–31. 73. Larsen FS, Schmidt LE, Bernsmeier C, et al. High-volume plasma exchange in patients with acute liver failure: an open randomised controlled trial. J Hepatol 2016;64:69–78.

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Hepatic Tumors and Cysts Adrian M. Di Bisceglie, Alex S. Befeler

CHAPTER OUTLINE MALIGNANT TUMORS . . . . . . . . . . . . . . . . . . . . . . . . . . . 1509 HCC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1509 Intrahepatic Cholangiocarcinoma . . . . . . . . . . . . . . . . . 1520 Hepatoblastoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1521 Angiosarcoma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1522 Epithelioid Hemangioendothelioma. . . . . . . . . . . . . . . . 1523 Others. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1523 Hepatic Metastases. . . . . . . . . . . . . . . . . . . . . . . . . . . . 1523 BENIGN TUMORS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1524 Hepatocellular Adenoma. . . . . . . . . . . . . . . . . . . . . . . . 1524 Cavernous Hemangioma. . . . . . . . . . . . . . . . . . . . . . . . 1526 Infantile Hemangioendothelioma. . . . . . . . . . . . . . . . . . 1527 Others. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1528 TUMOR-LIKE HEPATIC LESIONS . . . . . . . . . . . . . . . . . . . 1528 Focal Nodular Hyperplasia. . . . . . . . . . . . . . . . . . . . . . . 1528 Others. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1529 HEPATIC CYSTS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1529 Simple Cysts. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1529 Polycystic Liver Disease . . . . . . . . . . . . . . . . . . . . . . . . 1530 Autosomal Recessive Polycystic Kidney Disease. . . . . . 1531 von Meyenburg Complexes. . . . . . . . . . . . . . . . . . . . . . 1531 Caroli Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1531 APPROACH TO THE PATIENT WITH AN HEPATIC MASS 1531

Hepatic mass lesions include tumors, tumor-like lesions, abscesses, cysts, hematomas, and confluent granulomas. Hepatic tumors may originate in the liver—from hepatocytes, bile duct epithelium, or mesenchymal tissue—or spread to the liver from primary tumors in remote or adjacent organs. In adults in most parts of the world, hepatic metastases are more common than primary malignant tumors of the liver, whereas in children, primary malignant tumors outnumber both metastases and benign tumors of the liver. Except for cavernous hemangiomas, benign hepatic tumors are rare in all geographic regions and in all age groups.

MALIGNANT TUMORS HCC Epidemiology HCC is the most common primary malignant tumor of the liver. It is the fifth most common cancer in men and the eighth most common in women, and it ranks fourth in annual cancer mortality rates.1,2 Information on incidence is derived from an increasing but still limited number of cancer registries, and it is possible to classify countries into broad risk categories only. Moreover, in low-income (developing) countries, especially in sub-Saharan Africa, HCC is underdiagnosed and underreported, in some cases by as much as 50%. Despite these sources of inaccuracy, HCC clearly has an unusual geographic distribution (Fig. 96.1).

The incidence of HCC has increased considerably in Japan since the 1980s, and lesser increases have been recorded in developed Western countries, including North America and Western Europe.3 Interestingly, a study from Japan has shown that the rate of HCC began to decline in 2000, presumably because of the aging of the cohort of persons infected with HCV.4 A similar downward trend has been noted in some European countries, including France and Italy.5 By contrast, in the USA, HCC is the cancer that has been increasing in incidence most rapidly since 2000, at a time when the incidence of other major cancers such as cancers of the lung, breast, prostate, and colon is decreasing.6 Considerable racial and ethnic variation exists in the incidence of HCC in the USA. The incidence among Asians is highest, almost double that of white Hispanics and more than 4 times higher than that of whites.7 Migrants from countries with a low incidence to areas with a high incidence of HCC usually retain the low risk of their country of origin, even after several generations in the new environment. The consequences for migrants from countries with a high incidence to those with a low incidence differ, depending on the major risk factors for the tumor in their country of origin and whether chronic HBV infection, if this is the major risk factor, is acquired predominantly by the perinatal or horizontal route (see later and Chapter 79).2,8,9 Men are generally more susceptible than women to HCC. Male predominance is, however, more obvious in populations at high risk for the tumor (mean male-to-female ratio, 3.7:1) than in those at low or intermediate risk (2.4:1).1,2 In industrialized countries, the number of men and number of women with HCC in the absence of cirrhosis is almost equal. The incidence of HCC increases progressively with advancing age in all populations, although it tends to level off in the oldest age groups.1,2 In Chinese and particularly in black African populations, however, the mean age of patients with the tumor is appreciably younger than in other populations. This finding is in sharp contrast to the age distribution in Japan, where the incidence of HCC is highest in the cohort of men 70 to 79 years of age.4 HCC is rare in children.10,11 

Etiology and Pathogenesis In contrast to many other malignancies, for which risk factors can only sometimes be identified, the immediate cause of HCC can usually be identified and is most commonly chronic viral hepatitis or cirrhosis. HCC is multifactorial in cause and complex in pathogenesis. Four major causative factors have been identified (Box 96.1). The differing blend of risk factors in various parts of the world may explain, in part, the diverse biological characteristics of HCC in various populations.12 HBV Some 387 million carriers of HBV exist in the world today, and HCC will develop in as many as 25% of them (see Chapter 79). HBV infection accounts for up to 80% of HCCs, which occur with high frequency in East Asian and African populations.12,13 Persistent HBV infection antedates the development of HCC by several to many years, an interval commensurate with a cause-and-effect relationship between the virus and the tumor.

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High Intermediate Low Fig. 96.1  Incidence of HCC in different parts of the world. High, age-adjusted rate of more than 15 cases/100,000 population/yr; intermediate, age-adjusted rate of 5-15 cases/100,000/yr; low, age-adjusted rate of fewer than 5 cases/100,000/yr.

BOX 96.1 Risk Factors for HCC MAJOR RISK FACTORS Chronic HBV infection Chronic HCV infection Cirrhosis NAFLD OTHER LIVER CONDITIONS α1-Antitrypsin deficiency Hemochromatosis Membranous obstruction of the inferior vena cava Type 1 and type 2 glycogen storage disease Type 1 hereditary tyrosinemia Wilson disease INHERITED CONDITIONS NOT ASSOCIATED WITH LIVER DISEASE Ataxia-telangiectasia Hypercitrullinemia OTHER FACTORS Cigarette smoking Diabetes mellitus Dietary exposure to aflatoxin B1 Oral contraceptive steroid use

Indeed, in at-risk populations, the HBV carrier state is largely established in early childhood by perinatal or horizontal infection.14,15 Approximately 90% of children infected at this stage of life become chronic carriers of the virus, and these early-onset carriers face a lifetime relative risk for developing HCC of more than 100 compared with uninfected controls.16 An effective vaccine against HBV has been available since the early 1980s, and in countries where this vaccine has been included in the expanded program of immunization for a sufficient length of time, the HBV carrier rate among children has decreased by 10-fold or more. Studies in Taiwan, where universal

immunization was started in 1984 and where the rate of HBV carriage among children has decreased by more than 10-fold, have shown a 70% reduction in the mortality rate from HCC in children in the vaccinated age groups.17 This finding gives promise for the ultimate eradication of HBV-induced HCC and provides further evidence of the causal role of the virus in the development of this tumor. The precise mechanism by which HBV results in HCC is not known; however, the virus appears to be both directly and indirectly carcinogenic.18 HBV DNA is integrated into cellular DNA in approximately 90% of HBV-related HCCs.11 The sites of chromosomal insertion appear to be random, and whether viral integration is essential for hepatocarcinogenesis is still uncertain. Possible direct carcinogenic effects include cis-activation of cellular genes as a result of viral integration, changes in the DNA sequences flanking the integrated viral DNA, transcriptional activation of remote cellular genes by HBV-encoded proteins (particularly the X protein), and effects resulting from viral mutations. The transcriptional activity of the HBV X protein may be mediated by interaction with specific transcription factors, activation of the mitogen-activated protein kinase and Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways, an effect on apoptosis, and modulation of DNA repair. Studies have shown a clear link between the amount of HBV replication (measured as serum level of HBV DNA [viral load]) and subsequent risk of HCC. The long-term risk of HCC increases markedly in patients with serum HBV DNA levels higher than 104 copies/mL.19 A randomized controlled trial of antiviral therapy has also shown a reduction in the incidence of HCC in association with reductions in serum levels of HBV DNA during therapy (see later), although other studies have not been able to confirm this benefit.14 Indirect carcinogenic effects are the result of the chronic necroinflammatory hepatic disease, in particular cirrhosis, induced by the virus. The increased hepatocyte turnover rate resulting from continuous or recurring cycles of cell necrosis and regeneration acts as a potent tumor promoter. In addition, the distorted architecture characteristic of cirrhosis contributes to the loss of control of hepatocyte growth, and hepatic inflammation generates mutagenic reactive oxygen species. Data from the REVEAL

CHAPTER 96  Hepatic Tumors and Cysts

(Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer)-HBV study in Taiwan have shown that genotype C of HBV and specific alleles of the basal core promoter and precore regions of the HBV genome are associated with a higher risk of HCC,15 whereas in Alaska, genotype F has been more strongly associated with HCC.16 The transgenic mouse model of Chisari and coworkers has provided indirect support for the role of prolonged hepatocyte injury in hepatocarcinogenesis.17 The REACH-B (Risk Estimation for Hepatocellular Carcinoma in Chronic Hepatitis B) score provides a simple-to-use tool for risk estimation for HCC among individuals with chronic HBV infection and includes gender, age, serum ALT level, hepatitis B e antigen status, and serum HBV DNA level.15  HCV Approximately 71 million people in the world today are chronically infected with HCV and are at greatly increased risk for the development of HCC. In Japan, Italy, and Spain, HCV is the single most common etiologic factor for HCC, and in other industrialized countries, HCV infection, often in combination with alcohol abuse, has emerged as a major cause of the malignancy.8,18 Patients with HCV-induced HCC generally are older than those with HBV-related tumors, and the HCV infection is likely acquired mainly in adult life. Almost all HCV-induced HCCs arise in cirrhotic livers, and most of the exceptions are in livers with chronic hepatitis and fibrosis. This observation strongly suggests that chronic hepatic parenchymal disease plays a key role in the genesis of HCVrelated tumors. Because the HCV genome does not integrate into host DNA, the virus would have to exert a direct carcinogenic effect by some other means. Long-term follow-up of a large group of patients with chronic hepatitis C and cirrhosis or bridging fibrosis found a cumulative 5-year frequency of HCC of just over 5%. The rate was higher among those with cirrhosis (7.0%) than those with bridging fibrosis at baseline (4.1%).20 A multivariate analysis model showed that older age, black race, lower platelet count, presence of esophageal varices, and smoking were additional risk factors. It has become apparent that successful treatment of chronic HCV infection, with a sustained virologic response (see Chapter 80), is associated with regression of hepatic fibrosis and a lowerthan-expected rate of HCC.19,21,22 Modern DAAs have increased the rate of viral cure, although HCC may still occur in a cirrhotic patient after treatment has eliminated HCV19,22-24 Long-term maintenance therapy with peginterferon was not successful in preventing HCC in patients with chronic hepatitis C.25,26  Cirrhosis In all parts of the world, HCC frequently occurs against a background of cirrhosis.27 All causative forms of cirrhosis may be complicated by tumor formation. A long-term follow-up study of 2126 U.S. military veterans with cirrhosis found that HCC developed in 100 (4.7%) over an average period of 3.6 years.27 The calculated rate was 1.3/100 patient-years. Risk factors for HCC included obesity, a low platelet count, and the presence of antibody to hepatitis B core antigen. A similar study from Italy found an incidence of HCC of 3.7/100 patient-years among cirrhotic persons with HCV infection and 2.0/100 patient-years among persons with HBV infection. Older age and male gender were confirmed as risk factors among patients with cirrhosis.20 By contrast, a study from Denmark of more than 8000 patients with alcohol-associated cirrhosis found a 5-year cumulative risk of HCC of 1.0, suggesting that perhaps patients with this form of cirrhosis were at lower risk of HCC than, for example, those with HCV-related cirrhosis.28  Aflatoxin B1 Dietary exposure to aflatoxin B1, derived from the fungi Aspergillus flavus and Aspergillus parasiticus, is an important risk factor for

1511

HCC in parts of Africa and Asia. These molds are ubiquitous in nature and contaminate staple foodstuffs in tropical and subtropical regions (see Chapter 89). Epidemiologic studies have shown a strong correlation between the dietary intake of aflatoxin B1 and incidence of HCC.29 Moreover, aflatoxin B1 and HBV interact synergistically in the pathogenesis of HCC. Heavy dietary exposure to aflatoxin B1 may contribute to hepatocarcinogenesis through an inactivating mutation of the third base of codon 249 of the TP53 tumor suppressor gene.30,31  Other Conditions HCC develops in as many as 45% of patients with untreated hemochromatosis (see Chapter 75).32 Malignant transformation was previously thought to occur only in the presence of cirrhosis (and is certainly more likely to do so), but this complication also has been reported in patients without cirrhosis.33 Excessive free iron in tissues may be carcinogenic, perhaps by generating mutagenic reactive oxygen species.34 Further support for this theory comes from the observations that black Africans with dietary iron overload are at increased risk of HCC35 and that rats fed a diet high in iron develop iron-free dysplastic foci and HCC in the absence of cirrhosis.36 HCC occasionally develops in patients with Wilson disease, but only in the presence of cirrhosis (see Chapter 76).37 Malignant transformation has been attributed to the cirrhosis but may also result from oxidant stress secondary to the accumulation of copper in the liver.38 HCC also may develop in patients with other inherited metabolic disorders that are complicated by cirrhosis, such as α1-antitrypsin deficiency and type 1 hereditary tyrosinemia, and in patients with certain inherited diseases in the absence of cirrhosis—for example, type 1 glycogen storage disease (see Chapter 77). HCC develops in approximately 40% of patients with membranous obstruction of the inferior vena cava, a rare congenital or acquired anomaly (see Chapter 85). The roles of obesity, diabetes mellitus, and NAFLD have come to be recognized in the causation of HCC,39-41 although the mechanisms whereby these overlapping conditions contribute to the development of HCC are unknown. Cirrhosis caused by NASH appears to give rise to HCC less frequently than cirrhosis caused by HCV but nevertheless appears to carry significant risk.42 Diabetes mellitus is also a risk factor for HCC, although it is not clear if the risk is independent of NAFLD or not.41 A statistically significant correlation between the use of oral contraceptive steroids and the occurrence of HCC has been demonstrated in countries in which the incidence of HCC is low and no overriding risk factor for development of the tumor is present. Epidemiologic evidence of a link between cigarette smoking and the occurrence of HCC is conflicting, although most of the evidence suggests that smoking is a minor risk factor43; heavy smokers have an approximately 50% higher risk than nonsmokers. The incidence of HCC is increased in patients with HIV infection compared with controls in the general population, presumably because of the increased rate of chronic viral hepatitis in the HIV-positive population.44 Although the aforementioned risk factors have been identified, the precise mechanisms whereby they lead to HCC still need to be elucidated. Multiple cellular pathways are involved in causing unconstrained proliferation of hepatocytes and increased angiogenesis against a background of chronic liver disease. These pathways have become the targets for new molecular therapies against HCC (Box 96.2) (see later).45 

Clinical Features Although the typical clinical features of HCC are well recognized (including abdominal pain and weight loss in patients with cirrhosis), many patients are now diagnosed at an early stage when they have no specific symptoms or signs. This trend toward earlier diagnosis is probably the result of surveillance

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PART IX  Liver

BOX 96.2 Key Molecular Pathways Involved in Hepatocarcinogenesis Angiogenic signaling Epigenetic promoter methylation and histone acetylation Growth factor-stimulated receptor tyrosine kinase JAK/STAT signaling PI3-kinase/AKT/mTOR p53 and cell cycle regulation Ubiquitin-proteasome Wnt/β-catenin JAK/STAT, janus kinase/signal transducer and activator of transcription; mTOR, mechanistic (or mammalian) target of rapamycin. Adapted from Roberts L. Emerging experimental therapies for hepatocellular carcinoma: what if you can’t cure? In: McCullough A, editor. AASLD Postgraduate Course, 2007. Boston: AASLD; 2007. p 185.

TABLE 96.1  Symptoms and Signs of HCC Symptom

Frequency (%)

Abdominal pain

59-95

Weight loss

34-71

Weakness

22-53

Abdominal swelling

28-43

Nonspecific GI symptoms

25-28

Jaundice

5-26

Sign Hepatomegaly

54-98

Ascites

35-61

Fever

11-54

Splenomegaly

27-42

Wasting

25-41

Jaundice

4-35

Hepatic bruit

6-25

programs in patients with chronic liver disease (see later). In advanced disease, patients with HCC usually present with typical symptoms and signs, and diagnosis is straight forward. In addition, HCC often coexists with cirrhosis,46 and the onset of HCC is marked by a sudden unexplained change in the patient’s condition. Patients with HCC often are unaware of its presence until the tumor has reached an advanced stage. The most common (and frequently first) symptom is right hypochondrial or epigastric pain. Other symptoms are listed in Table 96.1. Physical findings vary with the stage of disease (see Table 96.1). Early in the course, evidence of cirrhosis alone may be present, or abnormal findings may be absent. When the tumor is advanced at the time of the patient’s first medical visit, the liver is almost always enlarged, sometimes massively. Hepatic tenderness is common and may be profound, especially in the later stages. The surface of the enlarged liver is smooth, irregular, or frankly nodular. An arterial bruit may be heard over the tumor47; the bruit is heard in systole, rough in character, and not affected by changing the position of the patient. Although not pathognomonic, a bruit is a useful clue to the diagnosis of HCC. Less often, a friction rub may be heard over the tumor, but this sign is more characteristic of hepatic metastases or abscesses.

BOX 96.3 Paraneoplastic Manifestations Associated with HCC Carcinoid syndrome Hypercalcemia Hypertension Hypertrophic osteoarthropathy Hypoglycemia Neuropathy Osteoporosis Polycythemia (erythrocytosis) Polymyositis Porphyria Sexual changes—isosexual precocity, gynecomastia, feminization Thyrotoxicosis Thrombophlebitis migrans Watery diarrhea syndrome

Ascites may be present when the patient is first seen or may appear with progression of the tumor. In most patients, ascites is the result of long-standing cirrhosis and portal hypertension (see Chapter 93), but in some cases it is caused by invasion of the peritoneum by the primary tumor or metastases or obstruction of the hepatic veins or superior vena cava.48 The ascitic fluid may be blood stained. Splenomegaly, if present, reflects coexisting cirrhosis and portal hypertension. Physical evidence of cirrhosis may also be noted. Severe pitting edema of the lower extremities extending up to the groins occurs when HCC has invaded the hepatic veins and propagates into and obstructs the inferior vena cava.48 A Virchow-Trosier (supraclavicular) node, Sister Mary Joseph’s (periumbilical) nodule, or enlarged axillary lymph node is rarely present. Paraneoplastic Manifestations Some of the deleterious effects of HCC are not caused by local effects of the tumor or metastases (Box 96.3). Each of the paraneoplastic syndromes in HCC is rare or uncommon. One of the more important is type B hypoglycemia, which occurs in less than 5% of patients, manifests as severe hypoglycemia early in the course of the disease,48 and is believed to result from the defective processing by malignant hepatocytes of the precursor to insulin-like growth factor II (pre-IGF II).49 By contrast, type A hypoglycemia is a milder form of glycopenia that occurs in the terminal stages of HCC (and other malignant tumors of the liver). It results from the inability of a liver extensively infiltrated by tumor, and often cirrhotic, to satisfy the demands for glucose by a large, often rapidly growing tumor and by the other tissues of the body. Another important paraneoplastic syndrome is polycythemia (erythrocytosis), which occurs in less than 10% of patients with HCC.50 This syndrome appears to be caused by the synthesis of erythropoietin or an erythropoietin-like substance by malignant hepatocytes. Patients with HCC, especially the sclerosing variety, may present with hypercalcemia in the absence of osteolytic metastases. When hypercalcemia is severe, it may result in the typical complications of hypercalcemia, including drowsiness and lethargy. The probable cause is secretion of parathyroid hormone– related protein by the tumor.51 Cutaneous paraneoplastic manifestations of HCC are rare except for pityriasis rotunda (circumscripta), which may be a useful marker of the tumor in black Africans. The rash consists of single or multiple, round or oval, hyperpigmented, scaly lesions on the trunk and thighs that range in diameter from 0.5 to 25 cm.52 

Diagnosis The gold standard for the diagnosis of HCC is pathology. For practical purposes (i.e., to apply treatment), HCC can be

CHAPTER 96  Hepatic Tumors and Cysts

1513

diagnosed in the presence of an abnormality on imaging of the liver. Dysplastic nodules and even regenerative cirrhotic nodules can be seen on imaging studies and are potentially confused with HCC. Although enhancement patterns with dynamic imaging of dysplastic nodules and HCC are fairly specific (see later), some overlap occurs.53,54 Nevertheless, there is a growing consensus that, based on guidelines from the major European and American hepatology societies and now backed by published experience, the diagnosis of HCC can be made in the appropriate clinical setting on the basis of specific imaging characteristics, with or without an elevated serum AFP level.54–57

sugar chains that are not found in AFP produced by non-transformed hepatocytes. One variant, Lens culinaris agglutinin reactive fraction (AFP-L3), has been suggested to improve the specificity of AFP, particularly AFP serum levels from 10 to 200 ng/mL.63,64 The recommended cutoff value for AFP-L3 to diagnose HCC is higher than 10%, although the specificity varies depending on the absolute level of AFP. Studies have not confirmed that AFP-L3 has greater sensitivity or specificity than AFP alone for the diagnosis of early HCC.60,63 Therefore, AFP-L3 is not sufficiently validated to confirm the diagnosis of HCC without other supporting findings, such as suggestive imaging. 

Serum Tumor Markers Serum tumor markers generally are not diagnostic for HCC by themselves but can be used in conjunction with imaging findings to diagnose HCC. Additionally, they may raise the suspicion of HCC and lead to more sensitive and serial imaging of the liver. Conventional liver biochemical tests do not distinguish HCC from other hepatic mass lesions or cirrhosis. Many of the substances synthesized and secreted by HCC are not biologically active. Nevertheless, a few are produced by a sufficiently large proportion of tumors to warrant their use as serum markers for HCC. The most helpful of these markers is AFP.

Des-γ-Carboxy Prothrombin Serum concentrations of des-γ-carboxy prothrombin (DCP) (also known as prothrombin produced by vitamin K absence or antagonist II) are raised in most patients with HCC.65 DCP is an abnormal prothrombin that is thought to result from a defect in the post-translational carboxylation of the prothrombin precursor in malignant cells.66 DCP has been suggested to be a better marker than, or at least complementary to, AFP.67–69 A large study in Western patients with HCV–related cirrhosis, however, did not confirm this finding.70 Therefore, because appropriate diagnostic cutoff values are not well established, the precise role of DCP in the diagnosis of HCC still requires validation. 

AFP AFP is an α1-globulin normally present in high concentrations in fetal serum but in only minute amounts thereafter. Reappearance of high serum levels of AFP strongly suggests the presence of HCC (or hepatoblastoma [see later]),58 especially in populations at risk for HCC. Measurement of AFP can potentially be used for the diagnosis of HCC, surveillance, and prognostication. With regard to diagnosis, existing guidelines are based on biopsy or liver imaging and do not require use of AFP. Clearly, markedly elevated AFP levels (>10,000 ng/mL to > 1,000,000 ng/mL) can be considered diagnostic for HCC in an appropriate clinical context. Although there is no specific diagnostic cutoff, values above 400 ng/mL in association with a liver mass can be considered diagnostic in most cases.59 In the context of surveillance for HCC, the tumor must be detected at an early stage when potentially curative treatment can still be applied. Measurement of AFP has been used for early diagnosis but with sometimes disappointing results. For example, Marrero and colleagues studied a large group of patients with HCC and matched controls and found that the optimal cutoff value of serum AFP level that resulted in the greatest sensitivity was 10.9 ng/mL; still, the sensitivity of the test using this value was only 66%.60 Therefore, routine use of AFP as part of a surveillance program for HCC remains controversial.61 Serum AFP levels appear to have some prognostic utility, particularly with regard to LT, for which levels above 1000 ng/mL have been associated with poorer outcomes and higher rates of tumor recurrence. An AFP level higher than about 500 ng/mL predicts worse outcomes with LT compared with lower levels.62 Attempts to correlate the degree of differentiation of HCC with production of AFP have produced conflicting results. False-positive AFP results (for HCC) also may occur in patients with tumors of endodermal origin, non-seminomatous germ cell tumors, pregnancy, and regenerating livers in the setting of ALF. A progressively rising serum AFP concentration is highly suggestive of HCC. Because both false-positive and falsenegative results are obtained when AFP is used as a serum marker for HCC, the search for an ideal marker continues; however, alternative markers have not proved to be more useful than AFP.  Fucosylated AFP AFP is heterogeneous in structure. Its microheterogeneity results from differences in the oligosaccharide side chain and accounts for the differential affinity of the glycoprotein for lectins. AFP secreted by malignant hepatocytes contains unusual and complex

Other Markers Multiple other potential serum markers for HCC have been identified, although none of them has an established high–throughput method of measurement, as required for a clinical test. The roles in the diagnosis of HCC for markers such as glypican-3 (GPC3), Golgi protein 73, hepatocyte growth factor, IGF 1, and transforming growth factor-β1 await further study.  Imaging The diagnosis of HCC generally requires imaging evidence of a focal lesion in the liver, although large infiltrating lesions can also be diagnostic. Arterial hyperenhancement, particularly seen on dynamic contrast imaging of the liver, is observed because the blood supply of HCC comes from newly formed abnormal arteries (neoangiogenesis).53,71,72 As a nodule transforms from low- to high-grade dysplasia and then to HCC, the primary blood supply shifts from portal to arterial; new abnormal arterial branches produce characteristic findings on dynamic contrast imaging of the liver and subsequent hypoenhancement in the portal venous and delayed phases (“washout”).57,73 European and American liver societies recommend that a noninvasive diagnosis of HCC can be made in a nodule greater than 1 cm in diameter that demonstrates arterial hyperenhancement and portal venous or delayed washout.74,75 The American College of Radiology created and updated the Liver Imaging Reporting and Data System (LI-RADS), which attempts to classify liver nodules based on size and imaging characteristics on CT or MRI76 and has been adapted as the terminology to be used for patients on the UNOS transplant list. The LI-RAD categories assist the clinician in assessing the risk that a nodule is HCC, with LI-RAD 3 being intermediate risk, LI-RAD 4 probable HCC, and LI-RAD 5 definite HCC. The individual criteria for LIRADS have been validated in prospective and retrospective cohort studies, but the system as a whole has not been fully validated73 and some studies show little difference between LI-RAD 4 and LI-RAD 5 nodules less than 2 cm in diameter if identified initially on US.77 US US detects most HCCs but may not distinguish this tumor from other solid lesions in the liver. Therefore, US is a more effective as a tool for screening than for diagnosis. As with all imaging methods, the sensitivity increases with increasing size of the lesion. A systematic review of 8 studies using histologic reviews of liver explants has shown that US has fair sensitivity (pooled estimate, 48%; 95% confidence interval [CI], 34% to 62%) with

96

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PART IX  Liver

Noncontrast

Arterial

Portal venous

Delayed

Fig. 96.2  Dynamic CT of a patient with HCC showing no lesion in the noncontrast phase, an enhancing lesion in the right lobe of the liver in the arterial phase of contrast administration (arrow), and a faint lesion in the portal venous phase, seen better in the delayed phase.

good specificity (97%; 95% confidence interval [CI], 95% to 98%).54 Advantages of US include safety, availability, and costeffectiveness. Drawbacks include lack of standardization, examiner dependence, and limited sensitivity with certain body habituses, particularly obesity, and with fatty infiltration of the liver. The US appearance of HCC is variable because it is influenced by the presence of fat, hemorrhage, and necrosis. Smaller tumors (2 years

>1 years

3 months

>5 years

Fig. 96.4  Barcelona Clinic Liver Cancer (BCLC) staging classification and treatment schedule with associated expected survival. Staging is based on tumor size and spread, the patient’s Eastern Cooperative Oncology Group (ECOG) performance status (PS) on a scale of 0 (good) to greater than 2 (poor), and liver function as assessed by the Child-Pugh class (see Chapter 92). Patients with very early (stage 0) HCC are optimal candidates for surgical resection. Patients with early (stage A) HCC are candidates for radical therapy (resection, deceased-donor LT, or live-donor LT, or local ablation via percutaneous ethanol injection or radiofrequency ablation. Patients with intermediate (stage B) HCC benefit from transarterial chemoembolization. Patients with advanced HCC, defined as the presence of macroscopic vascular invasion, extrahepatic spread, or cancerrelated symptoms (PS 1 or 2) (stage C), benefit from sorafenib or lenvantanib as first-line and regorafenib or nivolumab as second-line therapy. Patients with end-stage disease (stage D) should receive symptomatic treatment. The treatment strategy will transition from one stage to another when treatment fails or is contraindicated. (Adapted from Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet 2018;391:1301-14.)

survival rates of 40% and 26%, respectively, with a mean tumor diameter of 8.8 cm in noncirrhotic patients.101 Unfortunately, these patients represent less than 5% of Western cases.102,103 Resection is also effective if the tumor is limited to the left lobe or a portion of the right lobe, thereby permitting a segmental resection if the patient has Child-Pugh class A cirrhosis, the serum bilirubin level is normal, and portal hypertension is not present (based on imaging, a normal platelet count, absence of varices on endoscopy, and a directly measured hepatic venous pressure gradient 400 ng/mL) improve survival after sorafenib failure

Immune checkpoint inhibitors

Nivolumab and pembrolizumab are associated with improved survival after failure of or intolerance to sorafenib

rapidly under the influence of post-transplantation immunosuppression. Because the availability of donor livers is limited, the consensus is that anticipated outcomes of LT for HCC should be similar to those for other indications for LT and superior to those for other treatments for HCC. Several large series have demonstrated that if one selects candidates based on the Milan criteria—a single tumor up to 5 cm in size or 2 to 3 lesions, each up to 3 cm in size, with no large-vessel vascular invasion or metastasis—the 5-year survival rate is 70% to 75%, and the tumor recurrence rate is 10% to 15%.102,109-111 These criteria led to the HCC MELD exception pathway, which was adopted in the USA in 2002. Because of the change, the frequency of HCC as an indication for LT rose from 4.6% to 26% of the total adult liver transplant population. Additionally, progression of the tumor beyond the Milan criteria before a patient undergoes LT has largely been eliminated.62,112 If the estimated time to LT is greater than 6 months, bridging therapy with RFA or transarterial chemoembolization (TACE) can often be performed to prevent tumor growth beyond Milan criteria (see later). In other parts of the world, waiting times before transplantation remain critical, and when the waiting time increases to one year, as many as half of patients will not receive a transplant.102 An analysis of 4-year survival rates for all patients transplanted in the USA has confirmed that overall outcomes for those transplanted with HCC are only minimally worse than for those transplanted for other indications.62 Certain subgroups of patients do worse, including those with nodules 3 to 5 cm in diameter, a MELD score of 20 or greater, and a serum AFP level of 455 ng/mL or higher. Some authorities have advocated expansion of the Milan criteria, provided that the tumor shrinks to within Milan criteria

and remains stable for 3 months after application of locoregional therapy, based on prospective outcomes from small, single-­center series, but these patients generally need a special exception from the regional review board in the USA.113,114 Although these criteria are being widely applied, a larger multicenter study is needed to confirm the outcomes and define which patients would benefit.  Local Ablation Local ablative therapies are potentially curative treatments for patients with small tumors (usually 1.5

α1-Antitrypsin deficiency and cirrhosis

Unknown, probably >1.5

HBV carrier, Asian men > 40 yr

0.4-0.6

HBV carrier, Asian women > 50 yr

0.3-0.6

HBV carrier, family history of HCC

Unknown (higher than without family history)

HBV carrier, born in Africa

At least 0.5 (HCC occurs at a younger age)

HCV infection and stage 3 fibrosis*

17.5 mg/dL (300 μmol/L) Prothrombin time >50 sec or INR >3.5 CRITERIA OF HÔPITAL PAUL-BROUSSE, VILLEJUIF Hepatic encephalopathy and Factor V level 20 g/day for women and >30 g/ day for men) is associated with poorer long-term survival after LT, regardless of the primary indication for transplantation.163 Given the lack of data about the safety of more moderate alcohol consumption in liver transplant recipients, complete abstinence should be encouraged as a conservative approach. Osteopenia is a frequent cause of morbidity in liver transplant recipients.164 Although hepatic osteodystrophy is typically associated with cholestatic liver diseases, it is also common in patients with cirrhosis of other etiologies. Factors implicated in the pathogenesis of hepatic osteodystrophy include poor nutritional status, immobility, the calciuric effect of many diuretics, hypogonadism, and glucocorticoid use in patients with autoimmune hepatitis. In the initial several months after LT, osteopenia is accelerated further by high-dose glucocorticoid therapy as well as the other major immunosuppressive agents. Atraumatic fractures may occur in trabecular bone such as vertebrae or ribs. Bone mass increases after doses of immunosuppressive agents are reduced as mobility increases. Supplemental calcium and vitamin D are prescribed to patients with osteopenia, as is a bisphosphonate in patients with osteoporosis. De novo malignancies are increased in frequency following LT.165 Recipients need ongoing age-appropriate surveillance for common tumors such as breast, cervical, and colon cancer.166 In the absence of specific recommendations, screening for prostatic carcinoma by yearly digital rectal examination and/or prostate-specific antigen testing in male liver transplant recipients older than age 40 should be individualized. The incidence of prostate cancer in liver transplant

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recipients appears to be slightly higher to that in nontransplanted men.167 Screening for colorectal cancer by colonoscopy should also be performed every 5 years after age 50 in asymptomatic recipients; in patients with a history of PSC and UC, yearly colonoscopy with surveillance mucosal biopsies is recommended (see Chapters 68 and 116). Adherence to cervical cancer screening guidelines for the general population and screening female recipients older than age 40 for breast cancer by yearly mammography seem appropriate.166 Other malignancies that are increased in frequency in organ transplant recipients include those of the skin, lung, liver, female genital tract, and GI tract. Patients with alcohol use disorder may be particularly prone to malignancies of the oropharynx (see Chapter 86).168 Patients should be encouraged to use sunscreen regularly and have periodic examinations by a dermatologist. Post-transplantation lymphoproliferative disorder (PTLD) varies from a low-grade indolent process to an aggressive neoplasm.169 Uncontrolled proliferation of B cells after LT, typically in response to primary EBV infection, can be polyclonal or monoclonal. Pediatric recipients are at particular risk because of the absence of prior EBV infection. Intensive immunosuppression with OKT3 for severe rejection increases the risk of PTLD, which can present as a mononucleosis-like syndrome, lymphoproliferation, or malignant lymphoma. Clinical features suggestive of PTLD include lymphadenopathy, unexplained fever, and systemic symptoms such as weight loss. The majority of patients with PTLD present with extranodal masses, primarily involving the GI tract (stomach or intestine), lungs, skin, central nervous system, or hepatic allograft.168 The WHO classifies PTLD into 4 main categories based on clinical, morphologic, immunophenotypic, and genetic features: benign polyclonal lymphoproliferation (early lesions), polymorphic PTLD, monomorphic PTLD, and classic Hodgkin’s lymphoma–like PTLD. Management includes a reduction in immunosuppression and antiviral therapy directed against EBV, if present, with ganciclovir. Systemic chemotherapy, including the anti-CD20 monoclonal antibody rituximab, may be required in patients with malignant lymphoma.168 The higher frequency of PTLD in pediatric recipients has led to surveillance by PCR methodology for EBV viremia and reduction in the level of immunosuppression in patients with a positive result before clinical features of PTLD occur. In addition, antiviral prophylaxis is prescribed for high-risk recipients, including those who are seronegative for EBV and received a graft from a seropositive donor. Chronic graft rejection is increased in frequency in survivors of PTLD because of the reduction in the level of immunosuppression, which may be increased cautiously after PTLD is contained. 

Immunizations and Antibiotic Prophylaxis Immunization against HAV and HBV, influenza, pneumococcus, tetanus, and diphtheria is part of the standard pre-LT management. A substantial proportion of patients may be unable to mount adequate antibody responses because of the immunosuppression associated with end-stage liver disease. Vaccines based on live or attenuated microorganisms (i.e., measles, mumps, rubella, oral polio, bacille Calmette-Guerin, vaccinia, and varicella-zoster) are contraindicated because of the risk of reactivation. Prophylactic antibiotics are usually recommended for any dental procedure, although this recommendation is not evidence-based.170 

Hepatic Retransplantation Although improved immunosuppressive regimens have led to a lower rate of graft loss from chronic rejection, recurrence of the underlying liver disease has been recognized increasingly as a cause of graft failure, as illustrated most strikingly in HCVinfected recipients prior to the availability of DAAs that permit curative antiviral therapy in liver transplant recipients.171 Understanding the full effect of recurrent disease, especially nonviral disease, on patient and graft survival will require studies with long-term follow-up. For example, although the rate of histologic recurrence of viral hepatitis is greatest in the first year following LT, recurrent PBC or PSC develops in less than 5% of patients by the first year, whereas more than 20% demonstrate histologic recurrence 10 years after LT.172,173 As patients enter their second and third decades following LT, the number of patients who require retransplantation may deplete the donor pool further. This issue is compounded by the observation that patients who undergo re-transplantation experience an approximate 20% overall reduction in the rate of survival but consume an increased amount of resources when compared with primary liver transplant recipients. Major challenges remain in LT, including the shortage of donor organs, threat of recurrent disease, and morbidity associated with lifelong therapeutic immunosuppression. Nevertheless, the availability of LT has transformed the lives of patients with advancing liver disease and their health care providers from an ultimately futile effort to manage the complications of cirrhosis into a life-prolonging and life-enhancing intervention. Full references for this chapter can be found on www.expertconsult.com.

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References

51. Keswani RN, Ahmed A, Keeffe EB. Older age and liver transplantation: a review. Liver Transpl 2004;10:957–67. 52. Fede G, D’Amico G, Arvaniti V, et al. Renal failure and cirrhosis: a systematic review of mortality and prognosis. J Hepatol 2012;56:810–8. 53. Kim WR, Biggins SW, Kremers WK, et al. Hyponatremia and mortality among patients on the liver-transplant waiting list. New Engl J Med 2008;359:1018–26. 54. Leise MD, Kim WR, Kremers WK, et al. A revised model for endstage liver disease optimizes prediction of mortality among patients awaiting liver transplantation. Gastroenterology 2011;140:1952–60. 55. Merli M, Nicolini G, Angeloni S, et al. Malnutrition is a risk factor in cirrhotic patients undergoing surgery. Nutrition 2002;18:978–86. 56. Nair S, Verma S, Thuluvath PJ. Obesity and its effect on survival in patients undergoing orthotopic liver transplantation in the United States. Hepatology 2002;35:105–9. 57. Lai JC, Feng S, Terrault NA, et al. Frailty predicts waitlist mortality in liver transplant candidates. Am J Transplant 2014;148:1870–9. 58. Merion RM, Schaubel DE, Dykstra DM, et al. The survival benefit of liver transplantation. Am J Transplant 2005;5:307–13. 59. Heimbach JK, Kulik LM, Finn RS, et al. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology 2018;67:358– 80. 60. Parfitt JR, Marotta P, Alghamdi M, et al. Recurrent hepatocellular carcinoma after transplantation: use of a pathological score on explanted livers to predict recurrence. Liver Transpl 2007;13:543–51. 61. Sapisochin G, Bruix J. Liver transplantation for hepatocellular carcinoma: outcomes and novel surgical approaches. Nat Rev Gastroenterol Hepatol 2017;14:203–17. 62. Varela M, Sanchez W, Bruix J, et al. Hepatocellular carcinoma in the setting of liver transplantation. Liver Transpl 2006;12:1028–36. 63. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. New Engl J Med 1996;334:693–9. 64. Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology 2001;33:1394–403. 65. Yao FY, Kerlan Jr RK, Hirose R, et al. Excellent outcome following down-staging of hepatocellular carcinoma prior to liver transplantation: an intention-to-treat analysis. Hepatology 2008;48:819–27. 66. Mazzaferro V, Bhoori S, Sposito C, et al. Milan criteria in liver transplantation for hepatocellular carcinoma: an evidence-based analysis of 15 years of experience. Liver Transpl 2011;17(Suppl. 2):S44–57. 67. Clavien PA, Lesurtel M, Bossuyt PM, et al. Recommendations for liver transplantation for hepatocellular carcinoma: an international consensus conference report. Lancet Oncol 2012;13:e11–22. 68. Ioannou GN, Perkins JD, Carithers Jr RL. Liver transplantation for hepatocellular carcinoma: impact of the MELD allocation system and predictors of survival. Gastroenterology 2008;134:1342–51. 69. Wedd JP, Nordstrom E, Nydam T, et al. Hepatocellular carcinoma in patients listed for liver transplantation: current and future allocation policy and management strategies for the individual patient. Liver Transpl 2015;21:1543–52. 70. Llovet JM, Mas X, Aponte JJ, et al. Cost effectiveness of adjuvant therapy for hepatocellular carcinoma during the waiting list for liver transplantation. Gut 2002;50:123–8. 71. Pomfret EA, Washburn K, Wald C, et al. Report of a national conference on liver allocation in patients with hepatocellular carcinoma in the United States. Liver Transpl 2010;16:262–78. 72. Toso C, Merani S, Bigam DL, et al. Sirolimus-based immunosuppression is associated with increased survival after liver transplantation for hepatocellular carcinoma. Hepatology 2010;51:1237–43. 73. Chinnakotla S, Davis GL, Vasani S, et al. Impact of sirolimus on the recurrence of hepatocellular carcinoma after liver transplantation. Liver Transpl 2009;15:1834–42. 74. Gomez-Martin C, Bustamante J, Castroagudin JF, et al. Efficacy and safety of sorafenib in combination with mammalian target of rapamycin inhibitors for recurrent hepatocellular carcinoma after liver transplantation. Liver Transpl 2012;18:45–52. 75. Zavaglia C, Airoldi A, Mancuso A, et al. Adverse events affect sorafenib efficacy in patients with recurrent hepatocellular carcinoma after liver transplantation: experience at a single center and review of the literature. European J Gastroenterol Hepatol 2013;25:180–6.

76. Satapathy SK, Das K, Kocak M, et al. No apparent benefit of preemptive sorafenib therapy in liver transplant recipients with advanced hepatocellular carcinoma on explant. Clin Transpl 2018:e13246. 77. Friend BD, Venick RS, McDiarmid SV, et al. Fatal orthotopic liver transplant organ rejection induced by a checkpoint inhibitor in two patients with refractory, metastatic hepatocellular carcinoma. Pediatr Blood Cancer 2017;64(12). 78. Margarit C, Charco R, Hidalgo E, et al. Liver transplantation for malignant diseases: selection and pattern of recurrence. World J Surg 2002;26:257–63. 79. Darwish Murad S, Kim WR, Harnois DM, et al. Efficacy of neoadjuvant chemoradiation, followed by liver transplantation, for perihilar cholangiocarcinoma at 12 US centers. Gastroenterology 2012;143:88–98. 80. Schuppan D, Afdhal NH. Liver cirrhosis. Lancet 2008;371:838– 51. 81. Kim WR, Lake JR, Smith JM, et al. OPTN/SRTR 2016 Annual data report: liver. Am J Transplant 2018;18(Suppl. 1):172–253. 82. Mathurin P, Moreno C, Samuel D, et al. Early liver transplantation for severe alcoholic hepatitis. New Engl J Med 2011;365:1790– 800. 83. Iasi MS, Vieira A, Anez CI, et al. Recurrence of alcohol ingestion in liver transplantation candidates. Transpl Proc 2003;35:1123–4. 84. DiMartini A, Dew MA, Fitzgerald MG, et al. Clusters of alcohol use disorders diagnostic criteria and predictors of alcohol use after liver transplantation for alcoholic liver disease. Psychosomatics 2008;49:332–40. 85. Singal AK, Bashar H, Anand BS, et al. Outcomes after liver transplantation for alcoholic hepatitis are similar to alcoholic cirrhosis: exploratory analysis from the UNOS database. Hepatology 2012;55:1398–405. 86. Burra P, Lucey MR. Liver transplantation in alcoholic patients. Transpl Int 2005;18:491–8. 87. Bellamy CO, DiMartini AM, Ruppert K, et al. Liver transplantation for alcoholic cirrhosis: long term follow-up and impact of disease recurrence. Transplantation 2001;72:619–26. 88. Pais R, Barritt AS, Calmus Y, et al. NAFLD and liver transplantation: current burden and expected challenges. J Hepatol 2016;65:1245–57. 89. Dick AA, Spitzer AL, Seifert CF, et al. Liver transplantation at the extremes of the body mass index. Liver Transpl 2009;15:968–77. 90. Afzali A, Berry K, Ioannou GN. Excellent posttransplant survival for patients with nonalcoholic steatohepatitis in the United States. Liver Transpl 2012;18:29–37. 91. Charlton MR, Burns JM, Pedersen RA, et al. Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States. Gastroenterology 2011;141:1249–53. 92. Angulo P. Nonalcoholic fatty liver disease and liver transplantation. Liver Transpl 2006;12:523–34. 93. Heimbach JK, Watt KD, Poterucha JJ, et al. Combined liver transplantation and gastric sleeve resection for patients with medically complicated obesity and end-stage liver disease. Am J Transplant 2013;13:363–8. 94. Nesher E, Mor E, Shlomai A, et al. Simultaneous liver transplantation and sleeve gastrectomy: prohibitive combination or a necessity? Obes Surg 2017;27:1387–90. 95. Lin MY, Tavakol MM, Sarin A, et al. Safety and feasibility of sleeve gastrectomy in morbidly obese patients following liver transplantation. Surg Endosc 2013;27:81–5. 96. Berenguer M. Management of hepatitis C virus in the transplant patient. Clin Liver Dis 2007;11:355–76. 97. Berenguer M, Aguilera V, Prieto M, et al. Delayed onset of severe hepatitis C-related liver damage following liver transplantation: a matter of concern? Liver Transpl 2003;9:1152–8. 98. Narang TK, Ahrens W, Russo MW. Post-liver transplant cholestatic hepatitis C: a systematic review of clinical and pathological findings and application of consensus criteria. Liver Transpl 2010;16:1228–35. 99. Graziadei IW, Zoller HM, Schloegl A, et al. Early viral load and recipient interleukin-28B rs12979860 genotype are predictors of the progression of hepatitis C after liver transplantation. Liver Transpl 2012;18:671–9. 100. Dixon LR, Crawford JM. Early histologic changes in fibrosing cholestatic hepatitis C. Liver Transpl 2007;13:219–26.

References1550.e3 100a. Cimsit B, Assis D, Caldwell C, et al. Successful treatment of fibrosing cholestatic hepatitis after liver transplantation. Transpl Proc 2011;43:905–8. 101. Chhatwal J, Samur S, Kues B, et al. Optimal timing of hepatitis C treatment for patients on the liver transplant waiting list. Hepatology 2017;65:777–88. 102. Charlton M, Everson GT, Flamm SL, et al. Ledipasvir and sofosbuvir plus ribavirin for treatment of HCV infection in patients with advanced liver disease. Gastroenterology 2015;149:649–59. 103. Curry MP, O’Leary JG, Bzowej N, et al. Sofosbuvir and velpatasvir for HCV in patients with decompensated cirrhosis. New Engl J Med 2015;373:2618–28. 104. Carrion AF, Khaderi SA, Sussman NL. Model for end-stage liver disease limbo, model for end-stage liver disease purgatory, and the dilemma of treating hepatitis C in patients awaiting liver transplantation. Liver Transpl 2016;22:279–80. 105. Kim WR, Terrault NA, Pedersen RA, et al. Trends in waiting list registration for liver transplantation for viral hepatitis in the United States. Gastroenterology 2009;137:1680–6. 106. Nelson NP, Easterbrook PJ, McMahon BJ. Epidemiology of hepatitis B virus infection and impact of vaccination on disease. Clin Liver Dis 2016;20:607–28. 107. Gane EJ, Patterson S, Strasser SI, et al. Combination of lamivudine and adefovir without hepatitis B immune globulin is safe and effective prophylaxis against hepatitis B virus recurrence in hepatitis B surface antigen-positive liver transplant candidates. Liver Transpl 2013;19:268–74. 108. Perrillo RP, Wright T, Rakela J, et al. A multicenter United States-Canadian trial to assess lamivudine monotherapy before and after liver transplantation for chronic hepatitis B. Hepatology 2001;33:424–32. 109. Han SH, Martin P, Edelstein M, et al. Conversion from intravenous to intramuscular hepatitis B immune globulin in combination with lamivudine is safe and cost-effective in patients receiving long-term prophylaxis to prevent hepatitis B recurrence after liver transplantation. Liver Transpl 2003;9:182–7. 110. Yahyazadeh A, Beckebaum S, Cicinnati V, et al. Efficacy and safety of subcutaneous human HBV-immunoglobulin (Zutectra) in liver transplantation: an open, prospective, single-arm phase III study. Transpl Int 2011;24:441–50. 111. Schiff E, Lai CL, Hadziyannis S, et al. Adefovir dipivoxil for wait-listed and post-liver transplantation patients with lamivudine-resistant hepatitis B: final long-term results. Liver Transpl 2007;13:349–60. 112. Fung J, Cheung C, Chan SC, et al. Entecavir monotherapy is effective in suppressing hepatitis B virus after liver transplantation. Gastroenterology 2011;141:1212–9. 113. Saab S, Desai S, Tsaoi D, et al. Posttransplantation hepatitis B prophylaxis with combination oral nucleoside and nucleotide analog therapy. Am J Transplant 2011;11:511–7. 114. Fernandez I, Loinaz C, Hernandez O, et al. Tenofovir/entecavir monotherapy after hepatitis B immunoglobulin withdrawal is safe and effective in the prevention of hepatitis B in liver transplant recipients. Transpl Infect Dis 2015;17:695–701. 115. Teperman LW, Poordad F, Bzowej N, et al. Randomized trial of emtricitabine/tenofovir disoproxil fumarate after hepatitis B immunoglobulin withdrawal after liver transplantation. Liver Transpl 2013;19:594–601. 116. Carrion AF, Bhamidimarri KR. Liver transplant for cholestatic liver diseases. Clin Liver Dis 2013;17:345–59. 117. Gores GJ, Gish RG, Shrestha R, et al. Model for end-stage liver disease (MELD) exception for bacterial cholangitis. Liver Transpl 2006;12(12 Suppl. 3):S91–92. 118. Sylvestre PB, Batts KP, Burgart LJ, et al. Recurrence of primary biliary cirrhosis after liver transplantation: histologic estimate of incidence and natural history. Liver Transpl 2003;9:1086–93. 119. Campsen J, Zimmerman MA, Trotter JF, et al. Clinically recurrent primary sclerosing cholangitis following liver transplantation: a time course. Liver Transpl 2008;14:181–5. 120. Heffron TG, Smallwood GA, Ramcharan T, et al. Duct-to-duct biliary anastomosis for patients with sclerosing cholangitis undergoing liver transplantation. Transplant Proc 2003;35:3006–7. 121. Sutton ME, Bense RD, Lisman T, et al. Duct-to-duct reconstruction in liver transplantation for primary sclerosing cholangitis is associated with fewer biliary complications in comparison with hepaticojejunostomy. Liver Transpl 2014;20:457–63.

122. Vera A, Moledina S, Gunson B, et al. Risk factors for recurrence of primary sclerosing cholangitis of liver allograft. Lancet 2002;360:1943–4. 123. Bosch A, Dumortier J, Maucort-Boulch D, et al. Preventive administration of UDCA after liver transplantation for primary biliary cirrhosis is associated with a lower risk of disease recurrence. J Hepatol 2015;63:1449–58. 124. Vogel A, Heinrich E, Bahr MJ, et al. Long-term outcome of liver transplantation for autoimmune hepatitis. Clin Transplant 2004;18:62–9. 125. Oo YH, Neuberger J. Recurrence of nonviral diseases. Clin Liver Dis 2007;11:377–95. 126. Barshes NR, Lee TC, Balkrishnan R, et al. Risk stratification of adult patients undergoing orthotopic liver transplantation for fulminant hepatic failure. Transplantation 2006;81:195–201. 127. Yu L, Ioannou GN. Survival of liver transplant recipients with hemochromatosis in the United States. Gastroenterology 2007;133:489–95. 128. Crawford DH, Fletcher LM, Hubscher SG, et al. Patient and graft survival after liver transplantation for hereditary hemochromatosis: Implications for pathogenesis. Hepatology 2004;39:1655–62. 129. Valla DC. Primary Budd-Chiari syndrome. J Hepatol 2009;50:195– 203. 130. Membreno FE, Ortiz J, Foster PF, et al. Liver transplantation for sinusoidal obstructive syndrome (veno-occlusive disease): case report with review of the literature and the UNOS database. Clin Transplant 2008;22:397–404. 131. Geevarghese SK, Powers T, Marsh JW, et al. Screening for cerebral aneurysm in patients with polycystic liver disease. Southern Med J 1999;92:1167–70. 132. Monteiro E, Freire A, Barroso E. Familial amyloid polyneuropathy and liver transplantation. J Hepatol 2004;41:188–94. 133. Hanto DW, Fecteau AH, Alonso MH, et al. ABO-incompatible liver transplantation with no immunological graft losses using total plasma exchange, splenectomy, and quadruple immunosuppression: evidence for accommodation. Liver Transpl 2003;9:22–30. 134. Feng S, Goodrich NP, Bragg-Gresham JL, et al. Characteristics associated with liver graft failure: the concept of a donor risk index. Am J Transpl 2006;6:783–90. 134a. Maheshwari A, Maley W, Li Z, et al. Biliary complications and outcomes of liver transplantation from donors after cardiac death. Liver Transpl 2007;13:1645–53. 135. Nishimura N, Kasahara M, Ishikura K, et al. Current status of pediatric transplantation in Japan. J Intensive Care 2017;5:48. 136. Trotter JF, Wisniewski KA, Terrault NA, et al. Outcomes of donor evaluation in adult-to-adult living donor liver transplantation. Hepatology 2007;46:1476–84. 137. Hu A, Liang W, Zheng Z, et al. Living donor vs. deceased donor liver transplantation for patients with hepatitis C virus-related diseases. J Hepatol 2012;57:1228–43. 138. Muzaale AD, Dagher NN, Montgomery RA, et al. Estimates of early death, acute liver failure, and long-term mortality among live liver donors. Gastroenterology 2012;142:273–80. 139. Ghobrial RM, Freise CE, Trotter JF, et al. Donor morbidity after living donation for liver transplantation. Gastroenterology 2008;135:468–76. 140. Rosen HR. Transplantation immunology: what the clinician needs to know for immunotherapy. Gastroenterology 2008;134:1789– 801. 141. Geissler EK, Schlitt HJ. Immunosuppression for liver transplantation. Gut 2009;58:452–63. 142. Mehrabi A, Fonouni H, Kashfi A, et al. The role and value of sirolimus administration in kidney and liver transplantation. Clin Transpl 2006;20(Suppl. 17):30–43. 143. Fischer L, Saliba F, Kaiser GM, et al. Three-year outcomes in de novo liver transplant patients receiving everolimus with reduced tacrolimus: follow-up results from a randomized, multicenter study. Transplantation 2015;99:1455–62. 144. De Simone P, Nevens F, De Carlis L, et al. Everolimus with reduced tacrolimus improves renal function in de novo liver transplant recipients: a randomized controlled trial. Am J Transplant 2012;12:3008–20. 145. Chapman WC, Brown Jr RS, Chavin KD, et al. Effect of early everolimus-facilitated reduction of tacrolimus on efficacy and renal func-

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tion in de novo liver transplant recipients: 24-month results for the North American subpopulation. Transplantation 2017;101:341–9. 146. Lupo L, Panzera P, Tandoi F, et al. Basiliximab versus steroids in double therapy immunosuppression in liver transplantation: a prospective randomized clinical trial. Transplantation 2008;86:925–31. 147. Levitsky J, Thudi K, Ison MG, et al. Alemtuzumab induction in non-hepatitis C positive liver transplant recipients. Liver Transpl 2011;17:32–7. 148. Vivarelli M, La Barba G, Cucchetti A, et al. Can antiplatelet prophylaxis reduce the incidence of hepatic artery thrombosis after liver transplantation? Liver Transpl 2007;13:651–4. 149. Sawas T, Al Halabi S, Hernaez R, et al. Patients receiving prebiotics and probiotics before liver transplantation develop fewer infections than controls: a systematic review and meta-analysis. Clin Gastroenterol Hepatol 2015;13:1567–74. 150. Creput C, Blandin F, Deroure B, et al. Long-term effects of calcineurin inhibitor conversion to mycophenolate mofetil on renal function after liver transplantation. Liver Transpl 2007;13:1004–10. 151. Khalili M, Lim JW, Bass N, et al. New onset diabetes mellitus after liver transplantation: the critical role of hepatitis C infection. Liver Transpl 2004;10:349–55. 152. Gane EJ. Diabetes mellitus following liver transplantation in patients with hepatitis C virus: risks and consequences. Am J Transplant 2012;12:531–8. 153. Huprikar S. Update in infectious diseases in liver transplant recipients. Clin Liver Dis 2007;11:337–54. 154. Kotton CN, Kumar D, Caliendo AM, et al. The Third International Consensus Guidelines on the management of cytomegalovirus in solid-organ transplantation. Transplantation 2018;102:900–31. 155. Fishman JA. Infection in solid-organ transplant recipients. New Engl J Med 2007;357:2601–14. 156. Pappas PG, Kauffman CA, Andes DR, et al. Clinical practice guideline for the management of candidiasis: 2016 update by the infectious diseases Society of America. Clin Infect Dis 2016;62:e1–50. 157. Silveira FP, Kusne S, Practice ASTIDCo. Candida infections in solid organ transplantation. Am J Transplant 2013;13(Suppl. 4):220–7. 158. Sharma S, Gurakar A, Jabbour N. Biliary strictures following liver transplantation: past, present and preventive strategies. Liver Transpl 2008;14:759–69. 159. Lucey MR, Terrault N, Ojo L, et al. Long-term management of the successful adult liver transplant: 2012 practice guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation. Liver Transpl 2013;19:3–26.

160. Ojo AO, Held PJ, Port FK, et al. Chronic renal failure after transplantation of a nonrenal organ. New Engl J Med 2003;349:931–40. 161. Bianchi G, Marchesini G, Marzocchi R, et al. Metabolic syndrome in liver transplantation: relation to etiology and immunosuppression. Liver Transpl 2008;14:1648–54. 162. Zachoval R, Gerbes AL, Schwandt P, et al. Short-term effects of statin therapy in patients with hyperlipoproteinemia after liver transplantation: results of a randomized cross-over trial. J Hepatol 2001;35:86–91. 163. Faure S, Herrero A, Jung B, et al. Excessive alcohol consumption after liver transplantation impacts on long-term survival, whatever the primary indication. J Hepatol 2012;57:306–12. 164. Guichelaar MM, Schmoll J, Malinchoc M, et al. Fractures and avascular necrosis before and after orthotopic liver transplantation: long-term follow-up and predictive factors. Hepatology 2007;46:1198–207. 165. Aberg F, Pukkala E, Hockerstedt K, et al. Risk of malignant neoplasms after liver transplantation: a population-based study. Liver Transpl 2008;14:1428–36. 166. Chandok N, Watt KD. Burden of de novo malignancy in the liver transplant recipient. Liver Transpl 2012;18:1277–89. 167. Tillou X, Chiche L, Guleryuz K, et al. Prostate carcinoma in liver transplant recipients: think about it! Urologic Oncol 2015;33:265 e269–13. 168. Sampaio MS, Cho YW, Qazi Y, et al. Posttransplant malignancies in solid organ adult recipients: an analysis of the U.S. National Transplant Database. Transplantation 2012;94:990–8. 169. Kremers WK, Devarbhavi HC, Wiesner RH, et al. Post-transplant lymphoproliferative disorders following liver transplantation: incidence, risk factors and survival. Am J Transplant 2006;6(5 Pt 1):1017–24. 170. Guggenheimer J, Eghtesad B, Stock DJ. Dental management of the (solid) organ transplant patient. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2003;95:383–9. 171. Burton Jr JR, Rosen HR. Diagnosis and management of allograft failure. Clin Liver Dis 2006;10:407–35. 172. Mendes F, Couto CA, Levy C. Recurrent and de novo autoimmune liver diseases. Clin Liver Dis 2011;15:859–78. 173. Schreuder TC, Hubscher SG, Neuberger J. Autoimmune liver diseases and recurrence after orthotopic liver transplantation: what have we learned so far? Transplant Int 2009;22:144–52..

PART X

98

Small and Large Intestine

Anatomy, Histology, Embryology, and Developmental Anomalies of the Small and Large Intestine Lee M. Bass, Barry K. Wershil

CHAPTER OUTLINE ANATOMY �����������������������������������������������������������������������1551 Macroscopic Features���������������������������������������������������1551 Microscopic Features ���������������������������������������������������1553 EMBRYOLOGY�����������������������������������������������������������������1559 Intestinal Development�������������������������������������������������1559 Molecular Regulation of Intestinal Morphogenesis���������1560 Specific Structures and Systems�����������������������������������1561 Clinical Implications �����������������������������������������������������1563 ABNORMALITIES IN NORMAL EMBRYOLOGIC DEVELOPMENT ���������������������������������������������������������������1564 Abdominal Wall�������������������������������������������������������������1564 Omphalomesenteric (Vitelline) Duct Abnormalities���������1565 Malrotations�����������������������������������������������������������������1567 Proliferation �����������������������������������������������������������������1567 Intestinal Atresia and Stenosis���������������������������������������1569 Anorectum �������������������������������������������������������������������1570 Enteric Nervous System �����������������������������������������������1573 Miscellaneous and Genetic Defects�������������������������������1577

ANATOMY Macroscopic Features Small Intestine The small intestine is a specialized tubular structure within the abdominal cavity in continuity with the stomach proximally and the colon distally. The small bowel increases in length from about 250 cm in the term newborn to about 600 to 800 cm in the adult. The caliber of the small intestine gradually diminishes from proximal to distal, and there is a fourfold reduction in surface area from the distal duodenum to the terminal ileum. The duodenum is the most proximal portion of the small intestine. It begins with the duodenal bulb, travels in the retroperitoneal space around the head of the pancreas, and ends on its return to the peritoneal cavity at the ligament of Treitz. The biliary and pancreatic ducts usually join together 1 to 2 cm from the outer margin of the duodenal wall and drain into the medial wall of the second portion of the duodenum through the ampulla of Vater. In 5% to 10% of individuals, an accessory pancreatic duct, also known as the duct of Santorini, enters separately through the minor papilla 1 to 2 cm proximal to the ampulla of Vater. The remainder of the small

intestine is suspended within the peritoneal cavity by a thin broadbased mesentery that is attached to the posterior abdominal wall and allows relatively free but tethered movement of the small intestine within the abdominal cavity. The proximal 40% of the mobile small intestine is the jejunum, which occupies the left upper portion of the abdomen. The remaining 60% of small intestine is the ileum, and it is normally situated in the right side of the abdomen and upper part of the pelvis. There is no distinct anatomic demarcation between the jejunum and ileum, but the jejunum tends to be thicker, is more vascular, and has a greater diameter than the ileum. The luminal surface of the small intestine has visible mucosal folds called the plicae circularis or folds of Kerckring. They are more numerous in the proximal jejunum, decrease in number distally, and are absent in the terminal ileum. Microscopic aggregates of lymphoid cells are scattered throughout the small intestine and make up the GI-associated lymphoid tissue. Macroscopic lymphoid aggregates, or Peyer patches, are more concentrated in the ileum and can be seen extending through to the serosa. Peyer patches are more prominent in infancy and childhood and regress in size and number with advancing age. The jejunum and ileum are freely mobile in the abdominal cavity and are attached to the posterior abdominal wall by the intestinal mesentery. The entire length of jejunum and ileum is suspended in this mesentery, except for the distal terminal ileum at the cecum, which is retroperitoneal. The mesentery is formed by a fan-shaped anterior reflection of the posterior peritoneum that extends from the left side of the body toward the right sacroiliac joint. The mesentery envelops a number of important structures, including the jejunum, ileum, jejunal and ileal branches of the superior mesenteric artery (SMA) and superior mesenteric vein (SMV), nerves, lacteals, lymph nodes, and a variable amount of fat. The small bowel transitions to the colon at the ileocecal (IC) valve, which consists of 2 semilunar lips that protrude into the cecum. The IC valve functions like a flutter valve, allowing antegrade flow when a peristaltic wave is strong enough to overcome its resistance but preventing retrograde flow of colonic contents into the small intestine. The angulation between the ileum and cecum, supported by the superior and inferior IC ligaments, is important to the function of the IC valve. The IC valve typically contracts when the cecum is over-distended to prevent ceco-ileal reflux. This explains why during colonoscopy, excessive distention of the cecum with air should be avoided, because this may lead to IC valve contraction, which can then hinder successful intubation of the ileum and also lead to high intracolonic pressure with resultant barotrauma. 

Colon and Rectum The colon is a tubular structure about 30 to 40 cm in length at birth and measuring some 150 cm in the adult, or about one

1551

1552

PART X  Small and Large Intestine

Hepatic flexure

Greater omentum (cut away)

Free taenia (taenia libera)

Epiploic taenia

Greater omentum (cut away) Transverse mesocolon Haustra

Hook exposing epiploic Appendices taenia epiploicae Semilunar folds (plicae semilunares)

Ileocecal valve

Hook exposing mesocolic taenia

Free taenia (taenia libera) Sigmoid mesocolon

Cecum Appendix

Rectosigmoid junction

quarter the length of the small intestine. The colon begins at the IC valve and ends distally at the anal verge (Fig. 98.1). It consists of 4 segments: cecum and vermiform appendix, colon (ascending, transverse, and descending portions), rectum, and anal canal. The diameter of the colon is greatest in the cecum (7.5 cm) and narrowest in the sigmoid (2.5 cm) until it balloons out in the rectum just proximal to the anal canal. The colon is distinguished from the small intestine by several features. It is larger in caliber, mostly fixed in position, and has outer longitudinal muscle fibers that coalesce into 3 discrete bands called taeniae: the taenia liberis (free tenia), taenia omentalis (omental tenia), and taenia mesocolica (mesenteric tenia). Taeniae are located at 120-degree intervals around the colonic circumference and extend from the cecum to the proximal rectum. Outpouchings, or haustra, occur between the taeniae, and their mucosal surface is sectioned by semilunar folds to give the serosa a sacculated and puckered appearance. Small sacs of peritoneum filled with adipose tissue, the appendices epiploicae, are found on the external surface of the colon. The mesentery fully suspends the transverse colon and sigmoid colon, while the remainder of the colon has mesentery only on its free anterior surface. The appendix has a short mesentery called the mesoappendix. The cecum is the most proximal portion of the colon. It is about 6 to 8 cm in length and breadth and lies in the right iliac fossa, projecting downward as a blind pouch below the entrance of the ileum. The large diameter of the cecum makes it susceptible to rupture with distal obstruction and permits tumors to grow to substantial size before producing symptoms of obstruction. The cecum is normally nonmobile because it is fixed in position by a small mesocecum; anomalous fixation, however, occurs in 10% to 20% of the population, predominantly women, predisposing them to cecal volvulus. The IC valve passes perpendicularly through the posteromedial wall of the cecum and consists of a superior and inferior fold arranged in an elliptical manner at the IC orifice. The appendiceal

Splenic flexure

Haustra Fig. 98.1  Macroscopic characteristics of the colon. Note the taeniae, haustra between the taeniae, the semilunar folds, and the appendices epiploicae. (Netter illustration from www.netterimages.com. © Elsevier Inc. All rights reserved.)

orifice is roughly 2.5 cm inferior to the IC valve, and the vermiform appendix is a blind outpouching extending from the cecum in a direction that varies from person to person. Appendiceal anatomy is discussed further in Chapter 120. The ascending colon is narrower than the cecum and extends about 12 to 20 cm from the level of the IC valve to the inferior surface of the posterior lobe of the liver, where it angulates left and forward, forming the hepatic flexure. The ascending colon is covered with peritoneum in about 75% of individuals and thus is usually considered to reside in the retroperitoneum. At the hepatic flexure, the colon turns medially and anteriorly to emerge into the peritoneal cavity as the transverse colon, fully enveloped in mesentery. The transverse is the longest (40 to 50 cm) and most mobile segment of the colon. It lies between the hepatic and splenic flexures and drapes itself across the anterior abdomen and anterior to the stomach. The phrenocolic ligament anchors the colon at the splenic flexure, but the transverse colon is so mobile that in the upright position it may actually dip down into the pelvis. Abdominal or pelvic surgery that results in adhesion formation can fix the position of the normally mobile transverse colon. The descending colon is about 25 to 45 cm in length and travels posteriorly and then inferiorly in the retroperitoneal compartment to the pelvic brim. It emerges from the retroperitoneum into the peritoneal cavity as the sigmoid colon, an S-shaped redundant segment of variable length, tortuosity, and mobility. The mobility of the sigmoid colon renders it susceptible to volvulus, and because it is the narrowest part of the colon, tumors and strictures of this region typically cause obstructive symptoms early in the course of disease. The rectum is 10 to 12 cm in length and begins at the peritoneal reflection, follows the curve of the sacrum passing down and posteriorly, and ends at the anal canal. The rectum narrows at its junction with the sigmoid, expanding proximal to the anus. The rectum lies entirely below the peritoneum in close relationship with the structure of the pelvis. The anorectal junction is

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CHAPTER 98  Anatomy, Histology, Embryology, and Developmental Anomalies of the Small and Large Intestine

2 to 3 cm anterior to the tip of the coccyx. The rectum does not have sacculation, appendices epiploicae, or mesentery. The outer rectal wall is progressively thickened with prominent and anterior bands of muscle as it descends toward the anus. The luminal surface of the rectum has 3 transverse folds called the valves of Houston.

98 mp m

s

Anal Canal The anal canal is 2 cm long in the infant and 4.5 to 5 cm long in the adult. It occupies the ischiorectal fossa, passing inferiorly and outward toward the anal opening. The anorectal junction is situated within the pelvic diaphragm and made up of the levator ani, coccygeus, and puborectalis muscles which encircle it; contraction of these muscles allows the anorectum to retain stool, and relaxation allows for defecation. The internal anal sphincter is made up of the circular smooth muscular layer of the intestine, which surrounds the upper three quarters of the canal. The external sphincter is made up of striated muscle; it surrounds the anal canal, and its fibers blend with those of the levator ani muscle to attach posteriorly to the coccyx and anteriorly to the perineal body. Distally, the anal verge represents the transition of anoderm to true skin. The mucosa of the distal 3 cm of the rectum and anal canal contains 6 to 12 redundant longitudinal folds called the columns of Morgagni, which terminate in the anal papillae. These columns are joined together by mucosal folds called the anal valves, which are situated at the dentate line. The zona alba is a white zone that demarcates the transition to typical squamous epithelium. The anatomy and function of these muscles are described in more detail in Chapter 129.

Vasculature The proximal duodenum receives arterial blood from the right gastric artery, supraduodenal artery, right gastroepiploic artery, and superior and inferior pancreaticoduodenal arteries. Venous drainage is via the SMV and the splenic and portal veins. The SMA delivers oxygenated blood to the distal duodenum, jejunum and ileum, ascending colon, and proximal two thirds of the transverse colon. Branches of the inferior mesenteric artery supply the remainder of the colon. The arterial supply of the anal area is from the superior, middle, and inferior hemorrhoidal arteries, which are branches of the inferior mesenteric, hypogastric, and internal pudendal arteries, respectively. Venous drainage of the anus is by both the systemic and portal systems. The internal hemorrhoidal plexus drains into the superior rectal veins and then into the inferior mesenteric vein, which, with the SMV, joins the splenic vein to form the portal vein. The vascularity of the distal anus drains by the external hemorrhoidal plexus through the middle rectal and pudendal veins into the internal iliac vein. (See Chapter 118 for discussion of the intestinal blood supply and its disorders.)

Lymphatic Drainage Lymphatic drainage courses through the mesentery from villus lacteals and lymphatic follicles and converges at preaortic lymph nodes around the SMA and celiac artery. The lymphatic drainage of both the small intestine and colon follows their respective blood supplies to lymph nodes in the celiac, superior preaortic, and inferior preaortic regions. Lymphatic drainage proceeds to the cisterna chyli and then via the thoracic duct into the left subclavian vein. Proximal to the dentate line, lymphatic drainage is to the inferior mesenteric and periaortic nodes, whereas distal to the dentate line it flows to the inguinal lymph nodes. Therefore, inflammatory and malignant disease of the lower anal canal can manifest with inguinal lymphadenopathy. 

mm

sm

Fig. 98.2  Photomicrograph of small intestine showing its general microscopic architecture. m, Mucosa; mm, muscularis mucosae; mp, muscularis propria; s, serosa; sm, submucosa. (H&E, ×25.)

Extrinsic Innervation The autonomic nervous system—sympathetic, parasympathetic, and enteric—innervates the GI tract. The sympathetic and parasympathetic nerves constitute the extrinsic nerve supply and connect with the intrinsic nerve supply, which is composed of ganglion cells and nerve fibers within the intestinal wall. Innervation of the small intestine and colon is discussed in detail in Chapters 99 and 100, respectively. 

Microscopic Features General Considerations The small and large intestine share certain histologic characteristics. The wall of the small intestine and colon is composed of 4 layers: mucosa (or mucous membrane), submucosa, muscularis (or muscularis propria), and serosa (Fig. 98.2). Mucosa The mucosa consists of the glandular epithelium, lamina propria, and muscularis mucosae (Fig. 98.3A and B). The mucosa is thick and highly vascularized, although less so in distal portions. It has concentric folds (plicae circulares) that are also referred to as the valves of Kerckring. The surfaces of the mucosal folds are studded with villus projections, and these features combine to produce a 400- to 500-fold increase in mucosal surface area. An intestinal villus will typically project 0.5 to 1.5 mm into the lumen, and the height of the villus decreases from proximal to distal small intestine. Villi are wider and more leaf-shaped in the duodenal bulb and proximal duodenum, becoming more finger-like in the distal duodenum, proximal jejunum, and remainder of intestine. The villi are covered with mature absorbing enterocytes interspersed with mucus-secreting goblet cells. Each villus contains an artery, vein, and central lacteal. A capillary bed forms along the epithelium, allowing for rapid clearance of absorbed nutrients, fluids, and electrolytes into the systemic circulation. To facilitate the absorptive process, capillary walls are fenestrated with diaphragmatic covers. The core of the villus also contains nerve fibers, plasma cells, macrophages, eosinophils, and fibroblasts. The villi are surrounded by cylindrical structures called the crypts of Lieberkühn, which extend through the lamina propria down to

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PART X  Small and Large Intestine

ge

lp

A

A

mv

B B

mm

C

Fig. 98.3  Histologic and electron microscopic photographs of small intestine. A, Components of the mucosa: ge, glandular epithelium; lp, lamina propria. Note the absorptive cells that appear as high columnar cells with eosinophilic cytoplasm (arrow). (H&E, ×250.) B, Goblet cells (arrow) and brush border are stained red. mm, Muscularis mucosae. (Periodic acid–Schiff stain, ×150.) C, Microvilli (mv) are seen as delicate finger-like projections on electron microscopic examination, ×9000. (C, Courtesy S. Teichberg, PhD, Manhasset, New York)

the muscularis mucosae. The crypts are lined with more immature epithelium that primarily functions as a secretory rather than an absorptive epithelium. The epithelium of the small intestine is composed of various cell types: absorptive cells (columnar cells), secretory cells (goblet cells), undifferentiated cells, tuft cells, M cells, cup-like cells, and enteroendocrine cells. Crypts contain a similar cell population as the villi, with the addition of Paneth cells and stem cells. The lamina propria is a layer of reticular connective tissue that provides the structural support for the mucosa, but it also contains many cellular elements important for absorption and immunity. The lamina propria is rich in arterioles, venules lacteals, nerve fibrils, and fibroblasts, lymphocytes, macrophages, neutrophils, eosinophils, and mast cells. The muscularis mucosae consists of a thin layer of smooth muscle only 3 to 10 cells thick at the boundary of the mucosa and submucosa. Stem cells are pluripotential cells located at the bases of the intestinal crypts. With intense mitotic activity, stem cells give rise to all types of mature intestinal epithelial cells and at the same time replenish themselves through self-renewal. Mucosal epithelial cells turn over every 5 to 7 days. Intestinal epithelial cells are mature by the time they reach the upper third of the villus. Paneth cells are the only cells that do not migrate. Undifferentiated cells have fewer intracellular organelles and microvilli than absorptive cells. The absorptive cells (see Fig. 98.3A) are high columnar cells with oval basal nuclei, eosinophilic cytoplasm, and a periodic acid–Schiff (PAS)-positive free surface, the brush border (see Fig. 98.3B). On electron microscopic

C Fig. 98.4  Photomicrographs of large and small intestine demonstrating goblet cells. A, Clear, empty-looking cytoplasm (arrow) and basal nuclei are seen with use of H&E, ×250. B, Metachromatic staining of the cytoplasm results with use of the alcian blue stain, ×50. C, The cells demonstrate red staining with use of periodic acid–Schiff stain, ×150.

examination, the brush border is seen to be composed of microvilli (see Fig. 98.3C), which are more numerous in the small intestinal than in the colonic epithelium. Enterocyte microvilli are estimated to increase the luminal surface area of the cell 14to 40-fold. Goblet cells are mucin-producing cells that are scattered among intestinal villi but are more common in the distal ileum and large intestine. Goblet cells are oval or round with flattened basal nuclei (Fig. 98.4A); their cytoplasm is basophilic, metachromatic (see Fig. 98.4B), and PAS-positive (see Fig. 98.4C) and consists mostly of mucin-secreting granules. Mucin is secreted by 2 pathways: in a neutrally mediated continuous manner, and by the active exocytosis of granules in response to extracellular stimuli. Paneth cells are flask shaped with an eosinophilic granular cytoplasm and a broad base that is positioned against the basement membrane (Fig. 98.5). In the small intestine, Paneth cells are located exclusively in the crypts of Lieberkühn and secrete

CHAPTER 98  Anatomy, Histology, Embryology, and Developmental Anomalies of the Small and Large Intestine

α-defensins, antimicrobial proteins, lysozyme, and phospholipase A, thought to be important in protection from infectious pathogens and function to maintain enteric homeostasis.1 Cup cells and tuft cells are 2 intestinal epithelial cell types with unidentified functions. Cup cells are present in villi and crypts largely limited to the ileum. Tuft cells are marked by a tuft of long microvilli projecting from the apical surface of the cell. The mucosa also contains specialized cells called enteroendocrine or neuroendocrine cells (Fig. 98.6A) with specific endocrine functions. Intestinal endocrine cells are sparsely distributed and consist of 11 different cell types (Table 98.1). These are tall columnar cells present in both the crypts and villi and contain

lc

Fig. 98.5  Photomicrograph of small intestinal mucosa demonstrating the crypts of Lieberkühn (lc) and Paneth cells (arrow), which are characterized by granular eosinophilic cytoplasm. (H&E, ×250.)

Fig. 98.6  Microscopic characteristics of neuroendocrine cells of the small intestine. A, Features include clear cytoplasm and a round nucleus (arrow). (H&E, ×250.) B, Neurosecretory granules are seen as electron-dense, round black bodies (arrow) on electron microscopic examination, ×20,000. C, Granules in neuroendocrine cells are stained black with the Grimelius stain (arrow), ×150. D, Cells stained with synaptophysin have brown cytoplasm (arrow), ×250. (B, Courtesy S. Teichberg, PhD, Manhasset, New York.)

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prominent secretory granules. The neuroendocrine cells have been divided histologically into argentaffin (i.e., their granules are able to reduce silver nitrate) or enterochromaffin cells and argyrophilic cells (i.e., granules reduce silver nitrate only in the presence of a chemical reducer). These chemical properties subdivide the cell types, but a unifying concept derived from their common origin and functional capacity has led to the term APUD cells. The amine precursor, uptake, and decarboxylation concept characterizes the cells as having a common embryonic origin from the neural crest and displaying similar cytochemical and electron microscopic features.2 Ultrastructurally, enteroendocrine cells contain membranebound granules with variably sized electrodense cores (see Fig. 98.6B) that consist of large dense-core vesicles and smaller synaptic-type microvesicles. Neurosecretory granules can be demonstrated as dark granules with nonspecific agents (e.g., Grimelius stain [see Fig. 98.6C]), or more specific immunohistochemical stains can be used (e.g., neuron-specific enolase, chromogranin, synaptophysin). Chromogranin enables identification of the large dense-core vesicles, and synaptophysin targets the small synaptic-like microvesicles (see Fig. 98.6D). With specific immunohistochemical staining agents, it is possible to identify the individual chemical and protein components of neuroendocrine cells. The differential expression of certain proteins also makes it possible to subdivide neuroendocrine cell populations. For example, vesicular monoamine transporter (VMAT) has 2 isoforms: VMAT1 is restricted to serotonin-producing enterochromaffin cells, and VMAT2 is expressed by histamineproducing cells, enterochromaffin-like cells, and pancreatic islet cells.3 The hormone products of these cells are discharged into the extracellular space on the basal and basolateral surfaces and have paracrine effects on absorption, secretion, motility, mucosal cell proliferation, possibly immunobarrier control, and even some endocrine effects upon systemic absorption.

A

B

C

D

98

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PART X  Small and Large Intestine

TABLE 98.1  Enteroendocrine Cells of the Intestinal Tract: Cell Types and Products, Vesicle Markers, and Distribution Vesicle Markers Cell Type

Cell Product

LDCV

SLMV

Duod

Jej

Ileum

App

Colon

Rec

P/D1

Ghrelin

CgA, VMAT2

f

f

f

EC

5-HT

CgA, VMAT1

Syn

+

+

+

+

+

+

D

Somatostatin

CgA

Syn

+

+

f

f

f

f

L

GLI/PYY

SgII > CgA

Syn

f

+

+

+

+

+

PP

PP

CgA, SgII, VMAT2

Syn

e

G

Gastrin

CgA

Syn

CCK

Cholecystokinin

+

+

f

S

Secretin, 5-HT

CgA

+

+

GIP

GIP/Xenin

CgA

+

+

f

M

Motilin

+

+

f

N

Neurotensin

f

+

+

CgA

+

App, Appendix; CgA, chromogranin A; Duod, duodenum; e, presence of cells in fetus and newborn; EC, enterochromaffin cell; f, presence of few cells; GIP, gastric inhibitory polypeptide; GLI, glucagon-like immunoreactants (glicentin, glucagon-37, glucagon-29, GLP[glucagon-like peptide]-1, GLP-2); 5-HT, 5-hydroxytryptamine (serotonin); Jej, jejunum; LDCV, large dense-core vesicles; NESP55, neuroendocrine secretory protein 55; PP, pancreatic polypeptide; PYY, PP-like peptide with N-terminal tyrosine amide; Rec, rectum; SgII, secretogranin II (also known as chromogranin C); SLMV, synapticlike microvesicles; Syn, synaptophysin; VMAT1, VMAT2, vesicular monoamine transporter 1, 2; +, presence of cells; >, heavier staining than. Adapted from Solcia E, Capela C, Fiocca R, et al. Disorders of the endocrine system. In: Ming SC, Goldman H, editors. Pathology of the gastrointestinal tract. Philadelphia: Williams & Wilkins; 1998. p 295.

The preferred designation of neuroendocrine cells is by their stored peptide. Serotonin-producing enterochromaffin cells, vasoactive intestinal polypeptide cells, and somatostatin D cells are distributed throughout the small and large intestine. Cells that produce gastrin, ghrelin, gastric inhibitory peptide, secretin, and CCK are found predominantly in the stomach and proximal small intestine. Cells that secrete peptide YY, glucagon-like peptide-1, glucagon-like peptide-2, and neurotensin are found in the ileum.4 M cells are specialized epithelial cells overlying lymphoid follicles and Peyer patches in the small intestine and colon. M cells are an important site of luminal antigen sampling for immune processing by the mucosal lymphoid system. This process of sampling plays an important role in the development and maintenance of immune tolerance, host defense against pathogens, and intestinal homeostasis. The interstitial cells of Cajal (ICC) are found in both the small intestine and colon and are located in the myenteric plexuses within the muscularis propria and the submucosa (Fig. 98.7 [see Chapters 99 and 100]). The ICC are important in the regulation of intestinal peristalsis and function as the pacemaker cells of the intestine. They influence the frequency of smooth muscle contraction, amplify neuronal signals, mediate neurotransmission from enteric motor neurons to smooth muscle cells, and set the smooth muscle membrane potential gradient. The ICC are spindle-shaped or stellate cells with long, ramified processes and express c-kit (CD117), a tyrosine kinase receptor critical for their survival.5  Submucosa The submucosa is a fibrous connective tissue layer that lies between the muscularis mucosae and the muscularis propria. It contains lymphocytes, fibroblasts, mast cells, blood and lymphatic vessels, and a nerve fiber plexus—Meissner plexus— composed of non-myelinated postganglionic sympathetic fibers and parasympathetic ganglion cells. The submucosa supports the mucosa in specialized functions of nutrient, fluid, and electrolyte absorption by conveying a rich network of blood vessels, lymphatics, and nerves that ensure efficient handling of absorbates.

Fig. 98.7  Photomicrograph showing interstitial cells of Cajal in the small intestine. Brown-staining, elongated cells are evident around the myenteric plexus (arrow). (CD117 immunostain, ×250.)

Brunner glands are submucosal glands (see Fig. 98.9B) found primarily in the first portion of the duodenum and in decreased numbers in the distal duodenum; in children, these glands may also be present in the proximal jejunum. The function of Brunner glands is to secrete a bicarbonaterich alkaline secretion that helps neutralize gastric chyme; a mucinous secretion that helps lubricate the mucosa; EGF; a variety of trefoil peptides, bactericidal factors, proteinase inhibitors, and surface-active lipids. The secretions that drain into the base of the duodenal crypts contribute to increased luminal pH by promoting pancreatic secretion and gallbladder contraction. The mucous layer protects the epithelial surface from peptic digestion; this protection is thought to be due to glycoprotein class III mucin glycoproteins.6

CHAPTER 98  Anatomy, Histology, Embryology, and Developmental Anomalies of the Small and Large Intestine

il

1557

98

v

mp

ol

A

Fig. 98.8  Photomicrograph of muscularis propria of small intestine. The myenteric plexus (mp) is seen as a pale area with ganglion cells between the inner and outer layers (il, ol) of the muscularis propria (arrow). (H&E, ×250.)

Muscularis Propria The muscularis propria is mainly responsible for contractility and peristaltic movement of luminal contents through the GI tract. It consists of 2 layers of smooth muscle: an inner circular coat and an outer longitudinal coat arranged in a helicoidal pattern. A prominent nerve fiber plexus called the myenteric or Auerbach plexus is located in the plane between these 2 muscle layers (Fig. 98.8). The ganglia in the myenteric plexus are more prominent than their submucosal counterpart. Parasympathetic and postganglionic sympathetic fibers terminate in parasympathetic ganglion cells, and postganglionic parasympathetic fibers terminate in smooth muscle.  Serosa The serosa is the outermost layer of the intestinal wall and is composed of a thin layer of mesothelial cells, representing an extension of the visceral peritoneum and mesentery as it envelops the intestine. 

Microscopic Organization Small Intestine The mucosa of the small intestine is characterized by folds (plicae circulares, or valves of Kerckring) and villi. The mucosal folds actually comprise mucosa and submucosa. Villi are mucosal folds that decrease in size from the proximal to distal small intestine and are of different shapes in the various segments of the small intestine. They may be broad, short, or leaf-like in the duodenum, tongue-like in the jejunum, and finger-like more distally (Fig. 98.9A). The villous pattern may vary in different ethnic groups; biopsy specimens from Africans, Indians, South Vietnamese, and Haitians have shorter and thicker villi, an increased number of leaf-shaped villi, and more mononuclear cells in comparison with specimens from North Americans. The implications of these changes with regard to symptoms and subclinical GI infection are discussed in Chapter 108. The height of the normal villus is 0.5 to 1.5 mm; villus height should be more than half the total thickness of the mucosa and 3 to 5 times the length of the crypts. Villi are lined by enterocytes, goblet cells, and enteroendocrine cells. Enterocytes are tall columnar cells, each with a basally located, clear, oval-shaped nucleus and several nucleoli. The cells are tightly cemented to the basal lamina and adjoined to adjacent enterocytes at the apical pole by intracellular tight junctions. The luminal surface has microvilli that contain necessary enzymes for nutrient absorption; a central core cytoskeleton is made of actin, villin, fimbrin, brush border myosin, and spectrin. The apical

bg

B Fig. 98.9  Photomicrographs of duodenal mucosa. A, Villi are seen as finger-like projections. B, Brunner glands (bg) are found below the mucosa. (H&E. A, ×250; B, ×150.)

surface of the epithelium carries brush border transporters, Na+/ H+ exchangers, and anion exchangers (see Chapter 101). The junction complexes are made up of 3 components: the proximal tight junction (zonula occludens), the intermediate junction (zonula adherens), and the deep junction, which includes the spot desmosome and the macular adherens zone (see Chapter 101). Movement through junctions is by paracellular transport and is the dominant pathway for passive ion and fluid flow. Tight junctions consist of claudins, occludens, and junctional adhesion molecules that bind and prevent passage of molecules between them in a regulated manner. They are leakier and have a lower resistance in the proximal small intestine, and tighter in the distal intestine. The zonula adherens is less adherent and involved in cell signaling. Spot desmosomes are thought to augment transmembrane linkages spanning the intercellular gap and are involved in cell wall communications. The basolateral membrane is responsible for carriers to facilitate diffusion of organic solutes not coupled to ion movements. Gap junctions allow for communication and intercellular passage of ions and low molecular weight nutrients and intracellular messengers such as cyclic adenosine monophosphate.6-8 Two types of glands are present in the small intestine: Brunner glands (see previously) and crypts of Lieberkühn (intestinal crypts). The crypts of Lieberkühn are tubular glands that extend to the muscularis mucosae (see Fig. 98.5); they are occupied mainly by undifferentiated cells and Paneth cells. Cells are generated at the crypt base and migrate up the villus. During this migration, these cells mature and differentiate into a secretory lineage (goblet cells, enteroendocrine cells) and enterocytes. The commitment of the stem cells to differentiate is acquired in the upper third of the crypt where cells lose their ability to divide. The constant renewal of enterocytes is regulated by human acylcoenzyme A synthetase.9

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Paneth and columnar cells predominate in the base of the crypt. Above the base are absorptive cells and oligomucin cells; the latter originate from undifferentiated cells and differentiate into goblet cells. Goblet cells predominate in the upper half of the crypt. Enteroendocrine cells are admixed with goblet cells. A certain number of CD3+ intraepithelial T lymphocytes (up to 30 per 100 epithelial cells) are normally present in the villi. Smooth muscle is found in the lamina propria of the small intestinal villus, extending vertically up from the muscularis mucosae. Plasma cells containing primarily immunoglobulin A, and mast cells are also present. Lymphoid tissue is prominent in the lamina propria as both solitary nodules and confluent masses—Peyer patches—and is seen in the submucosa. Peyer patches are distributed along the anti-mesenteric border and are most numerous in the terminal ileum; their numbers decrease with age. Most types of enteroendocrine cells are present in the duodenum. Cells that produce ghrelin, gastrin, CCK, motilin, neurotensin, gastric inhibitory peptide, and secretin are restricted to the small intestine.2 The proportions of cells differ in the villi and crypts as well as in different segments of the intestine. Ninety percent of the villus epithelial cells are absorptive cells intermingled with goblet and enteroendocrine cells. The proportion of goblet to absorptive cells is increased in the ileum. The ICC are more abundant in the myenteric plexus of the small intestine than in the colon.5 Colon The colonic walls are similar to those of the small intestine. The outer layer forms the taeniae coli, which run in parallel to the long axis of the colon throughout its entire length. The width of the taeniae extends from 6 to 12 mm, and thickness gradually increases from the cecum to the sigmoid colon. The epithelial layer is smooth with crescentic folds corresponding to external sacculations. The surface epithelium is simple columnar type and is interspersed with vascular cells and goblet cells. The epithelial surface and upper third of the crypts are mostly lined with tall, slender absorptive columnar cells called principal cells. Goblet cells are the second most abundant cells on the surface of the colonic epithelium; they produce mucin, which aids in the passage of feces. Colonic epithelial cells are generated from stem cells at the base of the crypts and migrate toward the intestinal lumen 3 to 5 days after initiation of apoptosis. Most epithelial cells undergo apoptosis when they lose contact with the extracellular matrix and are shed into the lumen through caspase (cysteine-aspartic protease) activation. Caspase activation is responsible for the cleavage of essential intracellular proteins that leads to apoptosis and, therefore, loss of anchorage.10 The mucosa of the large intestine is characterized by the crypts of Lieberkühn, which dip to the muscularis mucosae and contain goblet cells, absorptive and enteroendocrine cells, and undifferentiated cells that are restricted to the lower third of the crypts. Glucagon-like immunoreactant pancreatic polypeptidelike peptide (PYY) with N-terminal tyrosine amide–producing L-cells predominate in the large intestine. Paneth cells are scarce and normally are noted only in the proximal colon. The lamina propria of the large intestine contains solitary lymphoid follicles that extend into the submucosa. Lymphoid follicles are more developed in the rectum and decrease in number with age. Confluent lymphoid tissue is present in the appendix. Macrophages (muciphages) predominate in the subepithelial portion of the lamina propria, are weakly PAS positive, and are associated with stainable lipids.  Anal Canal Microscopically, the anal canal is divided into 3 zones: proximal, intermediate or pectinate, and distal or anal skin. The proximal

rg

ep

A ep as

B Fig. 98.10  Photomicrograph of anal canal. A, Anorectal histologic junction. Transition from rectal glandular mucosa (rg) to proximal anal mucosa lined by stratified squamous epithelium (ep) is evident. B, Pectinate line is characterized by anal mucosa with stratified squamous epithelium (ep) and anal skin (as) containing adnexae (arrow). (A and B, H&E, ×150.)

zone is lined by stratified cuboidal epithelium, and the transition with the rectal mucosa, which is lined by high columnar mucus-producing cells, is called the anorectal histologic junction (Fig. 98.10A). The intermediate or pectinate zone is lined by stratified squamous epithelium but without adnexae (e.g., hair, sebaceous glands) and is also referred to as anoderm. Its proximal margin, in contact with the proximal zone, is called the dentate line; its distal margin, in contact with the anal skin, constitutes the pectinate line, also referred to as the mucocutaneous junction (see Fig. 98.10B). Some authors use the terms pectinate line and dentate line interchangeably. The anal skin is lined by squamous stratified epithelium and contains hair and sebaceous glands. Vasculature Large arterial branches enter the muscularis propria through the serosa and pass to the submucosa, where they branch to form large plexuses. In the small intestine, 2 types of branches arise from the submucosal plexuses: some arteries branch on the inner surface of the muscularis mucosae and break into a capillary network that surrounds the crypts of Lieberkühn; other arteries are destined for villi, each villus receiving 1 or 2 arteries, to set up the anatomic arrangement that allows a countercurrent mechanism, thus aiding absorption. One or several veins originate at the tip of

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each villus from the superficial capillary plexus, anastomose with the glandular venous plexus, and then enter the submucosa to join the submucosal venous plexus. In the colon, branches from the submucosal arterial plexus extend to the surface, giving rise to capillaries that supply the submucosa, and there branch to form a capillary meshwork around the crypts of Lieberkühn. From the periglandular capillary meshwork, veins form a venous plexus between the base of the crypts and the muscularis mucosae. From this plexus, branches extend into the submucosa and form another venous plexus from which large veins follow the distribution of the arteries and pass through the muscularis propria into the serosa.  Lymph Vessels The lymphatics of the small intestine are called lacteals and become filled with milky-white lymph called chyle after eating. Each villus contains 1 central lacteal, except in the duodenum, where 2 or more lacteals per villus may be present. The wall of the lacteal consists of endothelial cells, reticulum fibers, and smooth muscle cells. At the base of the villus, the central lacteals anastomose with the lymphatic capillaries between the crypts of Lieberkühn. They also form a plexus on the inner surface of the muscularis mucosae. Branches of this plexus extend through the muscularis mucosae to form a submucosal plexus. Branches from the submucosal plexus penetrate the muscularis propria, where they receive branches from plexuses between the inner and outer layers. Lymphatic vessels are absent in the colonic mucosa, but the distribution of lymphatics in the remaining colonic layers is similar to that in the small intestine.  Nerves The intrinsic nervous system (enteric nervous system [ENS]) consists of subserosal, muscular, and submucosal plexuses. The subserosal plexus contains a network of thin nerve fibers without ganglia that connects the extrinsic nerves with the intrinsic plexus. The myenteric plexus, or Auerbach plexus, is situated between the outer and inner layers of the muscularis propria (see Fig. 98.8); it consists of ganglia and bundles of unmyelinated axons that connect with the ganglia to form a meshwork. These axons originate from processes of the ganglion cells and extrinsic vagus and sympathetic ganglia. The deep muscular plexus, or Schabadasch plexus, is situated on the mucosal aspect of the circular muscular layer of the muscularis propria. It does not contain ganglia; it innervates the muscularis propria and connects with the myenteric plexus. The submucosal plexus, or Meissner plexus, consists of ganglia and nerve bundles. The nerve fibers of this plexus innervate the muscularis mucosae and smooth muscle in the core of the villi. Fibers from this plexus also form a mucosal plexus that is situated in the lamina propria and provides branches to the intestinal crypts and villi. The ganglion cells of the submucosal plexus are distributed in 2 layers; one is adjacent to the circular muscular layer of the muscularis propria, and the other is contiguous to the muscularis mucosae. Ganglion cells are large cells, isolated or grouped in small clusters called ganglia (Fig. 98.11). Ganglion cells have an abundant basophilic cytoplasm, a large vesicular round nucleus, and a prominent nucleolus. Ganglion cells are scarce in the physiologically hypoganglionic segment 1 cm above the anal verge. 

EMBRYOLOGY Intestinal Development The embryo is a bilaminar germ disk at 3 weeks’ gestation. Through a process called gastrulation, this disk becomes trilaminar and gives rise to the 3 primary germ layers: ectoderm, mesoderm, and endoderm. It also establishes bilateral symmetry, a dorsal-ventral orientation, and an anterior-posterior (A-P) axis.

98

g Fig. 98.11  Photomicrograph showing a normal submucosal plexus of the colon. Ganglia (g) are identified by their oval structure, and nerve trunks are thin (arrow). (H&E, ×150.)

The surface facing the yolk sac becomes endoderm, the surface facing the amniotic sac becomes ectoderm, and the middle layer becomes mesoderm. The oral opening is marked by the buccopharyngeal membrane; the future openings of the urogenital and digestive tracts become identifiable as the cloacal membrane. At 4 weeks’ gestation, the alimentary tract is divided into 3 parts: foregut, midgut, and hindgut, the endoderm connecting with the yolk sac (Fig. 98.12). These segments form a tube by growth and folding. The folding process brings together the endodermal, mesodermal, and ectodermal layers with the corresponding layers on the opposite side, converting the flat endodermal layer into the intestinal tube. Initially the foregut and hindgut are blind-ending tubes separated by a midgut that is open to the yolk sac. As the lateral edges of the midgut fuse to become a tube, there is a narrowing of the communication between the yolk sac and endoderm, producing the vitelline duct (see Fig. 98.12). With folding of the embryo during week 4 of development, the mesodermal layer splits. The portion that adheres to endoderm forms the visceral peritoneum, whereas the part that adheres to ectoderm forms the parietal peritoneum. The space between the 2 layers becomes the peritoneal cavity. The primitive intestine results from incorporation of the endoderm-lined yolk sac cavity into the embryo following embryonal cephalocaudal and lateral folding. The endoderm gives rise to the epithelial lining of the GI tract; muscle, connective tissue, and peritoneum originate from the splanchnic mesoderm. During the 9th week of development, the epithelium begins to differentiate from the endoderm, with villus formation and differentiation of epithelial cell types. Organogenesis is complete by 12 weeks’ gestation. Initially the foregut, midgut, and hindgut are in broad contact with the mesenchyma of the posterior abdominal wall. The intra-embryonic cavity is in open communication with the extraembryonic cavity. Subsequently the intra-embryonic cavity loses its wide connection with the extra-embryonic cavity. By week 5 of embryonic development, splanchnic mesoderm layers are fused in the midline and form a double-layered membrane, the dorsal mesentery, between the right and left halves of the body cavity. The mesoderm surrounds the intestinal tube and suspends it from the posterior body wall, allowing it to hang into the body cavity. The caudal portions of the foregut, midgut, and most of the hindgut are suspended from the abdominal wall by the dorsal mesentery, which extends from the duodenum to the cloaca. The dorsal mesentery forms the mesoduodenum in the region of the duodenum, the dorsal mesocolon in the region of the colon, and the mesentery proper in the region of the jejunum and ileum.11 

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Endoderm Ectoderm Angiogenic cell cluster Buccopharyngeal membrane

Amniotic cavity

Foregut Connecting stalk

Hindgut

Heart tube

Allantois

Pericardial cavity

Cloacal membrane

A

B Buccopharyngeal membrane

Cloacal membrane

Lung bud

Liver bud Midgut

Heart tube

Remnant of the buccopharyngeal membrane

C

Vitelline duct

D

Allantois

Yolk sac

Fig. 98.12  Formation of foregut, midgut, and hindgut (see text for details). (From Sadler YW, editor. Langman’s medical embryology. 10th ed. ­Philadelphia: Lippincott Williams & Wilkins; 2006.)

Molecular Regulation of Intestinal Morphogenesis

Epithelial Cells and Villus Formation

Molecular regulation of intestine formation is a complex network of carefully orchestrated gene expression, activation of signal transduction pathways, and cell-cell interactions that works in a cooperative manner; the balance of signals often determines the developmental pathways that follow. Only selected molecular elements are presented here, but comprehensive reviews are available.12-14

The endoderm transitions from simple epithelium to columnar epithelium in a rostral-caudal (proximal-distal) manner, including in the colon, which initially has villus-like structures until it undergoes reorganization. The mesenchyme invaginates to form longitudinal ridges that become epithelial folds. These folds evolve into villi, and crypt-shaped structures form as secondary lumina. This reorganization occurs through extensive crosstalk between the endoderm and mesoderm that involves transforming growth factor-β, PDGF, FGF, WNT, and EGF. BMPs also expressed in the mesenchyme influence endoderm-mesoderm interactions and epithelial development. A mutation in the receptor BMPR1a results in epithelial cell hyperproliferation and polyp formation, as seen in juvenile polyposis syndrome.13 Other important factors in the formation of the epithelium include the Hedgehog signals (Sonic [Shh] and Indian [Ihh]) and Gli transcription factors (Gli2, GLi3). The protein ezrin, which is required for polarization of the epithelium, and the transcription factor Elf3 interact with Crif1 to regulate epithelial differentiation and villus formation. The transcription factor HNF4α is expressed throughout the intestinal epithelium and, if deleted, causes the epithelium to develop into a colonic phenotype. Finally, beyond genes and transcription factors, global chromatin remodeling also has effects on intestinal epithelial development. 

Intestinal Tube Formation Development of the intestinal tube requires simultaneous inductive and patterning steps. The transforming growth factor-β superfamily member Nodal is required for the mesoderm and endoderm specification in all vertebrate species and plays a secondary role in anterior-posterior (A-P) patterning. Crosstalk and inductive cues exchanged between the mesoderm and endoderm are thought to play a critical role in gastrulation. The interruption of Fox factors (Fox A2, FoxH1), GATA factors, Sox17, Mixl1, or Smad signaling will result in a failure of tube formation, primarily by altering endoderm development and specification.12-14 The Wnt signaling pathway also plays a critical role in intestinal tube formation. Genes expressed during A-P patterning include Hhex, FoxA2, and Sox2 in the anterior gut, while Cdx is expressed posteriorly. Hox genes play an important role in patterning of the mesoderm and ectoderm, while Cdx2 is a critical gene in hindgut formation and intestinal specification and patterning, particularly in cecal development. Other genes and factors that play a role in A-P patterning of the endoderm include FGF, Wnt, BMP, and retinoic acid signaling. Intestinal elongation is also controlled by a number of genes. Deletion of Wnt5a results in an 80% reduction in small intestine and a 63% reduction in colonic length.13 The absence of any one of a family of proteins that interact with Wnt5a (secreted frizzled-related proteins) also adversely affect bowel length.13 

Proliferation and Differentiation of the Epithelium The formation of villi occurs as epithelial cells proliferate and reorganize from a pseudostratified appearance to a simple columnar epithelium. As villi form, distinct epithelial cell types can be identified by morphology and the expression of specific markers. Unlike other aspects of intestinal development, proliferation and differentiation of the epithelium remain important processes that must be maintained throughout adult life. Two major signaling pathways involved in these processes are Wnt/β-catenin and Notch. Wnt/β-catenin is important in crypt formation, for

CHAPTER 98  Anatomy, Histology, Embryology, and Developmental Anomalies of the Small and Large Intestine

Diaphragm

Esophagus

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Lesser omentum

Liver Falciform ligament Stomach

Gallbladder Duodenum Cecum Vitelline duct

Fig. 98.13  Physiologic umbilical herniation of the intestinal loop during normal development. Coiling of small intestinal loops and formation of cecum occur during herniation. The first 90 degrees of rotation occur during herniation; the remaining 180 degrees occur during return of intestine to abdominal cavity. (From Sadler YW, editor. Langman’s medical embryology. 10th ed. Philadelphia: Lippincott Williams & Wilkins; 2006, Fig. 14.26. p 219.)

Allantois

Descending colon

Jejunoileal loops

Cloacal membrane

maintaining the stem cell compartment, proliferation and differentiation in the embryonic and adult intestine, and for Paneth cell maturation. Notch proteins are transmembrane receptors that are important in both proliferation and differentiation of the developing intestine. Evidence suggests that Notch activity regulates factors that influence whether undifferentiated cells will become absorptive or secretory epithelial cells. There also are factors downstream of Wnt/β-catenin and Notch that effect specific lineages: neurogenin3 is required for the formation of enteroendocrine cells; SPDEF directs terminal differentiation of goblet cells; Sox9 regulates Paneth and goblet cell formation; and Klf4 regulates colonic goblet cell differentiation. 

Specific Structures and Systems Duodenum The duodenum originates from the terminal portion of the foregut and cephalic part of the midgut. Early during week 4 of gestation, the caudal foregut begins to expand to initiate formation of the stomach. The liver and pancreas arise at the junction of the midgut and foregut. With rotation of the stomach, the duodenum becomes C-shaped and rotates to the right; the fourth portion becomes fixed in the left upper abdominal cavity. The mesoduodenum fuses with the adjacent peritoneum; both layers disappear, and the duodenum becomes fixed in its retroperitoneal location. The lumen of the duodenum is obliterated during the second month of development by proliferation of its cells; this phenomenon is shortly followed by recanalization. Small intestinal villus and crypt formation occurs in a proximalto-distal progression. The villi appear during week 8 of gestation, along with the microvillus enzymes. At 12 weeks’ gestation, crypts are present and grow between the 10th and 14th week of gestation. At 14 weeks, the intestinal enzymes are at an adult level of activity. Because the foregut is supplied by the celiac artery and the midgut by the SMA, the duodenum is supplied by both arteries and therefore is relatively protected from ischemic injury.11 

Rectum

Midgut In a 5-week embryo, the midgut is suspended from the dorsal abdominal wall by a short mesentery and communicates with the yolk sac by way of the vitelline duct. The midgut gives rise to the duodenum distal to the ampulla, the entire small intestine, and the cecum, appendix, ascending colon, and proximal two thirds of the transverse colon. The midgut rapidly elongates with formation of the primary intestinal loop. Rapid growth of the midgut causes it to elongate, rotate, and to begin to form a loop that protrudes into the umbilical cord. The cephalic portion of this loop, which communicates with the yolk sac by the narrow vitelline duct, gives rise to the distal portion of the duodenum, jejunum, and a portion of the ileum; the distal ileum, cecum, appendix, ascending colon, and proximal two thirds of the transverse colon originate from the caudal limb. During week 6 of embryonic development, the primary intestinal loop enters the umbilical cord (physiologic umbilical herniation) (Fig. 98.13). At 7 weeks’ gestation, the small intestine begins to rotate counterclockwise around the axis of the SMA. At 9 weeks, growth of the intestine causes it to herniate further into the umbilical cord, where it continues to rotate 90 degrees before it returns to the abdominal cavity. At 11 weeks’ gestation, the intestine retracts into the abdominal cavity and continues its counterclockwise rotation another 180 degrees to a total of 270 degrees. The jejunum returns first and fills the left half of the abdominal cavity ultimately taking its position in the LUQ. The ileum returns next and fills the right half of the abdominal cavity ultimately assuming its final position in the RLQ. The colon enters last, with fixation of the cecum close to the iliac crest and the ascending and descending colon attaching to the posterior abdominal wall. Elongation of the bowel continues, and the jejunum and ileum form a number of coiled loops within the peritoneal cavity.11 The cecum originates as a small dilatation or bud of the caudal limb of the primary intestinal loop by approximately 6 weeks of development. Initially, after returning to the abdominal cavity, it lies in the RUQ, then it descends to the right iliac fossa, placing the ascending colon and hepatic flexure in the right side of the

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1st stage

3rd stage

2nd stage

Fig. 98.14  The 3 stages of normal intestinal rotation (see text for details). (From Gosche JR, Touloukian RJ. Congenital anomalies of the midgut. In: Wyllie R, Hyams JS, editors. Pediatric gastrointestinal disease. Pathophysiology, diagnosis, management. 2nd ed. Philadelphia: WB Saunders; 1999.)

abdominal cavity. The appendix originates from the distal end of the cecal bud. Because the appendix develops during descent of the colon, its final position is frequently retrocecal or retrocolonic (Fig. 98.14). 

Mesentery As the caudal limb of the primitive intestine moves to the right side of the abdominal cavity, the dorsal mesentery twists around the origin of the SMA. After the ascending and descending portions of the colon reach their final destinations, their mesenteries fuse with the peritoneum of the posterior abdominal wall, and they become retroperitoneal organs. The appendix, cecum, and descending colon retain their free mesentery. The transverse mesocolon fuses with the posterior wall of the greater omentum. The mesentery of the jejunum and ileum is at first in continuity with the ascending mesocolon; after the ascending colon becomes retroperitoneal, the mesentery only extends from the duodenum to the IC junction.11 

Hindgut The distal third of the transverse colon, the descending colon and sigmoid, the rectum, and the upper part of the anal canal originate from the hindgut. The fetal colon develops over 30 weeks in 3 stages. Primitive stratified epithelium similar to that in the small intestine appears between 8 and 10 weeks. Conversion to villus architecture with developing crypts occurs at 12 to 14 weeks. Remodeling to the adult-type crypt epithelium with loss of the villi occurs at 30 weeks. Initially the urinary, genital, and rectal tracts empty into a common channel, the cloaca. They become separated by the caudal descent of the urorectal septum into an anterior urogenital sinus and a posterior intestinal canal. The lateral fold of the cloaca moves to the midline, and the caudal extension of the urorectal septum develops into the perineal body. In a man, the lateral genital ridges coalesce to form the urethra and scrotum; in a woman, no fusion occurs, and the labia minora and majora evolve. The cloaca is lined by endoderm and covered anteriorly by ectoderm. The most distal portion of the hindgut enters into the posterior region of the cloaca, the primitive anorectal canal. The boundary between the endoderm and the ectoderm forms the cloacal membrane. This membrane ruptures by week 7 of embryonic development, creating the anal opening for the hindgut. The anal membrane separates the endoderm and ectodermal portions of the anorectal canal. The anal membrane marks the pectinate line. The pectinate line marks separation of vascular supply of the upper and lower parts of the anal canal.

This portion is obliterated by ectoderm but recanalizes by week 9. Thus, the distal portion of the anal canal originates from ectoderm and is supplied by the inferior rectal artery, which arises from the internal pudendal artery off the internal iliac artery; the proximal portion of the anal canal originates from endoderm and is supplied by the inferior mesenteric artery by way of the superior rectal artery. The inferior mesenteric ganglia and the pelvic splanchnic nerves innervate the superior portion of the anal canal. The inferior rectal nerve supplies the inferior rectal canal. 

Arterial System Vascular endothelial growth factor (VEGF)-A and its receptors, VEGFR-1 and VEGFR-2, are important for endothelial cell proliferation, migration, and sprouting. Angiopoietins and their receptors, Tie1 and Tie2, play a role in remodeling and maturation of the developing vasculature. For example, vascular dysmorphogenesis is seen with mutation in the Tie2 gene. Vascular malformation is briefly discussed in Chapter 38. Arteries of the dorsal mesentery, originating from fusion of the vitelline arteries, give rise to the celiac, superior mesenteric, and inferior mesenteric arteries. Their branches supply the foregut, midgut, and hindgut, respectively. 

Venous System Vitelline veins give rise to a periduodenal plexus that develops into a single vessel, the portal vein. The SMV originates from the right vitelline vein, which receives blood from the primitive intestinal loop; the left vitelline vein disappears. The umbilical veins join with the hepatic sinusoids, after which the right umbilical vein disappears and the left umbilical vein joins the inferior vena cava; ultimately the umbilical vein is obliterated and forms the ligamentum teres. The cardinal veins and the proximal portion of the right vitelline vein are involved with forming the inferior vena cava. 

Lymphatic System Lymphatic vessels originate from endothelial budding of veins, after which the peripheral lymphatic system spreads by endothelial sprouting into the surrounding tissues and organs. Flt4 (also known as VEGFR-3), a receptor for VEGF, plays a role in development of the vascular as well as the lymphatic systems. Overexpression of VEGF-C, a ligand of Flt4, results in hyperplasia of lymphatic vessels in transgenic mice. Based on animal studies, the homeobox gene Prox1 is essential for normal

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TABLE 98.2  Abnormalities in Normal Embryologic Development

98

Location

Defect

Body Wall Omphalocele

Failure of intestine to return to the abdominal cavity after its physiologic herniation

Gastroschisis

Weakening of abdominal wall

Mesentery Mobile cecum

Persistence of mesocolon

Volvulus

Failure of fusion of mesocolon with posterior abdominal wall

Vitelline Duct Meckel diverticulum

Persistence of vitelline duct (see Fig. 98.17)

Omphalomesenteric cyst

Focal failure of vitelline duct obliteration

Patent omphalomesenteric duct

Complete failure of vitelline duct obliteration

Rotation Malrotation

Failure of rotation of the proximal midgut; distal midgut rotates 90 degrees clockwise

Nonrotation

Failure of stage 2 rotation (see Fig. 98.18)

Reverse rotation

Rotation of 90 degrees instead of 270 degrees

Proliferation Duplication

Abnormal proliferation of intestinal parenchyma

Intestinal Atresia and Stenosis “Apple-peel” atresia

Coiling of proximal jejunum distal to the atresia around the mesenteric remnant

Duodenum

Lack of recanalization

Small and large intestine

Vascular “accident”

Anorectum

Disturbance in hindgut development

Enteric Nervous System Hirschsprung disease

Failure of migration of ganglion cells; microenvironment changes

Intestinal neuronal dysplasia

Controversial

Pseudo-obstruction

Multifactorial (see Chapter 124)

Miscellaneous Intestinal epithelial dysplasia

Abnormalities of the basement membrane

Microvillus inclusion disease

Defective protein trafficking and abnormal cytoskeletal and microfilament function

Other Genetic Defects Congenital chloride diarrhea

Abnormal Cl−-HCO3− exchange in ileum and colon (see Chapter 101)

Congenital glucose or galactose malabsorption

Absence of Na+-glucose co-transporter for glucose and galactose (see Chapter 102)

Congenital lactase deficiency

Decrease in lactase-phlorizin hydrolase (see Chapter 101)

Congenital sodium diarrhea

Defective sodium-proton exchange (see Chapter 101)

Congenital sucrase/isomaltase deficiency

Abnormal intracellular transport, aberrant processing, and defective function of sucrase or isomaltase (see Chapter 102)

Cystic fibrosis (CF)

Defective CF transmembrane conductance regulator (see Chapter 57)

development of the lymphatic system. Homeobox genes contain a conserved sequence of 183 nucleotides. The proteins encoded by homeobox-containing genes act as regulatory molecules that control the expression of other genes. Several families of homeobox-containing genes are known, including the murine Hox family, which has been implicated in pattern formation during embryogenesis. Disruption of this gene in mice causes a chylefilled intestine. Abnormalities in lymphatic system development can result in lymphangiectasia (see Chapter 31). 

Enteric Nervous System The ENS originates from vagal, truncal, and sacral neural crest cells. Most of the ENS cells derive from the truncal and vagal neural crest, enter the foregut mesenchyma, and colonize the developing intestine in a cephalocaudal direction. The truncal neural crest gives rise to ganglia of the proximal stomach, whereas the vagal neural crest supplies ganglia to the entire intestine, including the rectum; this colonization is complete

by 13 weeks of embryonic development. A small component of the ENS originates from sacral neural crest cells. These cells form extraintestinal pelvic ganglia that colonize the hindgut mesenchyma before arrival of the vagal-derived neural crest cells.15 Normal ENS development depends on the survival of cells derived from the neural crest and their proliferation, movement, and differentiation into neurons and glial cells. The prevertebral sympathetic ganglia develop next to the major branches of the descending aorta and innervate tissue supplied by the respective arteries. The vagus nerve and the pelvic splanchnic nerves provide preganglionic parasympathetic innervation to ganglia embedded in walls of visceral organs. Microenvironmental, genetic, or molecular mechanisms may intervene in these processes.

Clinical Implications Table 98.2 summarizes known congenital clinical entities that result from disturbances in embryologic development. GI

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Fig. 98.15  Newborn with omphalocele. Note the translucent sac-like structure with its attached umbilical cord.

malformations can be associated with extraintestinal defects when genes such as those that determine left-right asymmetry are involved. The CFC1 gene plays a role in establishing the leftright axis. Mutations of this gene have been reported in extrahepatic biliary atresia, the polysplenia syndrome (inferior vena cava abnormalities, preduodenal portal vein, intestinal malrotation, and situs inversus), and right-sided stomach and congenital heart disease.16,17 

ABNORMALITIES IN NORMAL EMBRYOLOGIC DEVELOPMENT Abdominal Wall Omphalocele Omphalocele, also known as exomphalos, occurs with a frequency of 1.5 to 3 in 10,000 births. A study evaluating data from the National Birth Defects Prevention Network demonstrated a prevalence of 1.92 per 10,000 births with a male predominance and occurring more frequently when the mother is younger than 20 years or 35 years of age or older, and in pregnancies with multiple gestations.18 Associated anomalies (e.g., sternal defects) result from failure of closure of the cephalic folds; failure of caudal fold development results in exstrophy of the bladder and, in extreme cases, exstrophy of the cloaca. Additional cranial fold abnormalities (i.e., anterior diaphragmatic hernia, sternal clefts, pericardial defects, and cardiac defects) in the setting of omphalocele is known as the pentalogy of Cantrell.19 Omphalocele is a congenital hernia involving the umbilicus. It is covered by an avascular sac composed of fused layers of amnion and peritoneum (Fig. 98.15). The umbilical cord is usually inserted into the apex of the sac, and the blood vessels radiate within the sac wall. Although a central defect is present in the skin and the linea alba, the remainder of the abdominal wall, including surrounding musculature, is intact. Because a small occult omphalocele may not be observed at birth, it is recommended that the umbilical cord be tied at least 5 cm from the abdominal wall at the time of delivery. Close inspection of the umbilical cord before clamping will avoid clamping an occult omphalocele.

Fig. 98.16  Gastroschisis. In this newborn, there is full-thickness disruption of the abdominal wall and protruding viscera without accompanying peritoneum. (From Feldman’s Online Gastro Atlas, Current Medicine.)

With a large omphalocele, the liver and spleen are frequently outside the abdominal cavity. Associated anomalies occur in about 75% of children with omphalocele and include chromosomal abnormalities (e.g., trisomy 13 or 18), nonchromosomal syndromes like Beckwith-Wiedemann syndrome (mental retardation, hepatomegaly, large body stature, hypoglycemia), fetal valproate syndrome, exstrophy of the bladder or cloaca, and OEIS (Omphalocele, Exstrophy of the bladder, Imperforate anus, Spinal defect). Musculoskeletal, cardiovascular, and CNS malformations can also occur.20,21 Prenatally, increased levels of maternal serum AFP suggest the possible presence of an omphalocele. US during pregnancy allows the diagnosis of this abdominal wall defect in most infants, which may allow for karyotyping or amniocentesis if required.22 A fetus with omphalocele is at high risk for intrauterine growth restriction, premature delivery, and fetal death.23 The best survival has been shown to be in isolated cases, and the worst in those with associated chromosomal abnormalities.18 Fetal management, including possible termination of pregnancy in cases of severe chromosomal defects, is determined by the physician in consultation with the family. If pregnancy is continued, mode of delivery and provision for care of a child with possibly coexisting anomalies should be considered before labor and delivery. Operative treatment is required in all patients with omphalocele. The size of the omphalocele determines whether a primary repair or delayed primary closure is selected. Negative pressure wound therapy has a low complication and may be an effective therapy for giant omphalocele.24 Reoperation is necessary in up to 25% of cases of omphalocele, either for stoma reclosure or for subsequent bowel obstruction. 

Gastroschisis Gastroschisis is an abdominal wall defect most commonly located to the right of an intact umbilical cord (Fig. 98.16); rarely, the defect is to the left of the umbilical cord.25 Incidence of gastroschisis is estimated at 3.1 per 10,000 pregnancies but is higher

CHAPTER 98  Anatomy, Histology, Embryology, and Developmental Anomalies of the Small and Large Intestine

in mothers younger than age 20.26 Gastroschisis occurs more frequently in whites and in Hispanic infants than in other races or ethnicities. The cause of gastroschisis is unknown, although several theories have been proposed, including abnormal body wall folding, disruption of the right vitelline artery, and failure of mesoderm formation.27 In gastroschisis, a sac is absent, and the exposure of the viscera to amniotic fluid and a compromised blood supply results in bowel that is edematous, thickened, shortened, and covered in fibrinous exudate.22 Histologically, the bowel is usually normal. Some affected infants may have an inflammatory peel, or serositis, of the bowel that may make individual bowel loops difficult to distinguish. Some 10% to 20% of infants with gastroschisis have associated anomalies (e.g., atresia) and almost all infants with gastroschisis also exhibit malrotation. Other congenital anomalies have been reported in a small number of patients.20 Prematurity is more common in children born with gastroschisis than it is in children with omphalocele, and extraintestinal anomalies are much more common with omphalocele than they are with gastroschisis. Morbidity and mortality in patients with gastroschisis are largely related to intestinal atresia. Gastroschisis may be complicated by necrotizing enterocolitis, with all its attendant short- and long-term complications. Increased maternal levels of AFP are suggestive of gastroschisis and omphalocele. Intrauterine growth restriction is frequently observed. In the fetus antenatally diagnosed with gastroschisis, serial US nonstress tests and delivery as close to term as possible are recommended. Early US markers during pregnancy may be able to be used for prognosis of patients with gastroschisis.28 Gastroschisis requires immediate operation to cover the viscera and prevent desiccation of the tissues. It is necessary to examine the entire bowel in cases of gastroschisis, owing to the intestinal atresias associated with this defect. In most children, the gastroschisis can be closed primarily, but if this is not possible, a silo can be used to provide a protected and moist environment while waiting for the viscera to reduce. For the child with significant intestinal atresia as an associated complication of gastroschisis, bowel exteriorization and secondary closure are often preferred. Most infants require special management and careful serial inspection of the bowel soon after delivery. Use of a spring-loaded silo to cover the bowel may assist with bowel decompression, as well as continuous inspection of blood flow.29 It is crucial to conserve intestinal length in these children. Adhesive SBO is a frequent and serious complication, especially in the first year of life.30 A multicenter cohort study demonstrated a 97.8% survival with sepsis as the only independent predictor of mortality.31

Omphalomesenteric (Vitelline) Duct Abnormalities Between 5 and 7 weeks’ gestation, the omphalomesenteric or vitelline duct (which connects the embryo to the yolk sac) attenuates, involutes, and separates from the intestine. Before this separation, the epithelium of the yolk sac develops an appearance similar to that of the gastric mucosa. Under normal circumstances the omphalomesenteric duct becomes a thin fibrous band that fragments and is absorbed spontaneously during the 5th to 10th week of gestation. Persistence of the ductal communication between the intestine and yolk sac beyond the embryonic stage may result in several anomalies of the omphalomesenteric duct (Fig. 98.17): (1) a blind omphalomesenteric duct, or Meckel diverticulum (Md); (2) an omphalomesenteric or vitelline cyst, in which the duct is closed at both ends but patent centrally with a cystic dilatation; (3) an umbilical-intestinal fistula (see Fig. 98.17A), resulting from the duct remaining patent throughout its length; and (4) complete obliteration of the duct, resulting in a fibrous cord or ligament that extends from the ileum to the umbilicus as an omphalomesenteric band.32 In 1% to 4% of all

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infants, some remnant of the embryonic yolk sac is retained, making the omphalomesenteric or vitelline duct the most common site of congenital GI anomaly; lack of expression of the homeobox gene CDX2 has been implicated in the pathogenesis of these anomalies.33

Meckel Diverticulum Md is an anti-mesenteric outpouching of the ileum that is usually found within 2 feet of the IC junction (see Fig. 98.17B). It occurs in 1.2% to 2% of the population and has a male-to-female ratio of 3:1.34 Md account for 67% of all omphalomesenteric duct remnants.32 Md is a true diverticulum, containing all 3 layers of bowel wall: mucosa, muscularis, and serosa.35 The length of the Md varies from 1 to 10 cm. Ectopic GI mucosa—duodenal, gastric, biliary, colonic, or pancreatic tissue—is present in about 50% of Md, although, 1 study of a series of Md demonstrated 27% had ectopic pancreatic or GI tissue.36 Gastric mucosa accounts for 80% to 85% of all Md-associated ectopic tissue (see Fig. 98.17C). Painless bleeding per rectum is the most common manifestation of Md. Blood in the stool is usually maroon, even in patients with massive bleeding and hypovolemic shock. BRBPR, as might be seen with bleeding from the left colon, is almost never encountered, but melena may be seen in patients with intermittent, less severe bleeding. The cause of bleeding is peptic ulceration secondary to acid production by the ectopic gastric mucosa within the Md; a “marginal” ulcer often develops at the junction of the gastric and ileal mucosae. Although Helicobacter pylori has been observed in the gastric mucosa within a Md, a relationship between bleeding from a Md and presence of this organism is unlikely. Despite massive bleeding, death seldom occurs in children because hypovolemia leads to contraction of the splanchnic blood vessels, causing the bleeding to diminish or cease. Also, children rarely have comorbid conditions that compromise their ability to compensate. Intestinal obstruction is the next most common manifestation of Md and is caused either by intussusception with the diverticulum as the lead point or by herniation through or volvulus around a persistent fibrous cord remnant of the vestigial vitelline duct. In children older than age 4, intussusception is almost always secondary to a Md, although Md–related intestinal obstruction may occur at almost any age; volvulus around a vitelline cord has been described in the neonatal period; as with other causes of obstruction, bilious vomiting and abdominal distention are usually the initial signs. Diverticulitis of a Md occurs as a result of acute inflammation. Most commonly, affected patients are diagnosed as having acute appendicitis, and the diagnosis of Meckel diverticulitis is made at exploratory laparotomy. Perforation occurs in about a third of patients with Meckel diverticulitis and may result from peptic ulceration.37 A chronic form of Meckel diverticulitis (Meckel ileitis) may mimic Crohn disease of the ileum. Rarely, Md has been reported as a predisposing factor to small intestinal ­malignancy.38,39 Md may be an incidental finding.34 The presence of a Md should always be considered in an infant or child with significant painless rectal bleeding although standard abdominal plain films, barium contrast studies, and US are seldom helpful in making the diagnosis; rarely, an enterolith (which is often indistinguishable from an appendicolith) or dilated bowel loops with air–fluid level within the Md may be seen on these conventional studies.40 On CT scan, the Md may present as a tubular blind-ending structure arising from the anti-mesenteric border of the terminal ileum, although it may be mistaken for a normal small bowel loop.40 CT enterography has further increased the ability to detect Md.41 Because bleeding is almost always from ectopic gastric mucosa within the diverticulum, a Meckel scan, which allows imaging of the gastric mucosa, should be the initial diagnostic study (see

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PART X  Small and Large Intestine

Meckel’s diverticulum Vitelline cyst

Umbilicus Vitelline ligament

Vitelline ligaments

A

C

Vitelline fistula

B 5 mins

10 mins

15 mins

20 mins

25 mins

30 mins

D

Fig. 98.17D). Uptake of 99mTc-pertechnetate is by the mucussecreting cells of the gastric mucosa, not the parietal cells. The sensitivity and specificity of Md scintigraphy can be improved by administration of pentagastrin, glucagon, or pretreatment with an H2RA. Pentagastrin increases the metabolism of mucus-producing cells, but this is not the preferred enhancement test because of an associated risk of inducing perforation. Glucagon enhances the study by inhibiting peristaltic dilution and washout of the radionuclide. H2RAs decrease peptic secretion but not radionuclide uptake, retarding the release of 99mTc-pertechnetate from the mucus-producing cells. Unfortunately, even an enhanced Meckel study has only 85% sensitivity and 95% specificity, so a negative scan does not necessarily rule out a Md. When the diagnosis of a bleeding Md is entertained and the Meckel scan is negative, splanchnic angiography and 99mTclabeled red blood cell studies may be used; diagnosis, however, is usually made at surgery. Small bowel wireless capsule endoscopy and in some cases double balloon enteroscopy, has detected a Md in some children with GI bleeding.42,43 

Omphalomesenteric (Vitelline) Cyst Omphalomesenteric (vitelline) cyst is more common in male subjects and is characterized by a mucosa-lined intestinal cystic mass within the center of a fibrous cord.32 The cyst may present as a palpable nodule within the umbilicus and be complicated by infection. 

Fig. 98.17  Vitelline duct abnormalities and features of Meckel diverticulum. A, Schematic representations of a Meckel diverticulum, vitelline cyst, and vitelline fistula. B, Surgical specimen revealing an outpouching of the ileum (Meckel diverticulum). C, Photomicrograph showing replacement of small intestinal mucosa by ectopic gastric oxyntic mucosa that lined a Meckel diverticulum. (H&E, ×150.) D, Meckel diverticulum scan demonstrating initial uptake of 99mtechnetiumpertechnetate (arrows) by the diverticulum at 10 minutes. (D, Courtesy Dr. I. Zanzi.)

Patent Omphalomesenteric (Vitelline) Duct Patent omphalomesenteric (vitelline) duct represents a persistent connection between the distal ileum and umbilicus. This fistula has a male-to-female ratio of 5:1 and accounts for 6% to 15% of omphalomesenteric duct remnants. Diagnosis is usually made in the first few weeks of life after separation of the umbilical cord from the newborn umbilicus. Foul-smelling discharge from the umbilicus is typical.44 Common presenting symptoms include SBO, an acute abdomen, and umbilical abnormalities. Ectopic tissue is seen in a third of cases.45 Examination of the umbilicus reveals either an opening or a polypoid mass resulting from limited prolapse of the patent omphalomesenteric duct. Definitive diagnosis can be made by fistulography. Complications of this type of fistula include prolapse of the patent duct or of the duct and the attached ileum through the umbilicus, which may lead to partial SBO. Prolapse should not be mistaken for an umbilical polyp, because excision of involved tissue might result in perforation. Resection is warranted.44

Omphalomesenteric Band Omphalomesenteric band is diagnosed when the solid cord connecting the ileum to the umbilicus remains intact. This cord may result in SBO from an internal hernia or volvulus. 

CHAPTER 98  Anatomy, Histology, Embryology, and Developmental Anomalies of the Small and Large Intestine

Vitelline Blood Vessel Remnants Failure of involution of vitelline blood vessel remnants results in complications similar to those seen with a retained fibrous cord within the peritoneal cavity. Intestinal obstruction occurs when a portion of the small intestine wraps itself around the band. Treatment of all vitelline duct abnormalities is surgical. 

Malrotations Rotation defects result from errors in the normal embryonic development of the midgut, which gives rise to the distal duodenum, jejunum, ileum, cecum, and appendix, as well as the ascending colon and proximal two thirds of the transverse colon. Aberrations in midgut development may result in a variety of anatomic anomalies, including disorders of rotation and fixation, atresias and stenoses, duplications, and persistence of embryonic structures. Such congenital anomalies may cause symptoms not only in the newborn or neonatal period, but also later in childhood and adulthood. Therefore, congenital anomalies of the midgut are appropriate considerations in the differential diagnosis of intestinal obstruction and ischemia in patients of all ages. Because anomalies of intestinal rotation may remain asymptomatic throughout life, their true incidence is unknown; a prevalence of 0.2% to 0.5% of live births has been reported.46,47 Symptoms usually manifest within the first month of life with bilious emesis and abdominal distention, but presentation may be delayed in mild cases to the fourth decade of life. Older patients may have cramping abdominal pain, vomiting, diarrhea, abdominal tenderness, and blood or even mucosal tissue in the stool from ischemia. If ischemia is allowed to progress, peritonitis and hypovolemic shock may develop, potentially culminating in death. Delay in surgery in patients with ischemic injury may result in a short bowel, necessitating chronic TPN therapy and eventually small bowel transplantation, with or without liver transplantation. Most adult patients with anomalies of intestinal rotation have chronic symptoms for several months or years before diagnosis.

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a counterclockwise direction in the first stage of rotation at about 5 weeks of gestation, however, with the result that the jejunum and ileum remain to the right of the SMA, and the cecum is situated in the sub-pyloric region. In this position, the small intestine and cecum now have the potential to twist around the SMA and each other.48 This is the rotation anomaly in adults most frequently associated with ischemic damage, mandating surgical correction. 

Associated Abnormalities Associated anomalies are seen in 30% to 60% of patients with defects in intestinal rotation. Nonrotation of the midgut is a significant finding in patients with omphalocele, gastroschisis, and diaphragmatic hernia. Rotation defects are seen in about 30% to 50% of infants with duodenal or jejunal atresia and in 10% to 15% of children with intestinal pseudo-obstruction. They are also associated with a variety of other conditions, including Hirschsprung disease (HD), esophageal atresia, biliary atresia, annular pancreas, meconium ileus, intestinal duplications, mesenteric cysts, Md, urologic anomalies, and imperforate anus.49 One recent study demonstrated that patients with omphalocele have a greater risk of developing midgut volvulus.50 Anomalies of rotation can cause acute or chronic intermittent obstruction due to volvulus (see Fig. 98.18D and E). Venous and lymphatic obstruction secondary to volvulus can lead to malabsorption and abnormalities in intestinal motility. Venous obstruction may also lead to ischemic injury of the bowel. Patients may fail to thrive and present with chylous ascites and other symptoms and signs of lymphangiectasia resulting from chronic lymphatic obstruction. Duodenal obstruction can result from midgut volvulus and peritoneal bands between a malpositioned cecum in the subpyloric region and the peritoneum. These bands, called Ladd bands, cross the second or third portion of the duodenum and cause obstruction by intestinal compression or kinking. Ladd bands are an anomaly of peritoneal embryogenesis and persist throughout life. 

Classification

Diagnosis and Management

Anomalies of rotation are usually characterized by the stage in the rotational process at which normal embryonic development of the midgut has been interrupted. Most anomalies of midgut rotation occur during the second stage of rotation and have been characterized as nonrotation, reverse rotation, and malrotation (Fig. 98.18). Of these, nonrotation is most common and reflects complete failure of the second stage of rotation. With this anomaly, the intestinal tract occupies the same position in the abdomen as it does in an 8-week-old embryo; the small intestine is located to the right of the midline, and the colon is positioned to the left. Defects in the first and third stages of rotation are uncommon. Abnormalities in the first stage are associated with extroversion of the cloaca; abnormalities of the third stage cause failure of cecal elongation, and the cecum remains in the RUQ. In adults, reverse rotation of the midgut loop is the most commonly diagnosed defect of the midgut. Reverse rotation of the midgut loop is rare, however, and accounts for only 4% of all rotational anomalies. In reverse rotation, the midgut rotates 180 degrees clockwise during the second stage of rotation, resulting in a net 90 degrees of clockwise rotation. This may produce either the retro-arterial colon type, in which the colon is located behind the SMA, or the liver and entire colon are on the right side of the abdomen, a so-called ipsilateral type of reverse rotation. Malrotation of the midgut loop, a developmental anomaly of intestinal fixation and rotation, occurs when the proximal midgut fails to rotate around the mesenteric vessels during the second stage of rotation. The distal midgut still does rotate 90 degrees in

If time allows, diagnosis can be made by UGI contrast examination and delineation of the site of the duodenojejunal junction. US findings may suggest malrotation if the SMV is seen located to the left of the SMA, in contradistinction to the normal anatomy. In the child with acute onset of bilious vomiting and peritoneal signs, no diagnostic studies should be performed if they delay surgical intervention. In the full-term infant with bilious emesis, anomalies of rotation should be considered first and foremost to avoid the morbidity and mortality associated with these lesions. Ladd procedure, which consists of division of Ladd bands, if present; widening of the mesentery; appendectomy; and fixation of the small intestine on the right and the colon on the left side of the abdomen, is the operation of choice and is may be done either laparoscopically or as an open procedure.51,52 The American Pediatric Surgical association has determined that for asymptomatic patients, one should give consideration to operate on asymptomatic patients who are younger in age, while observation may be appropriate in the older patient.53 

Proliferation Enteric Duplication Enteric duplications are rare, with an incidence of one in 4500 births. The term duplication was introduced by Ladd in 1937. Male individuals appear to be more commonly affected, at 60% to 80% of cases, and about one third have associated congenital

98

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PART X  Small and Large Intestine

Duodenum

Duodenum

Ladd’s bands

Transverse colon

Ascending colon

Jejunoileal loops

Transverse colon Descending colon

A

B

Cecum

D

Jejunoileal loops

Descending colon

C

E

Fig. 98.18  Rotation defects. A and B, Two examples of nonrotation. A, Ladd bands are seen crossing the duodenum; some authors would refer to this as a “mixed rotation.” B, In nonrotation, the small intestine is located to the right of the midline, and the colon is to the left of the midline. C, Reverse rotation. The transverse colon passes behind the duodenum. D, Malrotation with volvulus characterized by a clockwise twist of the mesentery and strangulation. E, Radiologic appearance of malrotation depicting the duodenum to the right of the spine, with a volvulus. (A-C, From Gosche JR, Touloukian J. Congenital anomalies of the midgut. In: Wyllie R, Hyams JS, editors. Pediatric gastrointestinal disease. Pathophysiology, diagnosis, management. 2nd ed. Philadelphia: WB Saunders; 1999. D, Netter illustration from www.netterimages.com. © Elsevier Inc. All rights reserved. E, Courtesy Dr. J. Levenbrown.)

anomalies. The most common GI duplications are in the small intestine followed by the esophagus, colon, rectum, and least commonly, stomach. Within the small intestine, duplications are estimated to occur in the duodenum, 2% to 12%; the ileum, 44%; and the jejunum, 50%. Duplication of the colon is a rare abnormality, accounting for 4% to 18% of all GI duplications. Colonic duplication frequently involves the entire colon but occasionally, several segments of the colon are affected leaving “skip areas” of normal colon; they often involve the cecum.54,55 Duplication of the rectum is the most common of the large bowel duplications. Duplications consist of an epithelial lining from some portion of the GI tract and a smooth muscle wall.35 Enteric duplications are either tubular or spherical; the tubular type communicates with the normal intestinal tract, whereas the spherical type does not. Tubular duplications may join the intestine at one or at both ends of the duplication. Most duplications do not communicate with the adjacent bowel. With the exception of duodenal

duplications, duplications occur on the mesenteric side of the bowel, and a common blood supply and muscular coat are shared by the duplicated segment and the adjacent bowel. Duplication cysts may be completely isolated and have their own blood supply. Small intestinal duplications often contain ectopic pancreatic tissue or gastric mucosa; the latter can be diagnosed by 99mTc radioisotopic imaging.56 The etiology of duplications is unclear but may involve a defect in intestinal recanalization. Duplications may present at any age with 60% to 80% manifesting in the first 2 years of life. Small cystic duplications can be the lead point of an intussusception. Larger tubular duplications can accumulate secretions, dilate, and cause obstructive type symptoms. Duplications that contain gastric epithelium may secrete acid which can result in ulceration and present with GI bleeding57 or perforation; rarely heterotopic gastric mucosa contains H. pylori. Other modes of presentation include chronic abdominal pain, nausea and

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vomiting, jaundice, pancreatitis, and as an abdominal mass.35,58 Duplication of the rectum may be associated with constipation or diarrhea. A high percentage of children with duplications have associated malformations. Adenocarcinoma, neuroendocrine carcinoma, and squamous cell carcinoma have been documented with gastric, small bowel, and colonic duplications,56,59and carcinoid has been described in duplications of the rectum. Neuroenteric cysts attach posteriorly to the spinal cord, are associated with asymptomatic hemivertebrae, and may occur at any level of the GI tract. An intra-abdominal mass may be appreciated in a child with intestinal duplication, either by abdominal palpation or on rectal examination. Stool may contain occult blood from ulcerated ectopic gastric mucosa or ischemic damage. Other symptoms and signs include abdominal distention, constipation, vomiting, and respiratory distress.60 Generalized peritonitis can be the first manifestation of a perforated duplication cyst. In adults, acute abdomen, intra-abdominal mass, symptoms of colonic diverticulitis, and chronic abdominal pain have been observed.61 Small intestinal duplications may be detected by US, which often shows an inner hyperechoic rim with an outer surrounding hypoechoic layer (double-wall sign); peristalsis may be present.35 Pre-operative diagnosis by radiologic evaluation is problematic, but radioisotope studies may prove diagnostic if ectopic mucosa is present in sufficient quantity to yield a positive test. 

Intestinal Atresia and Stenosis Of all the congenital anomalies of the midgut, atresias and stenoses occur most frequently. Intestinal atresia refers to a congenital complete obstruction of the intestinal lumen, whereas stenosis indicates a partial or incomplete obstruction. Atresias occur more commonly than stenoses, and small bowel atresias have a reported incidence of 1 in 1500 live births.62 Small bowel atresias are more common in black infants, low birth weight infants, and twins. Jejunoileal atresias are distributed equally throughout the jejunum and ileum, and multiple atresias are found in up to 20% of children. Colonic atresia occurs infrequently and accounts for less than 10% of all atresias. In the duodenum, atresia results from failure of recanalization of the solid stage of duodenal development, whereas in the remaining small intestine and colon, atresia is the result of intestinal ischemia. Evidence of a vascular “accident” is noted in 30% to 40% of infants with atresia; proposed mechanisms include volvulus, constriction of the mesentery in a tight abdominal wall defect like gastroschisis, internal hernia, intussusception, and obstruction with perforation. Jejunoileal atresia may follow maternal use of ergotamine or cocaine taken during pregnancy and is also associated with congenital rubella. Atresias may also result from lowflow states and placental insufficiency62; in such cases, evidence of a vascular accident will be absent. Absence of fibroblastic growth factor 10 may also result in intestinal atresia.63 In familial cases of jejunoileal atresia, there is probably a disruption of a normal embryonic pathway, making this type of atresia a true embryologic malformation rather than an acquired lesion.64 Duodenal obstruction may result from atresia (40% to 60%), stenosis (35% to 40%), or an intestinal web (5% to 15%); 80% of these atresias are contiguous with or distal to the ampulla of Vater, and virtually all webs are within a few millimeters of the ampulla. Atresias may be multiple. The incidence of duodenal obstruction varies, ranging from 1 in 10,000 to 20,000 live births. About 25% of patients with duodenal atresia are born preterm. Stenosis most often results from extrinsic duodenal obstruction from an annular pancreas. Other anomalies that may cause duodenal obstruction in children with malrotation are Ladd bands, an anterior or preduodenal portal vein, or aberrant intramural pancreatic tissue.

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Fig. 98.19  Plain film of the abdomen showing a “double bubble,” typical of duodenal atresia. The larger bubble is the gastric bubble; the smaller is the duodenal bubble. (Courtesy Dr. J. Levenbrown, Manhasset, New York.)

Clinically, the presentation is that of a proximal intestinal obstruction with bilious vomiting on the first day of life, usually without abdominal distention. With gastric dilatation, the epigastrium may appear to be full by inspection and palpation. Excessive retention of gastric bile-stained fluid is typical. Duodenal obstruction is easily diagnosed by abdominal films revealing a typical “double bubble” sign with a paucity of small intestinal air (Fig. 98.19). Mothers of infants with duodenal obstruction often have polyhydramnios, and US of the uterus may even demonstrate a double bubble in the unborn fetus. Vomiting, abdominal distention, delayed meconium passage, and jaundice are more frequent with jejunoileal than duodenal atresia.65 UGI series may reveal the classic windsock sign which may be seen when a duodenal web results in an intraluminal diverticulum.35 The classification system of Grosfeld and colleagues comprises 5 different types of jejunoileal and colonic atresias (Fig. 98.20).66 In the “apple-peel” atresia or “Christmas tree” deformity (type IIIb), proximal atresia with wide separation of the bowel loops is associated with absence of the distal SMA. The distal ileum receives its blood supply by retrograde perfusion through the ileocolic artery. Type IIIb atresias account for less than 5% of all atresias. Atresias are far more common than stenoses, with a frequency ratio of 15:1. With the exception of multiple atresias and perhaps the apple-peel atresia, heredity appears to be of little significance in most cases. Roughly 50% of children with duodenal atresia have associated malformations. Of this group, 30% have Down syndrome.65 Major anomalies occur less frequently with jejunoileal atresias and colonic atresias than with duodenal atresia. The most common anomalies are malrotation, volvulus, and gastroschisis, all of which can cause intestinal ischemia in-utero.67 Extragastrointestinal anomalies associated with atresias include cardiovascular, pulmonary, and renal malformations, and skeletal deformities. Prematurity is common, ranging in incidence from 25% with ileal atresias to 40% with jejunal lesions; 50% percent of babies

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PART X  Small and Large Intestine I

IIIa

II

IIIb

IV

Fig. 98.20  Classification of jejunoileal atresias. Type I, Mucosa and submucosa form a web or intraluminal diaphragm, resulting in obstruction. A defect in the mesentery is not present, and the intestine is not shortened. Type II, The dilated proximal intestine has a bulbous blind end connected by a short fibrous cord to the blind end of the distal intestine. The mesentery is intact, and the overall length of the small bowel is not usually shortened. Type IIIa, The defect in type IIIa is similar to that in type II in that both types have blind proximal and distal ends. In type IIIa, however, complete disconnection exists. In addition, a V-shaped mesenteric defect is present. The proximal blind end is usually markedly dilated and not peristaltic. The compromised intestine undergoes intrauterine absorption, and, as a result, the intestine is shortened. Type IIIb, In addition to a large defect of the mesentery, the intestine is significantly shortened. This lesion is also known as Christmas tree deformity because the bowel wraps around a single perfusing vessel like the tinsel coil wrapped around a Christmas tree; it is also called an apple-peel deformity. The distal ileum receives its blood supply from a single ileocolic or right colic artery, because most of the superior mesenteric artery is absent. Type IV, Multiple small intestinal atresias are present in any combination of types I to III. This defect often takes on the appearance of a string of sausages because of the multiple lesions. (From Grosfeld JL, Ballantine TVN, Shoemaker R. Operative management of intestinal atresia and stenosis based on pathologic findings. J Pediatr Surg 1979; 14:368-75.)

with multiple atresias are born prematurely. If the obstruction occurs beyond the ampulla of Vater, bilious or feculent vomiting with abdominal distention is seen. The presence of meconium in the colon is uncommon at surgery, but variable amounts may be noted. With distal obstruction, abdominal films may demonstrate multiple dilated air-filled bowel loops. If perforation has occurred in-utero, extraluminal air and intraperitoneal calcifications or calcifications within the scrotal sac may be present, suggesting meconium peritonitis. A “soap-bubble” appearance of the ileum may suggest meconium ileus (cystic fibrosis). Air-fluid levels are rarely seen in meconium ileus. Prenatal US findings in jejunoileal atresia include dilated bowel and polyhydramnios.68 Considerations in the differential diagnosis of distal bowel obstruction include small intestinal and colonic atresias, meconium ileus, HD, and meconium plug with or without small left colon syndrome. In small left colon syndrome, the descending and sigmoid colon are narrowed, usually with a caliber transition at or near the splenic flexure. Typically, neonates with small left colon syndrome are born to mothers with gestational diabetes and may experience resolution of obstruction without operation. Contrast studies of the colon are helpful in making a proper diagnosis. An upper GI contrast study may provide additional important information. Surgery is required to relieve the intestinal obstruction in the atretic or narrowed segment. Postoperative complications include fluid and electrolyte disorders, nutritional and feeding problems from diarrhea due to short bowel and small bowel failure, and failure to thrive. 

Anorectum Anorectal malformations comprise a wide spectrum of diseases that can involve the male and female anus and rectum as well as the urinary and genital tracts.69 Anorectal malformations occur in 1 in 4000 to 5000 newborns and are more common among boys and in children with Down syndrome.70 During normal development, after appearance of the urorectal septum, migration of the primitive anus down the posterior wall of the cloaca may occur. Some experts postulate that a craniocaudal fusion of the lateral urorectal ridges occurs from the walls of the cloaca. Migration of the anus is completed when the urorectal septum reaches the perineum. Anorectal malformations during the 4th to 12th weeks of gestation are believed to result from failure of migration of the anus and excessive fusion. Vascular accidents, maternal diabetes, and maternal ingestion of thalidomide, phenytoin, and trimethadione have all been proposed causes. Defective development of the dorsal cloaca has also been implicated,71 and distal 6q deletions have been reported in sacral or anorectal malformations.72 Alteration in Shh signaling may also play a role in producing abnormal notochord development and sacral or anorectal malformations.73,74 Anorectal malformations may occur with higher frequency in infants born after invitro fertilization.75 Different types of anorectal malformations are illustrated in Fig. 98.21. Anorectal malformations are divided into low (infraor translevator), high (supralevator), and intermediate categories.

CHAPTER 98  Anatomy, Histology, Embryology, and Developmental Anomalies of the Small and Large Intestine

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98

Type 2: Pouch ≤1.5 cm from the anal dimple

Type 3: A blind pouch >1.5 cm from the anal dimple

Type 4: Atresia of the rectum with a normal anus

In females

A

Type 1: A thin membrane over the anus

Rectofourchet

Rectoperineal

In males

Rectovaginal

Rectovesical

B

Rectourethral

Rectoperineal

Fig. 98.21  Anorectal malformations. A, Types of imperforate anus. B, Types of associated fistulas. (Netter illustration from www.netterimages.com. © Elsevier Inc. All rights reserved.)

A functional and practical classification of these malformations, the Wingspread classification, is summarized in Table 98.3A. The classification in Table 98.3B is designed, according to Pena,76 to increase the physician’s awareness of the possibility that these lesions are present as well as to establish therapeutic priorities (e.g., need for colostomy).

Anocutaneous Fistula In anocutaneous (or perineal) fistula, the rectum traverses normally through most of the anal sphincter, but its lower portion deviates anteriorly and ends as a perineal cutaneous fistula anterior to the center of the external anal sphincter. This anomaly is similar in the male and female child, and is the least severe

of all anorectal defects; associated urologic defects are uncommon (10%). All patients achieve bowel control after proper surgical treatment. Examination of the perineum may demonstrate features indicative of a perineal fistula, including a prominent midline skin ridge (“bucket-handle” malformation) and a subepithelial midline raphe fistula having the appearance of a black ribbon owing to its meconium content. Surgery consists of a simple anoplasty, usually done without a protective colostomy. 

Rectourethral Fistula In rectourethral fistula, by far the most frequent anorectal malformation in male children, the rectum descends through a portion of the pelvic floor musculature but focally deviates

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PART X  Small and Large Intestine

Male

Female

A. Wingspread Classification Low* Anocutaneous fistula

common wall. About 30% of affected children have associated urologic defects, and 90% of these achieve bowel control after surgery. In the case of vaginal fistula, the rectum opens in the lower or, less frequently, the upper half of the vagina. 

Anovestibular fistula

Anorectal Agenesis (Imperforate Anus) Without Fistula

Anal stenosis Anocutaneous fistula

In anorectal agenesis, the rectum ends blindly without a fistula approximately 1 to 2 cm above the perineum. Sphincter function is usually preserved, with 80% of these patients achieving bowel control after surgery. Some 50% of children with imperforate anus have Down syndrome. Conversely, 95% of children with Down syndrome who have anorectal malformations will have this specific type of defect. 

TABLE 98.3  Classifications of Anorectal Malformations

Anal stenosis Intermediate† Anal agenesis without fistula

Anal agenesis without fistula

Rectobulbar urethral fistula

Rectovaginal fistula Rectovestibular fistula

High‡ Anorectal agenesis

Anorectal agenesis

With rectoprostatic urethral fistula

With rectovaginal fistula

Without fistula

Without fistula

Rectal agenesis

Cloaca

B. Classification Based on Need for Colostomy76 Colostomy not required Colostomy not required Perineal (cutaneous) fistula

Perineal (cutaneous) fistula

Colostomy required

Colostomy required

Rectourethral fistula

Vestibular fistula

Bulbar

Rectal Agenesis (Atresia) Rectal agenesis occurs more frequently in female than in male children, and consists of complete (atresia) or partial (stenosis) interruption of the rectal lumen between the anal canal and the rectum. On inspection of the perineum, the anus appears normal, but an obstruction can be found 1 to 2 cm above the mucocutaneous junction of the anus. Sphincter function is normal in these patients, and associated urologic defects are rare. Prognosis is excellent, with 100% achieving full bowel control after anorectoplasty. 

Anal Stenosis

Prostatic Rectovesical fistula

Persistent cloaca

Imperforate anus without fistula

Imperforate anus without fistula

Rectal atresia

Rectal atresia

*Low: infra-, or translevator. †Intermediate: between high and low. ‡High: supralevator. B, From Pena A. Imperforate anus. In: Wyllie R, Hyams JS, editors. Pediatric gastrointestinal disease. Pathophysiology, diagnosis, management. 2nd ed. Philadelphia: WB Saunders; 1999. p 499.

anteriorly and communicates with the posterior urethra. This fistula may end in either the lower posterior (bulbar) or upper posterior (prostatic) urethra.76 Prenatal echogenic calcifications within the bowel (due to a mixture of meconium and urine) should suggest an anorectal malformation with rectourinary fistula and bladder outlet obstruction.77 Children with prostatic urethral fistulas more commonly have sacral and urologic defects (60%) than children with bulbar prostatic fistulas (30%). About 85% of children with rectourethral bulbar fistula achieve fecal continence after repair, compared with 60% of children with rectoprostatic fistula.

Rectovesical Fistula In rectovesical fistula, the most proximal anorectal defect in male children, the rectum opens into the bladder neck. These malformations are associated with significant urologic defects (90%), and only 15% of children achieve bowel control after surgical repair. 

Vestibular Fistula In vestibular fistula, the most common anorectal defect of female children, the rectum opens into the vestibular bulb of the clitoris. The vestibular bulbs are erectile structures situated on either side of the vulvovaginal orifice. The rectum and vagina share a thin

Anal stenosis, a fibrous ring located at the anal verge, causes constipation and gives the stool a ribbon-like appearance. Response to dilation or surgical disruption is excellent. 

Persistent Cloaca In the complex defect of persistent cloaca, the rectum, vagina, and urethra are fused into a single common channel that opens into one perineal orifice situated at the site of what should be the opening of the normal urethra. Prognosis depends on the intactness of the sacrum and the length of the common channel. Prognosis is better in children with a shorter common channel ( ileum). The entry mechanisms for these 3 monosaccharides across the BBM are different from the exit mechanism across the BLM (Fig. 102.5A). Glucose and galactose are taken up by the enterocytes via an active transport process whereas fructose enters the cells by a passive, but facilitated mechanism. SGLT1, also known as SLC5A1, is responsible for active uptake of glucose as well as galactose from the intestinal lumen into the cells.39 This transporter accepts either glucose or galactose as the substrate but does not transport both monosaccharides at the same time in a given transport cycle. The driving force for this active transport process comes from the electrochemical Na+ gradient present across the BBM. The Na+/K+ pump in the BLM maintains intracellular Na+ at low levels whereas the luminal contents have higher levels of Na+ originating from biliary, pancreatic, and intestinal secretions and also from the diet. The uptake of each monosaccharide via SGLT1 is coupled with the simultaneous transport of 2 Na+. As glucose and galactose are neutral molecules, their cotransport with 2 Na+ renders the transport process electrogenic, i.e., leading to depolarization of the membrane with a net transfer of 2 positive charges into the cell per transport cycle. Thus, the inwardly directed Na+ gradient as well as the inside-negative membrane potential that are present across the BBM provide the driving force for the active entry of glucose and galactose from the lumen into the absorptive cells of the small intestine. Fructose is not transported via SGLT1; its entry from the lumen into the intestinal absorptive cells occurs via the facilitative sugar transporter GLUT5, also known as SLC2A5.40 The transport process is energy-independent and has no involvement of Na+. Once all 3 monosaccharides enter the enterocyte, they are exported out of the cells into the portal circulation across the BLM. This process occurs via GLUT2, also known as SLC2A2, a low-affinity facilitative sugar transporter.39,40 All 3 monosaccharides are substrates for GLUT2. The low affinity of this transporter is physiologically relevant because it dictates that the net release of glucose, galactose, and fructose from the cells occurs only down their concentration gradients when the intracellular concentrations of these sugars exceed those in the portal blood. Even though the general scheme describing the role of various sugar transporters in the intestinal absorption of the 3 monosaccharides traditionally depicts GLUT2 as the transporter expressed exclusively in the BLM (see Fig. 102.5A), this transporter does traffic to the BBM when the intestinal lumen is faced with a high load of sugar, particularly glucose (see Fig. 102.5B).41 SGLT1-mediated glucose entry is the signal for this trafficking of GLUT2 to the BBM, which has physiologic importance not only in terms of glucose/galactose absorption but also fructose absorption. SGLT1 is a relatively high-affinity transporter for glucose and galactose, and, therefore, it is not efficient in absorbing glucose and galactose under high-sugar load conditions. In contrast, GLUT2 is a low-affinity transporter for all 3 monosaccharides, and therefore, its appearance in the BBM only when the concentrations of these monosaccharides are high in the intestinal lumen ensures maximal absorption. This phenomenon is also important for intestinal fructose absorption. SGLT1 plays no role in fructose transport whereas GLUT2 can transport fructose; therefore, the recruitment of GLUT2 to the BBM under high-sugar conditions suggests that intestinal absorption of fructose across the BBM involves not only GLUT5 but also GLUT2 when dietary intake of carbohydrate is high. In addition, the introduction of a high load of fructose to the small intestinal lumen itself increases the density of GLUT5 in the BBM.42 

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Low-glucose Load in Lumen Portal blood

Lumen SGLT1

2Na+ Glucose/ Galactose

Glucose Galactose Fructose

GLUT2

Defects in Carbohydrate Digestion Fructose GLUT5

A

BLM

BBM

High-glucose Load in Lumen Portal blood

Lumen SGLT1

Glucose Galactose Fructose

GLUT2

2Na+ Glucose/ Galactose Glucose Galactose Fructose

GLUT2

Fructose GLUT5

B

BLM

exocytosis). Deletion of Glut2 is much more lethal than deletion of Sglt1 and Glut5,46 which is expected given the fact that this low-affinity transporter functions in the pancreas as a sensor of circulating levels of glucose to promote insulin secretion in proportion to changes in blood glucose levels. As such, the wholebody deletion of this transporter has a severe phenotype because of the inability of the β cells in the pancreas to secrete insulin in response to blood glucose, thus leading to hypoinsulinemia and hyperglycemia. 

BBM

Fig. 102.5  Transport of monosaccharides across the enterocyte in the small intestine from lumen to portal blood under normal conditions (A) and under high-glucose load conditions (B). See text for details. BBM, brush-border membrane; BLM, basolateral membrane; GLUT2, facilitative glucose transporter 2 (SLC2A2); GLUT5, facilitative glucose transporter 5 (SLC2A5); SGLT1, sodium-coupled glucose cotransporter 1 (SLC5A1).

Knockout Mouse Models for Intestinal Sugar Transporters Genetic deletion studies with all 3 transporters have confirmed their biologic functions. Deletion of Sglt1 in mice leads to glucose/galactose malabsorption without affecting fructose absorption; the trafficking of Glut2 to the BBM in response to high glucose load in the intestine is absent in Sglt1-null mice, highlighting the essential role of Sglt1-mediated glucose entry as the signal for the trafficking of Glut2 to the BBM.43 Deletion of Glut5 leads to defective intestinal absorption of fructose without affecting glucose/galactose absorption.44 The biochemical phenotype of Glut2-knockout mice was a little surprising and unexpected.45 As this transporter was thought to be the only mechanism for the exit of all 3 monosaccharides, defective absorption of glucose in the intestine was expected in Glut2-knockout mice. Contrary to this expectation, however, no defect in the intestinal absorption of glucose was observed, suggesting the presence of other possible mechanisms for the exit of glucose from the cells (e.g.,

As the small intestine is capable of absorbing only monosaccharides, dietary polysaccharides and disaccharides must be digested completely prior to absorption. If the digestive process is faulty, either because of pancreatic insufficiency (i.e., decreased pancreatic amylase) or defects in brush-border carbohydrases, dietary carbohydrates cannot be digested. The undigested carbohydrates then reach the colon where they increase the osmotic pressure leading to secretion of water into the lumen, with resultant abdominal bloating and diarrhea (osmotic diarrhea). The resident bacteria in the colon hydrolyze these carbohydrates and ferment the released sugars. In the process, gas is produced, largely in the form of hydrogen, leading to flatulence and increased appearance of hydrogen in the expired air from lungs. This is the basis of the breath hydrogen test that is used to monitor defects in carbohydrate digestion in the intestine (see Chapter 105). Lactose intolerance is the most common defect in the digestion of dietary carbohydrates and results from deficiency of the brushborder disaccharidase lactase. Contrary to common assumption, however, lactose intolerance is the normal phenomenon and it is lactose tolerance that results from genetic mutations.47,48 In all mammals including humans, milk was supposed to be a normal dietary component only during infancy. Accordingly, the intestinal enzyme lactase that hydrolyzes the milk disaccharide lactose to generate the absorbable monosaccharides glucose and galactose is expressed at high levels at birth and stays high until the weaning period. Subsequently, the expression of the enzyme decreases significantly to the much lower levels found in adults. This makes teleologic sense because if milk is not a normal dietary constituent in adults, why would the intestine need to express the enzyme? However, when domestication of ruminants as a source of milk started during civilization in certain populations of the world tens of thousands of years ago, milk became a normal component of diet, even in adults. Milk has high nutritional value not only for the infant but also for the adult. Milk albumin is a protein with a 100% nutritional value and is the gold standard against which the nutritional value of any other protein is evaluated. Milk is also rich in carbohydrate (lactose) and calcium. However, the normal phenomenon of decreased lactase expression in adults became a problem for those who consumed milk because of their inability to digest lactose and the resultant clinical manifestations (see Chapter 104). Some adults, however, were able to tolerate milk in their diet and these individuals were found to have mutations in the gene coding for lactase, which prevented the normal age-related decline in expression of the enzyme. Such mutations provided a biologic and probably survival advantage in those civilizations in which milk and other dairy products were normal components of the adult diet, most notably peoples of Northern European descent and certain African nomads; as such, lactose intolerance is not common in these populations. Thus, the “wild type” is characterized by lactose intolerance whereas the “mutant type” is characterized by the ability to tolerate milk without undesirable clinical symptoms. The clinical manifestations in lactoseintolerant subjects are solely associated with the presence of milk and other dairy products in the diet. These individuals have no problems digesting carbohydrates from other sources. Therefore,

CHAPTER 102  Digestion and Absorption of Carbohydrate, Protein, and Fat

an increase in breath hydrogen in expired air from the lungs is seen in lactose-intolerant subjects only upon ingestion of lactosecontaining foods; ingestion of starch, glycogen, or sucrose does not increase the levels of breath hydrogen nor does it produce any of the symptoms associated with lactose intolerance. Sometimes there is a misconception in the lay public that lactose intolerance is due to an allergy to milk; this is not true. Congenital sucrase-isomaltase deficiency is a rare autosomal recessive disease that is associated with defective digestion of starch, glycogen, and sucrose.49,50 As this bifunctional enzyme possesses maltase, sucrase, and isomaltase activities, it is obligatory not only for the debranching of α-limit dextrins arising from the digestion of amylopectin and glycogen, but also for the hydrolysis of sucrose as well as maltose arising from the digestion of starch and glycogen. The clinical manifestations of the disease are again related to undigested carbohydrates reaching the colon, resulting in osmotic diarrhea, bacterial fermentation, and production of excess of gas. Congenital trehalase deficiency is another rare disorder that is associated with inability to digest the disaccharide trehalose, which is present in mushrooms50 and certain prepared frozen foods, like ice cream, to which it is added because it lowers the freezing point. Patients with trehalase deficiency cannot digest trehalose and as a consequence suffer from abdominal bloating, flatulence and diarrhea after ingestion of trehalose-containing foods. This disease is not common in Caucasian Americans but is quite prevalent in Greenland Inuit natives, occurring in 10% to 15% of the population.51 In addition to the aforementioned genetically driven brush-border enzyme deficiencies, there are secondary causes of defects in carbohydrate digestion in the intestine, examples of which include celiac disease and ZES. Celiac disease is a genetic disease that results in severe intestinal inflammation upon ingestion of gluten-containing foods such as wheat, rye, and barley (see Chapter 107). The inflammation begins in upper small intestine as this is the part of the intestinal tract that is exposed first to dietary gluten. As digestion and absorption of dietary carbohydrates occur primarily in the upper small intestine, celiac disease leads to defects not only in the digestion of carbohydrates but also in their absorption. The principal reason for the malabsorption of carbohydrate in celiac disease is the inflammation-associated blunting of the intestinal villi, thus resulting in a markedly decreased density of absorptive enterocytes and, hence, a decreased surface area of the BBM. The BBM is the membrane that expresses all the carbohydrases (except for amylase) and also the transporters for the monosaccharides; therefore, celiac disease results in carbohydrate malabsorption. ZES is a disease caused by gastrinoma; the resultant increased production of the hormone gastrin promotes massive acid secretion from parietal cells of the stomach (see Chapter 34). Due to the massive acid load from the gastric chyme, the bulk fluid in the lumen of the upper small intestine remains acidic, which is not conducive for the enzyme activities of amylase and brush-border carbohydrases, thereby causing defective digestion of dietary carbohydrates. 

Defects in Carbohydrate Absorption Glucose-galactose malabsorption is the primary defect associated with the transport of monosaccharides in the small intestine. It is an autosomal recessive disorder affecting only the absorption of glucose and galactose; fructose absorption is normal. Based on the substrate selectivity of the sugar transporters in the enterocyte, it is obvious that the disease is related to defective function of SGLT1 (SLC5A1), which is a Na+-coupled active transporter for glucose and galactose, but not fructose. This transporter is expressed in the BBM of the absorptive cells of the small intestine. Mutations in the gene coding for the transporter form the molecular basis for the disease.52,53 The SLC5A1 gene is located on human chromosome 22q13.1; disease-causing mutations can

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be either homozygous or compound heterozygous, and are of different types. The nonsense, frame shift, and splice-site mutations all generate truncated proteins that possess no transport activity. The protein has 14 transmembrane domains, and the disease-causing mutations are found throughout the protein. Some of these mutations cause trafficking defects that render the transporter protein trapped in intracellular compartments and not able to reach the BBM, whereas others do not interfere with the protein trafficking but compromise the transport function. Clinical manifestations of the disease become very obvious early in life. Affected neonates suffer from severe diarrhea and dehydration as soon as milk is introduced as the major dietary source of carbohydrate. Lactose is digested normally in these patients, but the resultant glucose and galactose are not absorbed because of the defective SGLT1, with resultant osmotic diarrhea, massive fluid loss and dehydration. Symptoms occur with exposure to any type of dietary carbohydrate that contains glucose and/or galactose (starch, glycogen, sucrose or even partially hydrolyzed starch). If left untreated, affected patients may develop kidney stones because of chronic dehydration and may die from hypovolemic shock. The only treatment available for these patients is to provide fructose in their diet, which is absorbed via GLUT5 and does not involve SGLT1. For affected neonates, fructose can be given in the form of fruit juices. With fructose in the diet to meet the energy requirements, normal growth and neurological development can be preserved.54 There are no genetic defects known in humans that involve fructose absorption. However, mutations in GLUT2, the transporter in the BLM and BBM of the intestinal absorptive cells for all 3 monosaccharides, have been identified in humans.55 Notable clinical manifestations in patients with mutations in GLUT2 include tubular nephropathy, fasting hypoglycemia, rickets, stunted growth, and hepatomegaly secondary to glycogen accumulation56; the disease resulting from GLUT2 defect is called Fanconi-Bickel syndrome and, interestingly, is not associated with any overt intestinal phenotype in terms of carbohydrate absorption. Many of the aspects of Fanconi-Bickel syndrome can be explained on the basis of expression of the transporter in the kidney, liver, and pancreas as well. As in the intestine, the transporter plays a role in the exit of glucose, galactose, and fructose from the renal tubular cells into blood. The same transporter also plays a role in the exit of glucose resulting from gluconeogenesis, which occurs in the liver and kidney during fasting; this is the likely explanation for the fasting hypoglycemia in patients with loss-of-function mutations in GLUT2. The transporter is also the glucose sensor in the β cells of the pancreas where it plays a role in glucose-induced insulin secretion. Based on this function, one would expect to see diabetes in patients with defective GLUT2, but this is not always the case. Some specific mutations in GLUT2 do lead to fasting hyperglycemia, which eventually transitions to type 2 diabetes. Some mutations, however, result in gain of function, which leads to stimulation of insulin secretion even in the absence of glucose. This observation indicates that the mutant transporter functions as a glucose receptor in β cells and that these mutations render the mutant transporter capable of eliciting the signaling pathways for insulin secretion even in the absence of glucose transport and metabolism.57 In fact, such mutants also promote differentiation of β cells. The lack of any defect in the intestinal absorption of sugars in patients with Fanconi-Bickel syndrome is also seen in Glut2-knockout mice, suggesting the presence of other mechanisms for the exit of monosaccharides from the enterocytes. 

Dietary Fiber and Colonic Bacteria Dietary fiber consists of carbohydrates such as cellulose, hemicellulose, gums, pectins, and chitin, but these are not digested by any of the enzymes arising from mammalian tissues associated with

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PART X  Small and Large Intestine GPR43 ↓cAMP, ↑Ca2+

Acetate Propionate Butyrate 2Na+

SLC5A8 GPR109A

↓HDAC

Acetate Propionate Butyrate

Acetate Propionate Butyrate SLC16A1

↑-HB

Immune cells

H+

↓cAMP, ↑Ca2+ Colonic epithelium

Dietary fiber Bacterial fermentation Acetate Propionate Butyrate (SCFA)

Butyrate GPR109A

Fig. 102.6  Fermentation of dietary fiber by colonic bacteria, and the transport and biologic functions of the fermentation products in colonocytes and immune cells. See text for details. cAMP, cyclic AMP; GPR43, cell-surface G-protein-coupled receptor for SCFA, also known as Free Fatty Acid Receptor FFAR2; GPR109A, cell-surface G-protein-coupled receptor for butyrate and β-hydroxybutyrate (βHB); HDAC, histone deacetylases; SCFA, Short-chain fatty acids; SLC5A8, solute-linked carrier, gene family 5A, member 8 (sodium-coupled monocarboxylate transporter SMCT1); SLC16A1, (solute-linked carrier, gene family 16A, member 1 (proton-coupled monocarboxylate transporter MCT1).

the function of the intestinal tract. Consequently, these carbohydrates remain undigested in the small intestine and reach the large intestine where they are subjected to digestion and fermentation by colonic bacteria. The end products of this process comprise SCFAs containing mostly 2 to 4 carbon atoms (acetate, propionate, and butyrate) (Fig. 102.6).5 These bacterial metabolites are effectively absorbed in the colon via H+-coupled and Na+-coupled monocarboxylate transporters, primarily MCT1 (SLC16A1) and SMCT1 (SLC5A8).5 SCFAs elicit a plethora of biologic functions locally in colon and also in other organs through mediators from immune cells and enteroendocrine cells. The most recognized function of SCFAs, especially butyrate, is their role as the preferred energy substrates for colonocytes. In addition, butyrate functions as an inhibitor of histone deacetylases and thus modulates the epigenetic profile and consequently the transcription of selective genes in the colon (e.g., the cell-cycle regulator p21, GI-selective transcription factor CDX2, intracellular signaling kinase p38); it also serves as the carbon source for the generation of the ketone body β-hydroxybutyrate by colonocytes (see Fig. 102.6).58 These bacterial metabolites also impact colonic function by serving as agonists for certain cell-surface G-protein-coupled receptors that are expressed on the luminal surface of the epithelial cells and enteroendocrine cells present in the colon and lower small intestine and also on certain specific immune cells present in the lamina propria (see Fig. 102.6).7,9 The receptor GPR109A is selectively activated by butyrate and β-hydroxybutyrate59,60 whereas GPR43 is activated by all 3 SCFAs.61,62 Intracellular signaling for both receptors includes a decreased cAMP and/or an increase in calcium. Butyrate also influences the biology of the gut-associated immune system.8 Inhibition of histone deacetylases caused by butyrate and propionate block the development of dendritic cells, which could be at least one of the mechanisms for immune tolerance that is necessary for the host-microbiome symbiosis in the lower intestinal tract.63 SCFAs function as effective tumor suppressors in the colon; the cell-surface receptors as well as transporters in the BBM play a role in this function. In particular, the butyrate receptor GPR109A59,60 and the Na+coupled monocarboxylate transporter SLC5A8 have been shown to protect against colon cancer.64-66 Recent studies with Slc5a8null mice have uncovered an interesting connection between

dietary fiber content and the tumor-suppressive function of the transporter.67 Because of the high-affinity transport of SCFAs, particularly butyrate, by the transporter, the ability of the transporter to protect against colon cancer becomes obvious only under conditions of low dietary fiber content when the luminal production of butyrate by bacterial fermentation becomes markedly reduced, thereby making the high-affinity and low-capacity transport of this SCFA by SLC5A8 quantitatively relevant. 

PROTEINS Dietary Intake Proteins in the diet serve as the source of essential as well as non-essential AAs for cellular metabolism. Deficiency of dietary protein intake will lead to negative nitrogen balance, primarily due to the non-availability of the essential AAs. Proteins provide approximately 10% to 15% of energy intake in an average Western diet, which amounts to about 70 to 100 g protein per day. In addition to the exogenous proteins present in the diet, the intestinal tract is also exposed to endogenous proteins, which arise from salivary, gastric, intestinal, pancreatic, and biliary secretions, and also from desquamated cells of the intestinal tract; collectively, this amounts to about 30 g protein per day. Proteins are digested and absorbed mostly in the small intestine with little or no proteins entering the large intestine under normal conditions. Dietary proteins are either of plant or animal origin. The nutritional value of dietary proteins depends primarily on their composition of AAs, particularly the essential AAs. The body needs all essential AAs; even when just one of the essential AAs is deficient, it will lead to negative nitrogen balance. Milk proteins and egg proteins are considered as the standard for comparing the nutritional value of dietary proteins, with the nutritional value of these standard proteins taken as 100. In general, animal proteins have higher nutritional value than plant proteins. However, plant proteins from different dietary sources can be combined to increase their overall nutritional value, and the deficiency of a given essential AA in one particular plant protein can be complemented by another plant protein that is rich in that selective

CHAPTER 102  Digestion and Absorption of Carbohydrate, Protein, and Fat

essential AA. The quality of dietary proteins is also determined to some extent by their digestibility. For example, a high content of proline generally compromises protein quality because of increased resistance to hydrolysis by proteases and peptidases in the intestinal tract. 

Differences Between Carbohydrate and Protein Digestion and Absorption There is an important difference between dietary carbohydrates and proteins in terms of their digestion and absorption in the intestinal tract. As detailed earlier, dietary carbohydrates must be broken down completely to their monomeric units (i.e., monosaccharides) before absorption can occur; furthermore, the entire process of digestion occurs outside the absorptive cells (luminal digestion and membrane digestion). In contrast, dietary proteins are only partially digested in the lumen of the intestinal tract, yielding a mixture of small peptides and free AAs, which are absorbed into enterocytes; their digestion into their monomeric units (i.e., free AAs) is completed inside the enterocytes. As recently as 15 years ago, it was widely believed that dietary proteins were absorbed in the small intestine only in the form of free AAs in a manner similar to the absorption of dietary carbohydrates in the form of monsaccharides.68 However, it is well accepted now that small peptides are absorbed in the intestine very efficiently; in fact, absorption of small peptides offers several advantages over absorption of free AAs.68 

Digestion Luminal Digestion Luminal digestion of dietary proteins begins in the stomach and is initiated by pepsin that is secreted by chief cells, deep in the mucosal crypts. Pepsin is released into the lumen in the form of inactive precursor (zymogen) known as pepsinogen. This precursor is activated by acidic pH, a process which involves changes in protein folding rather than covalent change, to expose the active site of the enzyme. The resultant active pepsinogen then acts on inactive pepsinogen by limited proteolysis to generate active pepsin which then acts on inactive pepsinogen in an autocatalytic manner to generate more of the active pepsin. Pepsin exhibits an optimal pH of about 3, an ideal feature for being active in the acidic gastric juice. Pepsin is an aspartate protease and its active site contains 2 aspartate residues. The proteolytic reaction catalyzed by pepsin is referred to as acid-base catalysis, and involves the side-chain carboxylic acid group of one aspartate residue functioning as an acid (−COOH) while that of the second aspartate residue functions as a base (−COO−). As the pKa value for this carboxylic acid group is ∼pH 3, this functional group can alternate between an acid and a base very efficiently under conditions of the gastric lumen to bring about the catalysis. Pepsin is an endoprotease and therefore does not generate free AAs but rather produces smaller polypeptides. The peptide bonds that are susceptible to hydrolysis by pepsin are formed by the carboxylic acid groups of the aromatic AAs phenylalanine and tyrosine and the branched chain AA leucine. Because an acidic pH is required for maximal activity of pepsin, the activity of this enzyme on dietary proteins is limited and short-lived. Once the gastric contents leave the stomach and reach the duodenum where the pH of the chyme is neutralized by the bicarbonate present in pancreatic and biliary secretions, pepsin becomes inactive. Interestingly, gastrectomy does not lead to noticeable impairment in the digestion or absorption of dietary proteins, indicating that pepsin is not necessary for the digestion and absorption of dietary proteins under normal conditions. Pancreatic proteases are the major contributors to luminal digestion of dietary proteins. There are at least 3 proteases and

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Trypsinogen Autocatalysis

Enteropeptidase Trypsin Trypsin

Chymotrypsinogen Proelastase Procarboxypeptidase A Procarboxypeptidase B

Chymotrypsin Elastase Carboxypeptidase A Carboxypeptidase B

Fig. 102.7  Proteases and peptidases in pancreatic secretion and their activation in the intestinal lumen by the brush-border enzyme enteropeptidase. See text for details.

2 peptidases that are produced by the acinar cells of the exocrine pancreas. The proteases are trypsin, chymotrypsin, and elastase; the peptidases are carboxypeptidase A and carboxypeptidase B. Just like pepsinogen in the stomach, the proteases and peptidases from the pancreas are released into the pancreatic duct as inactive precursors (zymogens): trypsinogen, chymotrypsinogen, proelastase, and procarboxypeptidases A and B. These enzymes are activated only after they reach the intestine (Fig. 102.7). The first step in this activation process is mediated by enteropeptidase, a proteolytic enzyme associated with the BBM of the enterocytes in the upper small intestine. The primary substrate for enteropeptidase is trypsinogen, which is subjected to limited proteolysis by enteropeptidase to release catalytically active trypsin. Trypsin then acts on the other 4 zymogens and releases catalytically active chymotrypsin, elastase, and carboxypeptidases A and B by limited proteolysis. Trypsin, chymotrypsin, and elastase are endoproteases, which hydrolyze peptide bonds located within the protein substrates, whereas carboxypeptidases are exopeptidases, which hydrolyze peptide bonds located on the carboxyl termini of the protein substrates. There are significant differences in the selectivity of the peptide bonds that are the targets for hydrolysis by these pancreatic enzymes. Trypsin targets peptide bonds that are formed by the carboxylic acid groups of the cationic AAs, lysine and arginine; for chymotrypsin, the peptide bonds must be formed by the carboxylic acid group of aromatic or neutral AAs. Elastase prefers the peptide bonds formed by the carboxylic acid group of small aliphatic (open-chained) AAs. As these are endoproteases, they generate smaller peptides but no free AAs. The target for carboxypeptidase A are the peptide bonds located at the carboxyl termini of polypeptides and formed by aromatic AAs; the target for carboxypeptidase B are the peptide bonds located at the carboxyl termini of polypeptides and formed by basic (cationic) AAs. These 2 exopeptidases generate free AAs. In addition to pancreatic proteases functioning in the digestion of dietary proteins, they are also critical for the absorption of vitamin B12 from natural sources, which explains B12 malabsorption in conditions associated with pancreatic insufficiency (see Chapters 59 and 103). Dietary vitamin B12 exists complexed with proteins and is converted to its free form in the gastric lumen by a process initiated by acid pH. The free vitamin B12 then binds to haptocorrin (also called R protein), a protein present in salivary and gastric secretions. Vitamin B12 preferentially binds to haptocorrin and not to intrinsic factor (IF) because of the acid pH of the stomach contents. The haptocorrin-B12 complex then passes to the proximal small intestine where the pH is neutral. Here pancreatic proteases cleave haptocorrin to release free vitamin B12, which then binds to IF, a process favored at neutral pH; pancreatic proteases have little effect on the IF. The resultant IF-B12

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complex then travels to the ileum where the complex is absorbed via receptor-mediated endocytosis. In the absence of pancreatic proteases, B12 cannot be cleaved from haptocorrin to bind to IF and hence intestinal absorption of vitamin B12 is compromised. 

Membrane Digestion The end products of digestion of dietary proteins, via the combined actions of gastric and pancreatic proteases and carboxypeptidases, are mostly oligopeptides with relatively smaller amounts of free AAs (Fig. 102.8). The BBM of the enterocytes in the jejunum and ileum possesses a battery of peptidases, the most important among them being aminopeptidase N, carboxypeptidase P, dipeptidylpeptidase IV, and angiotensin-converting enzymes. The first 2 enzymes are exopeptidases; aminopeptidase N acts on the amino termini of oligopeptides to release free AAs and carboxypeptidase P acts in a similar manner but at the carboxyl termini of oligopeptides. Aminopeptidase N prefers neutral AAs at the amino terminus for optimal hydrolysis, whereas carboxyl peptidase P prefers proline at the carboxyl terminus for optimal hydrolysis. In contrast, dipeptidylpeptidase IV and the angiotensin converting enzymes ACE1/ACE2 act on amino and carboxyl termini of oligopeptides respectively, to release dipeptides. With the combined effects of luminal digestion and membrane digestion, the end products of protein digestion in the lumen of the small intestine consist predominantly of small peptides (dipeptides and tripeptides) and, to a much smaller extent, free AAs. These products are absorbed efficiently across the BBM of the absorptive cells in the small intestine (see Fig. 102.8). 

Dietary protein Pepsin Polypeptides Trypsin Chymotrypsin Elastase Carboxypeptidases A/B Oligopeptides and amino acids Dipeptides and tripeptides Peptide H+ transporter (PepT1)

Amino acids Amino acid transporters BBM

Brush-border peptidases

Dipeptides and tripeptides

Amino acids

Cytoplasmic peptidases

Intracellular Digestion Even though dipeptides and tripeptides are absorbed into the enterocytes, very little, if any, of these small peptides appear in the portal circulation, suggesting that they are hydrolyzed further inside the cells to free AAs. In general, peptidases associated with the BBM prefer oligopeptides as substrates, whereas peptidases in the cytoplasm prefer relatively smaller peptides (dipeptides and tripeptides) as substrates. 

Absorption of Small Peptides The ability of the absorptive cells of the small intestine to take up intact dipeptides and tripeptides was not appreciated for a long time. Functional evidence for peptide absorption in the small intestine originally came from in vivo studies of patients who suffered from genetic defects of AA absorption. Detailed reviews of the historical perspective of this topic are available.69,70 In patients with AA transport defects, the intestine is unable to absorb the affected AAs: neutral AAs in Hartnup disease and cationic AAs in cystinuria. However, when the affected AAs were given orally in the form of dipeptides or tripeptides, their absorption was normal. This could not be explained if the peptides had to be broken down to free AAs in the intestinal lumen prior to absorption. Thus began the concept of intestinal peptide transport. Most of the early published work on peptide transport used cell-free BBM vesicles isolated from intestinal mucosa. Transport of intact dipeptides and tripeptides could be demonstrated in such vesicles, indicating the presence of a transport mechanism for small peptides in this membrane, bringing them from the intestinal lumen into absorptive cells. The transport process is selective for dipeptides and tripeptides, and does not accept free AAs. It is an active process not directly depending on Na+. Rather, the driving force for the process comes from the electrochemical H+ gradient that exists across the intestinal BBM, thus highlighting the nutritional significance of the microclimate acid pH on the luminal surface of the enterocytes

BLM Amino acid transporters Fig. 102.8  Digestion of dietary protein by gastric and pancreatic proteases/peptidases and brush-border peptidases and the transfer of the digestion products across the absorptive cells of the small intestine. See text for details. BBM, brush-border membrane; BLM, basolateral membrane.

(see Fig. 102.8).71,72 The mechanism involves cotransport of the peptide substrates with H+, although in intact cells in vivo, the transport process is indirectly dependent on Na+ because generation of the transmembrane H+ gradient across the BBM is mediated by Na+/H+ exchange, which in turn is dependent on the transmembrane Na+ gradient (see Fig. 102.1). Furthermore, ATP is the ultimate energy source for peptide transport in the intestine because of the obligatory role of Na+/K+ pump in maintaining the Na+ gradient across the BBM. The discovery of a H+coupled transport system in the plasma membrane of mammalian cells was initially viewed with skepticism because of the general concept held at the time that H+-coupled transport systems exist only in bacteria and that mammalian cells have evolved to use the Na+ gradient rather than the H+ gradient as the driving force for active transport systems.33-35 Today, several decades later, the role of a transmembrane H+ gradient as the energy source for many important nutrients in mammalian cells is an accepted physiologic phenomenon. The H+-coupled peptide transport in the BBM of the small intestinal absorptive cell sets the stage for this paradigm shift. H+-coupled transport systems for other nutrients (iron, folate, certain AAs) were discovered subsequently, thus establishing beyond doubt the role of a transmembrane H+ gradient as a driving force for active transport of at least some of the important nutrients in mammalian cells.

CHAPTER 102  Digestion and Absorption of Carbohydrate, Protein, and Fat

In addition to the involvement of the H+ gradient as a special feature of intestinal peptide transport, there are other characteristics of the transport process that deserve mention. As the process translocates dipeptides and tripeptides across the membrane, it is obviously more advantageous than the transport process for free AAs (i.e., transfer of 2 or 3 AAs instead of one AA per transport cycle). Another notable advantage is in the formulation of enteral diets that are used in various clinical settings. Enteral diets based solely on free AAs are hyperosmolar and tend to be associated with diarrhea. If these enteral diets are formulated with dipeptides and tripeptides as the source of AAs, it would decrease the osmolality of these solutions and abrogate the clinical complication. In addition, commonly used enteral diets based on free AAs are deficient in tyrosine, glutamine, and cysteine because of the poor stability and/or solubility of these AAs; this reduces the nutritional quality of such diets but his can be avoided if these AAs are added in the form of small peptides, which improves their stability and solubility. The peptide transport system prefers L-isomers of AAs in peptide substrates but tolerates D-isomers to some extent. There also seems to be a single transport system in the small intestine for the absorption of all possible 400 dipeptides and 8000 tripeptides that are expected to originate from dietary proteins. In addition, these peptides vary in physicochemical features because of the different constituent AAs (neutral, anionic, cationic, aromatic, aliphatic, and branched-chain AAs). This underlies the apparent promiscuity of the peptide transport process in terms of substrate recognition and the basis for its exploitation in the oral delivery of pharmacologic agents and therapeutic drugs, including β-lactam antibiotics and prodrugs such as valacyclovir and valganciclovir. There are a number of excellent reviews available for readers interested in this topic.73-76 Recent discoveries in the area of intestinal peptide transport have shown that the biologic function of the transport process goes well beyond its widely recognized role in the absorption of dietary proteins and in the oral bioavailability of drugs and prodrugs. The peptide transport system is functionally expressed in the enteroendocrine cells of the small intestine where the membrane depolarization associated with the electrogenic H+-coupled entry of small peptides via the transport system leads to calcium influx and consequent secretion of GLP1.77 These new findings underline the relevance of the intestinal peptide transport system to areas such as diabetes, metabolic syndrome, and brain function.78 The transporter responsible for H+-coupled transport of dipeptides and tripeptides in the intestinal BBM has been cloned and characterized at the molecular level79-81, the protein is called PepT1 or SLC15A1. The functional features of the cloned transporter recapitulate those described for peptide transport in intestinal BBM vesicles. In humans, the protein is expressed and distributed solely in the lumen-facing BBM of the absorptive cells in the duodenum, jejunum, and ileum. Expression of the transporter is regulated by its substrates and also by several hormones including insulin, leptin, EGF, and thyroid hormone, all of which increase the density of the transporter protein in the BBM with or without any accompanied change in mRNA.82,83 Involvement of luminal and membrane digestion, the resultant end products generated in the lumen, and their transport across the enterocyte are summarized in Fig. 102.8. PepT1 is also expressed in the large intestine under normal physiologic conditions, but only in the distal colon where it likely functions in the handling of bacteria-derived peptides and contributes to electrolyte and water absorption.84,85 Colonic expression of PepT1 can be induced under certain pathologic conditions such as inflammation, which might have relevance to the ability of PepT1 to transport the bacteria-derived peptides formyl-MetLeu-Phe as well as muramyl dipeptide.86-88 PepT1 expression in the colon is also induced by certain pathogenic bacteria (e.g., enteropathogenic E. coli).89 These findings indicate that inflammation drives colonic expression of PepT1 and that the function

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of the transporter plays a role in promoting the inflammatory process by providing a conduit between colonic bacteria and the host immune system via the delivery of bacterially derived peptides. This proposed role is controversial, however, because some studies have shown that colonic expression of PepT1 is actually down-regulated during inflammation and that its expression is not required for immune activation.90 Obviously, additional studies are needed to resolve this issue. Colonic expression of the peptide transporter is increased in colon cancer, including colitisassociated colon cancer.87,91 The appearance of PepT1 in cancer might have biologic relevance given that the transporter is energized by a H+ gradient and tumor microenvironment is acidic. Exit of intact peptides across the BLM of the enterocytes does not occur to any significant extent. The bulk of the dipeptides and tripeptides that enter the enterocytes via PepT1 from the lumen are hydrolyzed into free AAs inside the cells, thus eliminating any biologic need for the presence of a peptide transport system in the BLM. Nevertheless, transport of intact peptides has been described in the intestinal BLM although this process is not mediated by PepT1 as this transporter is not expressed in the BLM of intestinal absorptive cells. The physiologic significance and the molecular identity of this transport system remain to be determined. 

Absorption of Amino Acids In contrast to the single transport system that functions for the absorption of small peptides, multiple transport systems operate in the enterocytes for the absorption of free AAs. Before the identification of AA transporters at a molecular level, the intestinal AA transport systems were classified based on substrate selectivity and other biochemical features in patients with specific AA transport defects. Accordingly, there are at least 4 distinct transport systems for AA absorption in the small intestine, each specific for neutral AAs, cationic AA, anionic AAs, and imino acids. The function of these transport systems is defective, respectively, in the following diseases: Hartnup disease, cystinuria, dicarboxylic aciduria, and iminoglycinuria. With the establishment of the molecular identity of most of the AA transporters in mammalian cells, we now know much more about the specifics of intestinal AA transport. A recent review provides a detailed insight into the molecular identity, functional features, and genetic defects related to the intestinal AA transporters.92 Amino Acid Transporters in the Brush-Border Membrane The AA transporters expressed in the intestinal BBM are depicted schematically in Fig. 102.9, which illustrates substrate selectivity, ionic dependence, and the direction of movement of the AA substrates and cotransported ions. System B0 mediates the uptake of neutral AAs across the BBM; it has broad substrate specificity, accepting all of the neutral AAs except for the imino acids proline and hydroxyproline. The transport process is electrogenic and coupled to the transmembrane electrochemical Na+ gradient. The transporter responsible for system B0 has been cloned and characterized at the molecular level.93,94 The B0 transporter gene, SLC6A19, is located on human chromosome 5p15.33 and codes the protein SLC6A19. SLC6A19 requires a chaperone for translocation to the BBM, which is the angiotensin converting enzyme isoform ACE2. System B0,+ is responsible for the uptake of neutral and cationic AAs across the BBM, but its expression is greater in the distal parts of the small intestine and in the large intestine. The transport process is highly concentrative, driven by a Na+ gradient, a Cl− gradient, and the membrane potential, and is obligatorily dependent on Na+ as well as Cl−. System B0,+ is the only transporter that can transport the cationic AA arginine in a Na+/Cl− -coupled

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PART X  Small and Large Intestine

In

Cl–

3Na+

AA0

AA0

AA–

K+

Aromatic amino acids

Na+ AA0

Na+

Na+ AA0

AA+

Pro Hyp H+ Gly

Asn Gln

β Cl– 2Na+ β -Amino acids SLC6A6

2Na+

H+

PAT

SLC36A1

AA+

N

SLC38A5

Iminoacids

ASC

SLC2A5

Cl–

Cystine

X–AG

SLC1A1

SLC6A14

2Na+

ACE2

BBM

SLC6A19

Out Na+ AA0

Imino

ACE2

AA0,+

b0,+

SLC6A20

B0,+

rBAT

B0

SLC7A9

Lumen

H+

AA+

Out

AA0

Blood

L

Na+/AA0 T

+ y L

Na+/AA0 + y L

Na+

SLC6A9

SLC38A2

4F2hc

SLC7A6

4F2hc

SLC7A7

SLC16A10

4F2hc

BLM

SLC7A8

In

AA0

2Na+

Cl– Gly

A

Gly

Fig. 102.9  Amino acid transporters in the brush-border membrane (BBM) and basolateral membrane (BLM) of the absorptive cells of the small intestine with their substrate selectivity, co-transported ions, and direction of transport. The top and bottom rows represent the classical nomenclature corresponding to each of the transporters represented in the lipid bilayer with their Human Genome Organization nomenclature. See text for details. 4F2hc, heavy chain of the antigen 4F2; AA0, neutral amino acids; AA+, cationic amino acids; AA−, anionic amino acids; AA0,+, neutral and cationic amino acids; ACE2, angiotensin converting enzyme 2; AG, Aspartate/Glutamate. The chaperones rBAT, 4F2hc, and ACE2 and their corresponding transporter partners are also represented. rBAT, related to b0,+ amino acid transporter.

manner. An interesting aspect of this transport system is its ability to transport D-AAs and various AA-based drugs and prodrugs,95 which include nitric oxide synthase inhibitors,96 the acyclovir prodrug valacyclovir,97 and the ganciclovir prodrug valganciclovir.98 The transporter responsible for system B0,+ has been cloned.99,100 The gene is SLC6A14 and the protein is SLC6A14. The gene is located on human chromosome Xq23 to q24. System b0,+ is a Na+-independent transport system for neutral and cationic AAs in the intestinal BBM. This system is distinct from system B0,+ even though the substrate specificity is similar for both systems; Na+-dependence is the striking difference between the 2 systems and system b0,+ transports cystine. Cloning studies have demonstrated that system b0,+ functions as a heterodimer, consisting of the transporter (known as b0,+AT) and a chaperone known as rBAT (i.e., related to b0,+ AA Transporter).101 In contrast to system B0 and system B0,+, system b0,+ functions as an obligatory exchanger. It transports cationic AAs and cystine into cells in exchange for neutral AAs. Following cloning of the transport system, b0,+AT is now denoted as SLC7A9 and its gene is located on human chromosome 19q13.1. The chaperone is called SLC3A1 and its gene is located on human chromosome 2q16.3 to p21. System IMINO functions exclusively in the transport of imino acids (proline, hydroxyproline) across the intestinal BBM. Similar to system B0,+, system IMINO is obligatorily dependent on Na+ and Cl−; the transport process is electrogenic, indicating a Na+:Cl−:AA stoichiometry of 2:1:1.102 The transporter responsible for system IMINO has been cloned; it is called SLC6A20.103 The gene is located on human chromosome 3p21.3. SLC6A20 also requires the chaperone ACE2 for translocation to the intestinal BBM.

System X−AG is a Na+-coupled transport system for anionic AAs aspartate and glutamate in the intestinal BBM.104-106 An outward-directed K+ gradient stimulates the transport process, suggesting that the influx of Na+ and AA substrate into cells is coupled to the efflux of K+ out of the cells. H+ also appears to be an additional co-transported ion in the transport process. The transporter responsible for system X−AG has been cloned; it is called SLC1A1 (also as Excitatory Amino Acid Transporter 3)107 and its gene is located on human chromosome 9q24. System ASC is a transport process in the intestinal BBM that mediates the transfer of the AAs alanine, serine, and cysteine in a Na+-dependent manner. Following successful cloning of the transport system, it is now identified as SLC1A5 (also as ASCT2 or system ASC Transporter 2).108,109 The cloned transporter was once believed to represent system B0 because of its ability to transport neutral AAs in a Na+-coupled manner,108 but it is now clear that system B0 is SLC6A19, and not SLC1A5. In contrast to system B0 (SLC6A19), which mediates the unidirectional influx of neutral AAs and Na+, system ASC (SLC1A5) is an obligatory exchanger involving the entry of Na+ and a neutral AA into the cells coupled to the exit of Na+ and another neutral AA out of the cells.110,111 The gene coding for SLC1A5 is located on human chromosome 19q13.3. System N is a Na+-coupled transporter specifically for glutamine, asparagine, and histidine and is expressed in the BBM of intestinal crypt cells.112 The transporter has been cloned; it is called system N2 (SN2) or SLC38A5113, 114 and its gene is located on human chromosome Xp11.23. It transports its AA substrates along with Na+ into cells; interestingly, the transport process also involves simultaneous efflux of H+. Intestinal crypt cells exhibit a

CHAPTER 102  Digestion and Absorption of Carbohydrate, Protein, and Fat

high proliferative capacity, and influx of glutamine via SN2 supports DNA/RNA synthesis via promotion of de novo production of purines and pyrimidines in these cells, while the efflux of H+ maintains a relatively alkaline pH inside the cell, which is known to promote cell proliferation. Thus, SLC38A5 might play an important role in crypt cell proliferation and hence in the renewal of enterocytes in the small intestine under physiologic as well as various pathologic conditions. System PAT is a H+-coupled transport system for small AAs such as glycine, alanine, and proline.115 The protein responsible for this activity is called PAT1 (Proton-coupled Amino Acid Transporter 1).116,117 It is identified as SLC36A1 and the gene coding for the transporter is located on human chromosome 5q33.1. This protein is expressed exclusively in the intestinal BBM in humans.118 System β is a transport system in the intestinal BBM that mediates the Na+/Cl− -coupled uptake of the non-protein AAs taurine and β-alanine.119-121 The protein responsible for the transport function of system β has been identified at the molecular level.122,123 This transporter is known as TAUT (Taurine Transporter) and identified as SLC6A6. The gene coding for the transporter protein is located on human chromosome 3p26 to p24.  Amino Acid Transporters in the Basolateral Membrane The AA transporters expressed in the intestinal BLM are depicted schematically in Fig. 102.9, which illustrates substrate selectivity, ionic dependence, and direction of movement of AA substrates and cotransported ions. These transport systems serve a dual purpose. The Na+-independent transport systems participate in the efflux of AAs from the cells so as to complete their transcellular transfer from the lumen to the portal circulation whereas the Na+-dependent transport systems play a role in the influx of AAs from the blood into cells as a means of supplying AAs for cellular metabolism under conditions of starvation or during the periods between meals. System L is the primary Na+-independent transport system for neutral AAs in the intestinal BLM.124 Molecular cloning studies have identified several isoforms with the characteristic features of system L. The major form that is present in the BLM is LAT2101 and it functions as a heterodimer, consisting of the actual transporter, known as SLC7A8, and its chaperone, known as CD98 or 4F2hc (i.e., heavy chain associated with the 4F2 antigen) or SLC3A2. LAT2 is an obligatory exchanger that is capable of releasing AAs from the cells into the portal circulation, although the process is obligatorily coupled to the influx of certain other AAs into cells. The gene coding for the actual transporter LAT2 is located on human chromosome 14q11.2 and the gene for the chaperone SLC3A2 is on human chromosome 11q13. System T is also a Na+-independent AA transporter like system L, but is not an obligatory exchanger. System T mediates the efflux of aromatic AAs (phenylalanine, tyrosine, and tryptophan) from the cells into portal circulation. The transporter has been cloned and is called SLC16A10 or TAT1 (T Amino Acid Transporter 1).125 There is evidence for functional coupling between TAT1 and LAT2, supported by the expression of both transport systems in the same membrane.126 TAT1 releases aromatic AAs from the cells, but LAT2, being an exchanger and also capable of recognizing aromatic AAs as substrates, uses the aromatic AAs released by TAT1 for exchange to promote the release of nonaromatic AAs from the cells. System y+L transports neutral AAs in a Na+-dependent manner but transports cationic AAs in a Na+-independent manner.127 This feature plays an important role in the ability of the transport system to mediate the efflux of cationic AAs from the intestinal cells into portal blood. Because the cationic AAs (arginine and lysine) carry a net positive charge, the inside-negative membrane potential that normally exists in these cells poses a problem for

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the exit of these AAs. The unique ion-dependence of system y+L, combined with its mode of transport as an obligatory exchanger, offers a solution to this problem. The transport system mediates the influx of neutral AAs in a Na+-coupled manner and this process is coupled to the simultaneous efflux of cationic AAs. With this mode of action, the entire coupled transport process becomes electroneutral, thus making it feasible for the cationic AAs to leave the cells. There are 2 isoforms of system y+L, each functioning as a heterodimer.101 The actual transporter proteins are called y+LAT1 and y+LAT2 and both work with CD98/4F2hc/SLC3A2 as the common chaperone. Both isoforms operate in the intestinal BLM. Following successful cloning of the actual transporters, y+LAT1 is called SLC7A7 and y+LAT2 is called SLC7A6; the corresponding genes are located on human chromosomes 14q11.2 and 16q22.1 to q22.2, respectively. Three transport systems work solely for the influx of AAs into cells across the intestinal BLM. These are system y+, system A, and system GLY. System y+ is Na+-independent and selective for the cationic AAs.124 It is not an obligatory exchanger, which makes it work for the influx of arginine and lysine into cells, facilitated by the inside-negative membrane potential. Several isoforms of system y+ have been identified from the molecular cloning studies; they are called the isoforms of CAT (Cationic Amino Acid Transporter).101 CAT1 is primarily responsible for the activity of system y+ in the BLM. This transporter is identified as SLC7A1, and its gene is located on human chromosome 13q12 to q14. System A is a Na+-coupled transport system for all neutral AAs as well as imino acids. It holds a special place in the field of AA transport because it was the first AA transport system to be identified functionally in mammalian cells. The presence of this transport system in the intestinal BLM was described using glutamine as a substrate; the characteristics of glutamine uptake across this membrane show all the features ascribed to system A.128 As the transport process is Na+-coupled, electrogenic, and does not involve obligatory exchange, thermodynamically it is suitable only for the influx of its substrates into cells. Based on the molecular cloning studies, system A consists of 3 different isoforms.129 The pattern of tissue expression of each of these isoforms suggests that the isoform known as SNAT2 (Sodiumcoupled Neutral Amino Acid Transporter 2) or ATA2 (Amino Acid Transporter A2) is likely to be responsible for the system A transport in the BLM. This isoform mediates Na+-coupled influx of neutral AAs, including glutamine, in an electrogenic manner.130,131 The transporter is identified as SLC38A2 and the gene is located on human chromosome 12q. System GLY is a Na+/Cl− -coupled transport system for glycine. The transport process is electrogenic, with a Na+:Cl−:glycine stoichiometry of 2:1:1. There are 2 isoforms of this transport system, known as GLYT1 and GLYT2. GLYT1 is the isoform expressed in the small intestine. The localization of GLYT1 in the BLM has been demonstrated by immunohistochemical studies.132 The principal function of this transporter is to provide glycine to intestinal cells from blood for cellular metabolic pathways such as glutathione synthesis and purine synthesis.133 The transporter is identified as SLC6A9 and the gene is located on human chromosome 1p31.3.  Function of Brush-Border Peptidases in the Transport of Peptides and Amino Acids Two peptidases associated with the intestinal BBM merit special mention with regard to their role in the absorption of dipeptides and AAs. Dipeptidylpeptidase IV and angiotensin converting enzymes ACE1 and ACE2 release dipeptides from the amino terminus and the carboxyl terminus of larger peptides, respectively. As the peptide transporter PepT1 accepts dipeptides as substrates, the function of these 2 peptidases is linked to the transport function of the peptide transporter. The expression of the

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PART X  Small and Large Intestine

peptidases and the peptide transporter in the same membrane of the intestinal absorptive cells makes this functional link feasible; this has been demonstrated elegantly for dipeptidylpeptidase IV.134 In addition to the role of ACE2 as a supplier of dipeptide substrates for PepT1, it also functions as a chaperone for the AA transporters B0AT1 (SLC6A19) and IMINO (SLC6A20) (see Fig. 102.9).135,136 These 2 transporters are absent in the intestinal BBM of Ace2-null mice.136 Physical interaction between ACE2 and SLC6A19 has been demonstrated.137 SLC6A19 also interacts with aminopeptidase N in the intestinal BBM,137 and it is likely that the functional significance of this interaction is similar to that of the interaction between the dipeptide-releasing peptidases (dipeptidylpeptidase IV and ACE1/ACE2) and the peptide transporter PepT1. SLC6A19 is the primary transporter for neutral AAs in the BBM, and aminopeptidase N is an enzyme that releases neutral AAs from the amino terminus of oligopeptides; therefore, the physical interaction between the AA transporter SLC6A19 and the amino-acid-releasing aminopeptidase N brings the 2 proteins close to each other to make it efficient for the transporter to transport the AAs immediately after their release by the peptidase.  Amino Acid Transporters in the Colon The digestion and absorption of dietary proteins occurs primarily in the small intestine, and very little, if any, of the dietary proteins reaches the large intestine. Nonetheless, significant amounts of AAs are generated in the colon by bacterial metabolism, most of which are synthesized endogenously by these bacteria. Two specific AA transporters, namely SLC6A14 (ATB0,+ or system B0,+) and SLC36A1 (PAT1), are expressed in the BBM of colonic epithelial cells.138,139 Expression levels of SLC6A14 are higher in the colon than in the small intestine; in contrast, the expression of SLC36A1 is lower in the colon than in the small intestine. It is likely that these transporters play a role in the absorption of bacteria-generated AAs, although because the colonocyte BBM does not express the whole battery of AA transporters as does the small intestine, the colonic epithelial cells rely more on AAs in the circulation than on AAs in the lumen for their AA supply. Furthermore, colonic absorption of AAs is unlikely to be a major determinant of AA levels in the circulation. A recent study in mice has shown that plasma levels of AAs are similar with or without Slc6a14, the major AA transporter in the colon.140

Defects in Protein Digestion Digestion of dietary proteins in the intestinal tract occurs predominantly in the small intestine. The process becomes defective under conditions of diminished proteolytic enzymes responsible for luminal digestion of the proteins. This can occur in CF, a genetic disease associated with decreased function of the exocrine pancreas with defective secretion of pancreatic enzymes, including all the proteases (see Chapter 57).141 But the defect in pancreatic secretion is not restricted only to proteases; secretion of all the enzymes related to the digestion of dietary fat and carbohydrate (e.g., lipase, phospholipase, amylase) is also affected.142 Consequently, CF is associated with generalized malabsorption of all major nutrients in the diet. Digestion of proteins is also compromised in patients with genetic absence of the brush-border enzyme enteropeptidase.143 Because this enzyme is responsible for the activation of trypsinogen, the inactive zymogen form of trypsin secreted by the pancreas, in the intestinal lumen, deficiency of enteropeptidase leads to defective protein digestion. This defect, however, is not solely due to trypsin deficiency. Activation of zymogen forms of other proteases in pancreatic secretion is dependent on trypsin; therefore, the activity of all pancreatic proteases is affected in the intestinal lumen. Consequently, the major effect of enteropeptidase deficiency is seen in protein digestion. A recent study proposed that enteropeptidase has potential as a drug target for

obesity.144 This idea is based on the fact that enteropeptidase is also responsible for the conversion of pancreatic pro-colipase to colipase in the intestinal lumen. Active colipase is needed for maximal activity of pancreatic lipase and, therefore, pharmacologic blockade of enteropeptidase could interfere with the digestion, and hence absorption, of dietary fat. Celiac disease (non-tropical sprue) is also associated with defective digestion of proteins; this is due to gluten-induced inflammation of the small intestine resulting in decreased surface area of the BBM (see Chapter 107).

Defects in Protein Absorption As protein digestion products are absorbed primarily in the form of small peptides via PepT1 and free AAs via several AA transporters, defects in these transporters can interfere with the absorption of dietary protein. 

Polymorphisms in PepT1 (SLC15A1) There are no known genetic disorders associated with PepT1 (SLC15A1); however, polymorphisms in the gene coding for the transporter that influence its transport function have been reported in humans.145,146 These polymorphisms are found in the protein-coding region of the gene resulting in non-synonymous substitution of AAs. Substitution of proline at position 586 with leucine results in a trafficking defect, thereby reducing the density of the transporter protein in the BBM.145 This polymorphism reduces the velocity of the transport process without affecting the affinity for substrates. Another polymorphism leads to the substitution of phenylalanine at position 28 with tyrosine, which reduces substrate affinity.146 Despite these data from in vitro expression studies, these polymorphisms do not seem to influence protein nutrition to any noticeable extent in vivo.

Disorders of Amino Acid Absorption Hartnup Disease Hartnup disease is a genetic disorder affecting the intestinal and renal absorption of neutral AAs. Based on the defect in the small intestine and kidney, it could be surmised that the affected transport system plays a similar role in both tissues, namely absorption in intestinal epithelial cells and re-absorption in renal epithelial cells; in both tissues, the defect lies in the lumen-facing BBM.147,148 The most easily noticeable biochemical phenotype is the excessive urinary excretion of the affected AAs (neutral amino aciduria). It is a recessive disorder. The clinical manifestations of the disease are primarily related to tryptophan deficiency, which results from urinary loss of this AA. Symptoms resemble those of niacin deficiency (pellagra) because a significant amount of niacin is endogenously synthesized using tryptophan as the precursor. Supplementation of B-complex vitamins is effective in alleviation of symptoms. Even though the defect is present in the intestine and kidney, there are few intestinal manifestations of the defect, particularly in patients residing in developed countries. This is because absorption of free AAs contributes significantly less to the overall absorption of dietary protein than does absorption of small peptides and because dietary protein intake is more than optimal in developed countries. It is important to note that 8 of 10 essential AAs are neutral AAs and that phenylalanine, tyrosine, and tryptophan serve as precursors for important neurotransmitters in the brain (norepinephrine, dopamine, and serotonin). This could provide a molecular basis for the development of severe neurological complications in patients with Hartnup disease in underdeveloped countries where dietary protein intake tends to be less than optimal nutritional needs. Metabolism of neutral AAs by colonic bacteria is another relevant factor to explain the etiology of symptoms in Hartnup

CHAPTER 102  Digestion and Absorption of Carbohydrate, Protein, and Fat

disease, although little is known on this aspect. As the transport system for tryptophan and other neutral AAs is defective in the intestine in these patients, unabsorbed tryptophan is expected to reach the colon where the resident bacteria would metabolize the AA to generate various indole derivatives. Such derivatives are potent activators of the nuclear receptor AhR (aryl hydrocarbon receptor)9,10; this could have implications for the colon in terms of gene expression and hence function. Furthermore, recent studies have shown that oral feeding of tryptophan drastically alters the colonic microbiome and reduces susceptibility to fungal infection; this too involves bacterial metabolites of tryptophan and their ability to activate AhR.149 Tryptophan is also an agonist for the G-protein–coupled receptor GPR142, which is expressed in enteroendocrine cells; these cells secrete GLP-1 in response to tryptophan.22 The relevance of these findings to Hartnup patients remains unknown, but studies with a mouse model of Hartnup disease (Slc6a19-null mouse)150 provide strong support for profound systemic effects of unabsorbed neutral AAs in the intestinal tract.151,152 The defective transporter in Hartnup disease is SLC6A19.93, 94 All mutations identified thus far in this gene in Hartnup patients lead to loss of function of the transporter.147,148 Interestingly, there are patients who exhibit defective neutral AA transport either only in the small intestine or only in kidney. This cannot be explained simply based on loss-of-function mutations in SLC6A19 because the same transporter is expressed in both tissues. However, this transporter employs distinct chaperones for proper trafficking to the BBM in the intestine and kidney; ACE2 is involved in the intestine, whereas collectrin fulfills this function in the kidney. Therefore, loss-of-function mutations in these tissue-specific chaperones are likely to be responsible for the intestine-only and kidney-only subtypes of Hartnup disease.135

Cystinuria Cystinuria is another genetic disorder of AA transport and, as in Hartnup disease, the defect affects both the intestine and kidney. It is the transport of cationic AAs, however, not that of neutral AAs, that is affected in cystinuria153,154 and, in addition, the transport of cystine (Cys-S-S-Cys) is defective. Consequently, patients with cystinuria exhibit a characteristic amino aciduria with increased excretion of all cationic AAs (lysine, arginine as well as ornithine) and cystine; hence the name cystinuria. It is important to note that the transport of cysteine is not affected in this disease. Even though the defect occurs in the intestine and kidney, clinical manifestations are almost solely related to the consequences of the defect in the kidney. Cystine has limited solubility in water and when its concentration is greater than 300 mg/L, cystine crystallizes. The normal plasma level of this AA is 10 to 20 mg/L. In patients with cystinuria, cystine, along with cationic AAs, is not reabsorbed and the concentration of cystine and cationic AAs rise in the tubular lumen as the glomerular filtrate passes through the nephron. Under these conditions, the cationic AAs remain in solution as a result of their better solubility in water, but cystine crystallizes and forms stones. Nephropathy due to cystine stones is the major, and often life-threatening, clinical problem in cystinuria. The urinary excretion of neutral AAs is normal; this biochemical phenotype differentiates cystinuria from Hartnup disease. The defective transport system in cystinuria is system b0,+. At the molecular level, system b0,+ is a heterodimer consisting of a transporter (SLC7A9) and a chaperone (rBAT or SLC3A1); mutations in either of the genes can lead to cystinuria. Analysis of mutations in patients with cystinuria has provided evidence for the involvement of both genes in the disease155,156; Slc7a9-null

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mice phenocopy cystinuria.157 As b0,+ transports cationic as well as neutral AAs, increased urinary excretion of only cationic AAs without evidence of excess excretion of neutral AAs in patients with cystinuria is surprising but can be explained by the fact that b0,+ functions as an exchanger with the influx of cystine and cationic AAs into cells coupled to the efflux of neutral AAs; as a consequence, this transport system plays little or no role in the influx of neutral AAs from the lumen into cells. In addition, there are several other transporters for the handling of neutral AAs in the intestinal and kidney BBM. 

Lysinuric Protein Intolerance Lysinuric protein intolerance (LPI) is another genetic disorder of cationic AA transport that affects both intestine and kidney.158 Unlike Hartnup disease and cystinuria, however, in which the defect lies in the BBM, the defect in LPI is in the BLM. Because of the difference in the location of the defects, the intestinal handling of the affected AAs when presented in the form of small peptides differs among the 3 diseases. Patients with Hartnup disease and cystinuria are capable of absorbing the affected AAs in the form of dipeptides or tripeptides, which patients with LPI are unable to do.159 These small peptides traverse the BBM normally via PepT1, and then are hydrolyzed to free AAs within the cells for exit via the BLM. However, as the defect in LPI is in the BLM, the exit of the released cationic AAs is impaired. In LPI, cationic AAs are absorbed normally across the BBM as free AAs or as small peptides, but the exit of cationic AAs is impaired, thus causing protein malnutrition. In Hartnup disease and cystinuria, the affected AAs are absorbed mostly in the form of small peptides across the BBM; only the absorption of the free form across this membrane is affected. However, as peptide absorption is the major mode of absorption of protein digestion products across the BBM, impairment in the absorption of free AAs in this membrane does not lead to protein malnutrition in Hartnup disease and cystinuria. Patients with LPI cannot tolerate protein in their diet. With the intake of protein-containing meals, these patients suffer from nausea and vomiting and also postprandial hyperammonemia. The etiology of these symptoms and protein intolerance involves a defective urea cycle and inability to detoxify ammonia in the liver.160 As these patients cannot absorb cationic AAs in the intestine and also lose these AAs in urine, plasma levels of these AAs decrease to a significant extent. LPI is actually a multi-organ disease even though the primary defect involves only the intestine and kidney. Arginine and ornithine are necessary for the urea cycle; therefore deficiency of these 2 AAs leads to impairement of the urea cycle, thus precipitating hyperammonemia, which increases the risk of mental retardation. Exposure of the brain cells to excess ammonia leads to conversion of α-ketoglutarate into glutamate and ultimately to glutamine, thus siphoning the citric acid cycle intermediate α-ketoglutarate toward detoxification of ammonia; this suppresses the citric acid cycle and causes ATP depletion, the underlying etiology for mental retardation. Affected children tend to avoid proteins in the diet, including dairy products; this leads to calcium deficiency and hence osteopenia. Because lysine is a precursor for the synthesis of carnitine, LPI also leads to carnitine deficiency. In addition, the altered food preferences toward high-fat and high-carbohydrate meals because of the inability to tolerate protein in the diet cause hyperlipidemia with elevated levels of cholesterol and triglycerides in circulation. The transport system that is defective in this disease is y+LAT1 (SLC7A7), one of the isoforms of system y+L.161,162 There is no evidence of the involvement of the other isoform y+LAT2 (SLC7A6). Even though this second isoform is expressed in the BLM of the intestine and kidney, apparently it does not compensate for the loss of y+LAT1.

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TABLE 102.1  Enzymes Involved in Fat Digestion in the Intestinal Lumen Enzyme

Source

Substrate

Product

Activation by Trypsin

Gastric lipase

Stomach

Triglycerides

Diglycerides and fatty acids

No

Pancreatic lipase

Pancreas

Triglycerides

2-Monoglycerides and fatty acids

No

Colipase

Pancreas

Phospholipase A2

Pancreas

Phospholipids

Lysophospholipids and fatty acids

Yes

Carboxylic ester hydrolase

Pancreas

Cholesteryl esters

Cholesterol and fatty acids

No

Yes

FAT Dietary Lipids Dietary lipids account for approximately one-third of daily caloric intake in the Western diet (∼100 g/day) and consist primarily of triglycerides (∼95%), with phospholipids and cholesterol making up the remainder. Dietary cholesterol comes from animal fat, and exists mostly in its free form, with only 10% to 15% in the form of cholesteryl esters with fatty acids. Dietary cholesterol is absorbed only partially whereas dietary triglycerides are absorbed very efficiently in humans. Triglycerides are made up of glycerol with its 3 hydroxyl groups esterified with fatty acids. The major fatty acids in dietary triglycerides are long-chain fatty acids with a greater than 14 carbon chain length (e.g., palmitate, stearate, oleate, linoleate) that may be saturated or unsaturated. Dietary lipids also provide the essential fatty acids linoleic acid and linolenic acid, both of which are polyunsaturated and belong to the omega-3 fatty acid class (i.e., the first double bond in these polyunsaturated fatty acids begins at carbon atom 3 from the -CH3 end of the molecule (ω-end); these fatty acids are derived from phospholipids of plant origin. Naturally occurring polyunsaturated fatty acids contain the double bonds in the cis configuration. Commercial hydrogenation of unsaturated fatty acids as a means to enhance shelf life and to modify physical consistency not only leads to saturation of some of the double bonds, but also conversion of the remaining double bonds from cis to trans configuration, so-called transfat. Medium-chain triglycerides (MCTs) contain fatty acids with a 6 to 12 carbon chain length. Aside from milk fat, which is rich in MCTs, dietary fat that is derived from most natural sources contains only 10% to 20% in the form of MCTs. These triglycerides have found several medical uses because their absorption mechanism in the intestine is different from that of long-chain triglycerides.

Unique Features of Fat Digestion and Absorption There are several features unique to the digestion and absorption of dietary fat that are dictated by the fact that fat is insoluble in aqueous medium. Therefore, physical forces and detergents are needed to disperse dietary fat in the intestinal lumen so that enzymes can gain access to the molecules for digestion. Bile salts serve as detergents, without which digestion and absorption of dietary fat cannot occur. Most dietary fat is subjected to digestion by enzymes in the intestinal lumen prior to uptake into the absorptive cells of the small intestine. Once inside the cell, however, these digested components are used to re-synthesize triglycerides, phospholipids, and cholesteryl esters and then assembled in a macromolecular form before exiting the cell on the serosal side. Finally, the fat digestion products do not enter portal circulation as do their counterparts of dietary carbohydrate and protein; instead, they are released into lacteals and travel through the lymphatic system before entering the systemic circulation. The fat-soluble vitamins A, D, E, and K go through the same mechanism, requiring bile salts for intestinal absorption and entering

the lymphatics. MCTs, however, do not go through this elaborate pathway; they do not undergo digestion in the intestinal lumen and hence are not dependent on bile salts for intestinal absorption. They simply diffuse across the intestinal absorptive cells and enter the portal bloodstream. 

Digestion of Fat in the GI Lumen Details of the enzymes involved in the digestion of dietary fat in the intestinal lumen are given in Table 102.1. Fat digestion begins in the stomach with gastric lipase, which is secreted by chief cells located primarily in the fundus. This enzyme works optimally in the pH range of 3 to 6, suitable for action in the gastric lumen. It has been cloned and is a 379-amino acid protein that does not share homology with pancreatic lipase.163 Gastric lipase acts efficiently on triglycerides containing medium-chain fatty acids, and the products of its activity are diglycerides and free fatty acids. Because it has affinity for MCTs, a significant component of milk fat, gastric lipase plays a critical role in fat digestion in human neonates. Moreover, pancreatic function is not fully developed in neonates, thus making the contribution of gastric lipase even more relevant to fat digestion at this stage of life. There is another lipase, known as bile salt-stimulated lipase, which is distinct from both gastric lipase and pancreatic lipase,164 that is relevant to the digestion of milk fat in neonates. Bile salt-stimulated lipase originates from the mammary epithelium and is present in human milk; it is also present in pancreatic secretion, originating from the acinar cells. Gastric lipase is responsible for 20% to 30% of the luminal digestion of dietary fat, but has no activity on phospholipids and cholesteryl esters. Under normal conditions, the activity of gastric lipase is lost once the chyme enters the small intestine where the pH of the fluid is not suitable to maintain the activity of the enzyme. If neutralization of stomach contents in the small intestine is impaired, however, the activity of gastric lipase can be extended. Such a situation can be seen in patients with CF, in whom pancreatic secretion of bicarbonate may be impaired and explains why the dietary fat absorption can be greater than 50% (range 25% to 80%) in CF patients even with a complete absence of pancreatic lipase and without any supplementation of exogenous pancreatic enzymes.165 In addition, the deficiency in pancreatic lipase in CF is compensated to some extent by an increase in the secretion of gastric lipase.165 The same might be true with chronic use of PPIs that reduce acid production in the stomach, thereby enabling gastric lipase to be active in the small intestine for an extended period. The stomach also plays a critical role in the emulsification of dietary fat and the fat-digestion products arising from the activity of gastric lipase. This transformation in the physical nature of the fat in gastric chyme is important for subsequent digestion in the small intestine by pancreatic lipase. Emulsification is promoted in the gastric antrum by trituration, followed by powerful squirting of the contents into the duodenum. Emulsification is also enhanced by free fatty acids generated by the action of gastric lipase. The resultant fat droplets in the emulsion are stabilized by being coated with phospholipids.

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CHAPTER 102  Digestion and Absorption of Carbohydrate, Protein, and Fat

Pancreatic lipase is the major enzyme responsible for the digestion of triglycerides in the small intestine. The important features of the activity of this enzyme in the intestinal lumen include the following: it is secreted by the exocrine pancreas in an active form; it requires a cofactor, known as colipase, for its activity; colipase is also secreted by the exocrine pancreas, but in an inactive form called pro-colipase; activation of pro-colipase occurs in the intestinal lumen by proteolysis mediated by trypsin; bile salts are also needed for the activity of pancreatic lipase; pancreatic lipase acts on the ester bonds associated with carbon atoms 1 and 3 of the glycerol moiety, thus generating free fatty acids and 2-monoglyceride; it is the molecular target for the antiobesity drugs such as orlistat and cetilistat. Human pancreatic lipase has been cloned and its structure elucidated.166,167 It is a 50-kd protein with a catalytic domain and a colipase-binding domain. The triglyceride substrates for this enzyme in the intestinal lumen are present in the form of emulsion droplets coming from the stomach, and the enzyme acts on its substrates at the lipid-aqueous interface of these droplets, thus requiring the detergent action of bile salts. Colipase is needed to anchor the pancreatic lipase to the lipid-aqueous interface; this is accomplished by the ability of colipase to bind to pancreatic lipase and also to the lipid-aqueous interface of the emulsion droplets.168 Human pro-colipase is a 95-amino acid protein169; in the intestinal lumen, it is activated by trypsin with the removal of a 5-amino peptide from the amino terminus. The released pentapeptide (Val-Pro-Asp-Pro-Arg) is referred to as enterostatin because the peptide is generated in the intestinal lumen and it suppresses appetite, at least in animal studies.170 Phospholipids in the intestinal lumen arise from the diet and also from bile. The most predominant phospholipid is phosphatidylcholine (also known as lecithin). In gastric chyme, phospholipids coat the emulsion droplets, and in the intestinal lumen they are found in mixed micelles along with cholesterol and bile salts. Phospholipase A2 is responsible for the digestion of phospholipids, hydrolyzing the ester bond associated with the second carbon in the glycerol moiety, releasing fatty acid and lysophospholipid. Phospholipase A2 is secreted by the exocrine pancreas as an inactive precursor and is activated in the intestinal lumen via limited proteolysis by trypsin. Cholesteryl esters are digested by a separate enzyme known as carboxylic ester hydrolase that has broad substrate specificity and is activated by bile salts.  Fig. 102.10  Steps involved in the absorption of fat digestion products from mixed micelles across the absorptive cells of the small intestine into the lymphatic system. Step 1: Transfer of fat digestion products into enterocytes across the BBM; Step 2: Re-synthesis of triglycerides, phospholipids, and cholesteryl esters in SER and formation of lipid droplets (yellow dots); Step 3: Synthesis of apolipoprotein B-48 in RER (brown dots); Step 4: Movement of apolipoprotein B-48 from the cisternae of RER to the cisternae of SER to form chylomicrons; Step 5: Movement of chylomicrons to the cis side of Golgi; Step 6: Budding off chylomicrons on the trans side of Golgi; Step 7: Fusion of chylomicrons with BLM and release into the intercellular space on the serosal side; Step 8: Entry of chylomicrons into lacteals. Chylomicrons are represented as yellow dots (lipids) with a brown envelope (apolipoprotein B-48).B-48, apolipoprotein B-48; BBM, brush-border membrane; BLM, basolateral membrane; BS, bile salts; C, cholesterol; LCFA, long-chain fatty acids; LPL, lysophospholipids; MG, 2-monoglycerides; RER, rough endoplasmic reticulum; SER, smooth endoplasmic reticulum.

Assembly of Fat-Digestion Products into Micelles With the digestion of various constituents of dietary fat by gastric lipase and the other lipolytic enzymes secreted by the pancreas, the lumen of the small intestine now contains free fatty acids, 2-monoglycerides, lysophospholipids, cholesterol, and also the fat-soluble vitamins. Almost all of these products are insoluble in water, and therefore they never exist in free form in the intestinal lumen. In fact, digestion proceeds with the emulsion droplets in the beginning and, as the digestion products are generated, the emulsion droplets gradually transform into multilamellar vesicles, unilamellar vesicles, and finally into mixed micelles. Just like the digestion of fat, this change in the physical state of the end products of fat digestion is also obligatorily dependent on bile salts. These mixed micelles now have to move from the bulk phase of the luminal fluid to the BBM of the enterocytes for absorption, which involves diffusing across the 40-μm-thick unstirred water layer and the mucous gel layer that overlies the luminal surface of the BBM. Because the microclimate of the luminal surface of the enterocytes has an acidic pH, free fatty acids become protonated and pass through the BBM either by non-ionic diffusion or by transporters. Similarly, cholesterol crosses the BBM by diffusion or via transporters. 2-Monoglycerides, lysophospholipids, and fat-soluble vitamins enter the enterocytes mostly by diffusion. Once all the products of fat digestion leave the mixed micelles, what remains are the bile salt micelles, which return to the bulk phase of the luminal fluid (Fig. 102.10). A small amount (∼5%) of the bile acids get protonated in the unstirred water layer because of the microclimate acid pH and get absorbed into the enterocytes and then into portal blood by non-ionic diffusion. Most bile acids do not go through this route, however; they travel to the ileum where they get absorbed actively in deprotonated form via a transporter known as the apical sodium-bile acid transporter (ASBT or SLC10A2).171,172 This process is one of the several steps in the enterohepatic circulation of bile salts, which includes: (1) exit of bile salts from the ileal enterocytes via the heterodimeric transporter OSTα/OSTβ (organic solute and steroid transporter α/organic solute and steroid transporter β) in the BLM172; (2) travel to the liver via portal blood; (3) uptake into hepatocytes via another transporter in the liver sinusoidal membrane; and finally, (4) secretion into bile via yet another transporter in the liver canalicular membrane. 

102

2

MG, C, LPL, LCFA

SER

1

5

6

BS Mixed micelle

7

4

B-48

8

Golgi

3 RER BBM

BLM

Lacteal

Downloaded for Reddy Sandeep ([email protected]) at University of Southern California from Clinic For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All right

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Transport Systems for Fat-Digestion Products Fatty Acids There is evidence for the involvement of at least 3 different proteins in the uptake of fatty acids in enterocytes (Table 102.2); these are CD36 (also known as scavenger receptor B2 or SR-B2), fatty acid transport protein 4 (FATP4 or SLC27A4), and scavenger receptor B1 (SR-B1).173, 174 CD36 is expressed abundantly in the BBM of enterocytes in the proximal intestine and interacts with free fatty acids. Evidence in support of a role for this protein in intestinal fatty acid uptake comes from CD36-null mice; fatty acid uptake is decreased to a significant extent in enterocytes from the proximal small intestine of null mice compared with enterocytes from wild type mice.175 However, the interaction between CD36 and free fatty acids occurs at nanomolar concentrations175 and this extremely high-affinity interaction raises doubts about the contribution of CD36 to fatty acid uptake in the intestine under physiologic conditions where the luminal concentrations of fatty acids after a fatty meal are likely to be in millimolar range. Nonetheless, there is overwhelming support for a role of CD36 in the processing of dietary fat in the intestine, most likely via alterations in intracellular signaling and packaging of the fatdigestion products into chylomicrons.176, 177 CD36 deficiency in humans and deletion of CD36 in mice are associated with postprandial dyslipidemia, including elevated levels of triglycerides, free fatty acids, free glycerol, and apolipoprotein B-48 after oral fat loading. In particular, lipoproteins that are much smaller in size than normal chylomicrons are found at higher levels in CD36-deficient humans and mice, indicating a role for this protein in the assembly of chylomicrons. Furthermore, the satiety signal induced by dietary fat is lost in CD36-null mice.176 In wild type animals, oleic acid present in dietary fat is transported into enterocytes and used for the synthesis of oleoylethanolamide, which serves as a satiety signal; this process is impaired in CD36null mice. Based on the evidence that CD36 is able to mediate fatty acid uptake in enterocytes, the loss of the satiety signal in the null mice is interpreted as the consequence of impaired entry of diet-derived oleic acid into enterocytes and the resultant decrease in the synthesis of the lipid messenger. CD36 does not function as a classical transporter; fatty acid uptake via CD36 occurs via receptor-mediated endocytosis, most likely involving caveolins and lipid rafts (Fig. 102.11).178,179 The fatty acid transport protein FATP4 (SLC27A4) is expressed in enterocytes and possesses acyl CoA synthetase activity (see Table 102.2).180 Its expression in the small intestine and biochemical features suggest a potential role in fatty acid uptake. It is reasoned that the protein could mediate the entry of fatty acids across the BBM, immediately followed by intracellular conversion of the fatty acid to its CoA derivative by the constitutive acyl CoA synthetase activity of the same protein. This concept could provide an ideal mechanism for effective cellular uptake of fatty acids by coupling the entry process to metabolic conversion to trap the fatty acid inside the cells. Unlike free fatty acids, the CoA derivatives are not likely to diffuse across biological membranes. Despite this logic, studies with FATP4-null mice failed to support a role for the protein in intestinal fatty acid uptake.181 Loss-of-function mutations in FATP4 occur in humans; these mutations cause a skin disorder known as ichthyosis prematurity, but there is no intestinal phenotype related to digestion and absorption of dietary fat in this disease.181 

Cholesterol Two major mechanisms operate in the transport of cholesterol across the intestinal BBM, one mediated by the protein NiemannPick C1-like 1 (NPC1L1) for influx from the lumen into the cells and the other by the heterodimeric ABC transport system ABCG5/ABCG8 for efflux from the cells into the lumen (see

Caveolin Endocytosis

CD36 LCFA

Late endosome

Endoplasmic reticulum Fig. 102.11  Role of caveolin-1 in fatty acid uptake mediated by CD36 (cluster of differentiation 36) by enterocytes. CD36 and caveolin-1 are clustered in specific locations in the plasma membrane known as lipid rafts. These special structures present in the brush-border membrane (BBM) of enterocytes play a role in the entry of long-chain fatty acids (LCFA) into cells. When LCFA binds to CD36, the membrane containing the caveolin-1 and CD36 clusters invaginate and gets pinched off from the BBM to form endosomes as a component of the process known as receptor-mediated endocytosis. The invaginated structures are called caveolae when they are still attached to the BBM (plasma membrane).

Table 102.2). NPC1L1 is structurally and functionally related to NPC1, the cholesterol transport protein that is defective in the lysosomal storage disease Niemann-Pick type C1.182,183 But unlike NPC1, which is located in the lysosomal membrane, NPC1L1 is expressed in the BBM of the enterocytes and also in the canalicular membrane of hepatocytes. The involvement of NPC1L1 in intestinal cholesterol absorption is supported by the alterations seen in the lipid profile in NPC1L1-null mice; these mice have reduced cholesterol in circulation and are also resistant to high-fat diet-induced obesity, hepatic steatosis, and insulin resistance.184 Interestingly, the null mice also show reduced intestinal absorption of long-chain fatty acids despite the fact that NPC1L1 does not interact with fatty acids. This has been explained by the reduced expression of the fatty acid transport protein FATP4 in the intestine in these null mice.185 It is important to note that NPC1L1 is the pharmacological target for the cholesterol-lowering drugs such as Ezetimibe (Zetia); these drugs block the function of NPC1L1 in intestinal cholesterol absorption.186,187 ABCG5/ABCG8 is an obligate heterodimeric transporter that is expressed in the BBM of enterocytes and also in the canalicular membrane of hepatocytes; the 2-protein complex mediates the efflux of cholesterol and plant sterols from the cells in an ATPdependent manner.188-191 This transport system limits intestinal absorption of cholesterol and plant sterols and promotes the excretion of cholesterol and plant sterols from the liver into bile. Loss-of-function mutations in either of the proteins lead to a genetic disease called sitosterolemia, which is associated with elevated circulating levels of the plant sterol sitosterol along with cholesterol; as a consequence, patients with these mutations have increased risk of atherosclerosis. Loss of function of the transporter complex also limits the excretion of cholesterol and other

CHAPTER 102  Digestion and Absorption of Carbohydrate, Protein, and Fat

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TABLE 102.2  Transporters in the Intestinal Brush-Border Membrane for Absorption of Fat-Digestion Products Transporter

Substrate

Mode of Transport

Unique Features

CD36 (SR-B2)

LCFA

Influx

Receptor-mediated endocytosis

FATP4 (SLC27A4)

LCFA

Influx

Acy1 CoA synthetase activity

ABCG5/ABCG8

Cholesterol Plant sterols

Efflux

ATP-dependent; Mutated in sitosterolemia

NPCIL1

Cholesterol

Influx

Target for Ezetimibe

LCFA, long-chain fatty acid.

Monoglyceride Pathway 1 2-Monoglyceride

2 1,2-Diglyceride

Fatty acyl CoA

Triglygeride

Fatty acyl CoA

Glycerophosphate Pathway α-Glycerophosphate

3

2 Fatty acyl CoA

4 Phosphatidic acid

2 1,2-Diglyceride

Phosphate

Triglyceride

Fatty acyl CoA

Fig. 102.12  Steps involved in the re-synthesis of triglycerides within the enterocytes via the monoglyceride pathway and the glycerophosphate pathway. 1, monoglyceride acyl transferase 2 (MGAT2); 2, Diglyceride acyl transferase 1 (DGAT1); 3, Glycerophosphate acyl transferase; 4, Phosphatidate phosphatase.

sterols into bile, which reduces the risk of gallstones. Interestingly, there are mutations in the transporter complex that lead to gain of function as a result of which plasma levels of cholesterol and plant sterols are reduced because of increased efflux from the intestine, while the secretion of cholesterol into bile is increased; as expected, such mutations reduce the risk of atherosclerosis but increase the risk of gallstones.192, 193 

Reassembly of Fat-Digestion Products into Chylomicrons in Enterocytes Re-synthesis of Triglycerides, Cholesteryl Esters, and Phospholipids The fat-digestion products that enter the enterocytes by uptake across the BBM consist of 2-monoglycerides, free fatty acids, non-esterified cholesterol, and lysophospholipids. Once inside the cells, 2-monoglycerides, cholesterol, and lysophospholipids are re-esterified in the smooth endoplasmic reticulum to generate triglycerides, cholesteryl esters, and phospholipids (see Fig. 102.10). Two different fatty acid binding proteins (FABPs), known as liver-type FABP and intestine-type FABP, are present in the cytoplasm of the enterocytes in the proximal small intestine, which function in the transfer of free fatty acids from the apical compartment to the smooth endoplasmic reticulum for use in re-esterification.194, 195 For the synthesis of triglycerides, there are 2 pathways: the monoglyceride pathway and the glycerophosphate pathway (Fig. 102.12). The monoglyceride pathway is predominant during the fed state, whereas the glycerophosphate pathway becomes predominant during fasting. Synthesis of triglycerides via the monoglyceride pathway occurs stepwise: first the conversion of 2-monoglycerides into diglycerides, and then the conversion of diglycerides into triglycerides. These reactions require fatty acyl CoA, which is primarily derived from long-chain fatty acids. Acyl CoA synthetases generate these CoA derivatives using the fatty acids that enter the cells from the absorption of fat-digestion products. Monoglyceride acyl transferases (MGATs) mediate the first esterification step and

diglyceride acyl transferases (DGATs) mediate the second esterification step. All these reactions occur on the cytoplasmic surface of the smooth endoplasmic reticulum. There are 3 MGAT isoforms; it is the isoform MGAT2 that is expressed in the proximal intestine where the absorption of the fat-digestion products occurs. MGAT2-null mice show defective absorption of dietary fat and are resistant to high-fat diet-induced obesity.196 There are 2 DGAT isoforms; it is the isoform DGAT1 that is responsible for triglyceride synthesis in the proximal intestine. DGAT1-null mice show defective absorption of dietary fat and are resistant to high-fat diet-induced obesity.197, 198 The glycerophosphate pathway does not use the diet-derived 2-monoglycerides; instead, it uses α-glycerophosphate derived from glycerol by the action of glycerol kinase. Two fatty acids are added to α-glycerophosphate in the form of acyl CoA to generate phosphatidic acid, which is subsequently de-phosphorylated to generate diglycerides for subsequent conversion into triglycerides as the final step. Esterification of cholesterol also occurs with the use of acyl CoA derivatives. The enzyme responsible for the reaction is acyl CoA cholesterol acyl transferase (ACAT), which exists in 2 isoforms, ACAT1 and ACAT2. ACAT2 is the isoform that is expressed in the small intestine, and ACAT2-null mice show impaired absorption of dietary cholesterol.199 Conversion of lysophospholipids to phospholipids occurs with the esterification at carbon 2, again using acyl CoA derivatives. 

Assembly of Chylomicrons—Apolipoprotein B-48 Among the 5 lipoprotein particles known (chylomicrons, verylow-density lipoprotein, low-density lipoprotein, intermediatedensity lipoprotein, and high-density lipoprotein), chylomicrons are the largest in size. Chylomicrons are assembled and secreted by the enterocytes as a mechanism to transfer of fat-digestion products (and fat-soluble vitamins) into the circulation; entry into circulation does not occur directly but rather via the lymphatic system. Chylomicrons contain predominantly triglycerides, with small amounts of cholesteryl esters and phospholipids. The assembly requires apolipoprotein B-48, each chylomicron particle containing one apolipoprotein B-48. The apolipoprotein B gene actually codes for 2 distinct forms of the protein, namely apolipoprotein B-100 and apolipoprotein B-48, the former primarily in the liver and the latter primarily in the small intestine.200 Accordingly, apolipoprotein B-48 is the form found in chylomicrons. Production of the 2 forms of the protein involves a novel mechanism. In the liver, the apolipoprotein B gene generates mRNA, which then produces apolipoprotein B-100. In the small intestine, the gene generates the same mRNA, which then is subjected to an editing process in which one of the codons (CAA) is converted to a stop codon (UAA).201 Consequently, the mRNA in liver generates the full-length protein (apolipoprotein B-100) whereas in small intestine the shorter form of the protein (apolipoprotein B-48) is generated. Apolipoprotein B-48 is an obligatory component of chylomicrons and without the protein, the assembly of chylomicrons is markedly impaired. 

102

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Assembly of Chylomicrons—Microsomal Triglyceride Transfer Protein

Secretion of Chylomicrons and Very Low Density Lipoprotein into Lacteals

Re-synthesis of triglycerides, cholesteryl esters, and phospholipids occurs in the smooth endoplasmic reticulum whereas the synthesis of apolipoprotein B-48 occurs in the rough endoplasmic reticulum and is present in the lumen of the cisternae (see Fig. 102.10). The apoprotein then moves to the lumen of the cisternae in the smooth endoplasmic reticulum where the newly synthesized triglycerides are transferred to the protein to begin the chylomicron assembly along with smaller amounts of cholesteryl esters and phospholipids. The transfer of these newly generated lipids, now associated with membranes or present in the form of lipid droplets, to the apoprotein requires microsomal triglyceride transfer protein (MTTP).202 This protein is absolutely essential for the assembly of chylomicrons consisting of apolipoprotein B-48 and the lipids. Loss-of-function mutations in MTTP leads to impairment of chylomicron assembly and secretion from the intestine; this causes a disease called abetalipoproteinemia, characterized by markedly decreased levels of apolipoprotein B-48 in blood203 and manifest in the first few months of life with failure to thrive, diarrhea (steatorrhea), acanthocytosis, and, later in childhood, impaired intellectual development, muscle incoordination, ataxia, and retinitis pigmentosa. Most of the symptoms are due to defects in the absorption and transport of the fat-soluble vitamin E. It is important to note that the mutations in abetalipoproteinemia occur in the gene coding for MTTP, not in the gene coding for apolipoprotein B. MTTP-null mice are embryonically lethal.204 The essential role of the protein in the digestion and absorption of dietary fat is however demonstrable with intestine-specific knockout of the gene; these mice show impaired intestinal secretion of chylomicrons.205 Anderson disease is another disorder associated with defective chylomicron secretion from the enterocytes. The assembly is not affected, only the secretion. In this disease, the enterocytes contain chylomicron particles, but the particles are not found in intercellular spaces, a step necessary for entry into the lacteals206; this indicates that the defect in Anderson disease lies in chylomicron secretion. 

Chylomicrons as well as VLDL are secreted into lacteals and then travel through the lymphatic duct, which then empties into the left subclavian vein to enter into systemic circulation. After assembly in the lumen of the endoplasmic reticulum, both lipid particles travel to the Golgi apparatus and bud off as vesicles on the trans side of the Golgi and travel to the BLM (see Fig. 102.10). The mechanism for the transfer of these lipid particles across the BLM involves fusion of the vesicles on the cytoplasmic side followed by their appearance on the exoplasmic side. The size of both chylomicrons and VLDL is too large to diffuse across the endothelial cell barrier of portal blood vessels, as a consequence of which, these particles appear in lacteals.

Chylomicrons Versus Very Low Density Lipoprotein Fat-digestion products are secreted into lacteals in the form of chylomicrons, whereas VLDL is secreted from enterocytes only in between meals. In contrast to chylomicrons which contains triglycerides as the major lipid component, VLDL is not enriched in any particular lipid; it contains triglycerides, cholesteryl esters, and phospholipids. However, apolipoprotein B-48 is a component of both forms of lipoprotein particles. Nonetheless, chylomicrons and VLDL are assembled in enterocytes by separate pathways.207,208 The evidence in support of this comes from the fact that the presence of palmitate in the intestinal lumen stimulates VLDL secretion from the enterocytes without any effect on chylomicron secretion, whereas the presence of oleate and linoleate stimulates chylomicron secretion without any effect on VLDL secretion. Furthermore, infusion of phospholipids in the intestinal lumen results in the assembly of VLDL in enterocytes, whereas infusion of triglycerides results in the assembly of chylomicrons. In addition, the fatty acid composition of triglycerides in chylomicrons is different from that of triglycerides in VLDL. The particle size is also different; chylomicrons are much larger than VLDL. 

Medium-Chain Fatty Acids and Medium-Chain Triglycerides The route for the digestion and absorption of medium-chain fatty acids and MCTs is different from that for long-chain fatty acids and long-chain triglycerides. First, there is no need for bile salts for the digestion of medium-chain triglycerides. Second, gastric and pancreatic lipases are also not needed because these triglycerides can enter the enterocytes in an intact form. Third, transfer of medium-chain fatty acids and MCTs across the BBM does not require the formation of mixed micelles. Once inside the cells, medium-chain fatty acids are not used for re-esterification. The free and the triglyceride form of medium-chain fatty acids do not appear in chylomicrons or in VLDL but instead are transferred directly into portal blood. This mode of absorption makes MCTs highly suitable dietary fat substitutes for patients suffering from defects in fat digestion and absorption and for those with pancreatic insufficiency.209,210 Digestion and absorption of dietary carbohydrates, protein, and fat occur primarily in the small intestine. The digestive process begins with enzymes in gastric and pancreatic secretions and with bile salts in hepatobiliary secretion. The hormones secretin and CCK secreted from enteroendocrine cells present in the duodenum and jejunum play a critical role in coordinating the digestive process. Carbohydrates are absorbed in the form of monosaccharides, whereas proteins are absorbed in the form of small peptides and free AAs. Small peptides are broken down further inside the cells to generate free AAs. These end products of dietary carbohydrates and protein digestion then pass into the portal circulation. In contrast, dietary fat is digested into smaller units before absorption, but reassembled back within enterocytes, packaged into chylomicrons, and secreted into lacteals. The large intestine plays a critical role in the handling of dietary fiber, and bacterial fermentation products impact the biology of not only the colon but also distant organs. Acknowledgments This work was supported by National Institutes of Health grant CA190710 and Welch Endowed Chair in Biochemistry, Grant No. BI-0028, at Texas Tech University Health Sciences Center. Full references for this chapter can be found on www. expertconsult.com.

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Digestion and Absorption of Micronutrients Michelle Pearlman, Jaime Almandoz

CHAPTER OUTLINE WATER-SOLUBLE VITAMINS �������������������������������������������1657 Ascorbate (Vitamin C) ���������������������������������������������������1657 Biotin (Vitamin B7)���������������������������������������������������������1658 Cobalamin (Vitamin B12) �����������������������������������������������1661 Folate (Vitamin B9)���������������������������������������������������������1663 Niacin (Vitamin B3, Nicotinic Acid)���������������������������������1665 Pantothenic Acid (Vitamin B5) ���������������������������������������1665 Pyridoxine (Vitamin B6) and Derivatives�������������������������1665 Riboflavin (Vitamin B2)���������������������������������������������������1666 Thiamine (Vitamin B1)���������������������������������������������������1667 FAT-SOLUBLE VITAMINS�������������������������������������������������1668 Vitamin A�����������������������������������������������������������������������1668 Vitamin D ���������������������������������������������������������������������1670 Vitamin E�����������������������������������������������������������������������1671 Vitamin K ���������������������������������������������������������������������1672 MINERALS AND TRACE ELEMENTS���������������������������������1673 Calcium�������������������������������������������������������������������������1673 Magnesium�������������������������������������������������������������������1674 Iron�������������������������������������������������������������������������������1674 Zinc�������������������������������������������������������������������������������1675 Copper �������������������������������������������������������������������������1676 Iodine���������������������������������������������������������������������������1676 Selenium�����������������������������������������������������������������������1676 Other Trace Elements ���������������������������������������������������1676

The U.S. Department of Health and Human Services and the U.S. Department of Agriculture publish dietary guidelines for Americans every 5 years based on the most current evidence in nutrition science. These recommendations aim to promote health, prevent chronic disease and help individuals maintain a healthy weight. These guidelines also influence federal nutrition policies and product development. (https://health.gov/diet aryguidelines/purpose.asp). It is critical to remember, however, that these intake recommendations are targeted towards healthy Americans and do not include specific disease states, which often require different guidelines.

the regulation of CFTR-mediated chloride secretion in epithelial cells (see Chapter 101). Vitamin C deficiency leads to a variety of clinical abnormalities, including scurvy, poor wound healing, vasomotor instability, and some connective tissue disorders. 

Sources and Recommended Daily Allowance Primates, including humans, and guinea pigs, in contrast to most mammals, lack the enzyme l-gulonolactone oxidase and thus cannot synthesize vitamin C; as a result, they must obtain vitamin C from dietary sources. Rich dietary sources of vitamin C include fruits (citrus, cantaloupe, mango, strawberries, watermelon) and vegetables (cabbage, broccoli, cauliflower, potatoes, tomatoes). The recommended daily allowance (RDA) varies depending on age, gender and co-morbidities, but ranges between 90 and 120 mg/day for most adults. 

Digestion and Absorption Physiologic Aspects Unlike a number of other water-soluble vitamins (see biotin, folate, niacin, pantothenic acid, pyridoxine, and riboflavin), where 2 sources are available to the host (dietary and production by normal colonic microbiota), vitamin C is only available through dietary consumption.1 Intestinal absorption of AA occurs via a concentrative, carrier-mediated, Na+-dependent mechanism that is localized to the apical brush border membrane (BBM) domain of polarized enterocytes (Fig. 103.1).2 Once absorbed, AA leaves the absorptive cells across the basolateral membrane (BLM) via another carriermediated mechanism.2 Intestinal absorption of dietary DHAA occurs via a Na+-independent carrier-mediated process that is competitively inhibited by glucose because of structural similarities between these compounds.3 Internalized DHAA is subsequently metabolized to AA by the enzyme DHAA-reductase. 

WATER-SOLUBLE VITAMINS

Molecular Aspects The 2 AA transport systems that have been identified in humans and other mammals consist of the Na+-dependent vitamin C transporter-1 (SVCT-1; product of the SLC23A1 gene) and the Na+-dependent vitamin C transporter-2 (SVCT-2; product of the SLC23A2 gene), both of which are expressed in the small intestine. Neither SVCT-1 nor SVCT-2 can transport DHAA; however, both transporters can act as Na+ uniporters in the absence of AA, allowing Na+ to enter cells.4 DHAA is absorbed via the glucose transporters GLUT1, GLUT3, and GLUT4, which are not capable of transporting AA.2,3 

Ascorbate (Vitamin C)

Intestinal Absorption

Metabolic role and effect of deficiency

Intestinal inflammation and prolonged infectious states are associated with decreased vitamin C absorption in both in-vitro and invivo models. Data suggest that pro-inflammatory states with elevated serum and intestinal mucosal levels of TNF-α inhibit AA transport and intestinal uptake.5 Observational data suggest that 35% of people can be deficient in vitamin C after Roux-en-Y gastric bypass for weight loss,6 but this is not a consistent finding when malabsorptive weight loss procedures are evaluated prospectively.7

Ascorbate exists in both reduced (ascorbic acid [AA]) and oxidized (dehydro-l-ascorbic acid [DHAA]) forms. The physiologically important form is AA, which acts as a cofactor in a variety of metabolic pathways. AA keeps metal ions like iron and copper in their reduced forms, scavenges free radicals, synthesizes collagen and other connective tissue proteins, and plays a role in

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Lumen Ascorbic acid SVCT 1

Dehydroxy ascorbic acid

Riboflavin

Pyridoxine

Biotin/ pantothenic acid

Folate

Niacin

THTR2

GLUT RFT2

SVCT 2

Thiamine

RFT1

??

THTR1

THTR2

SMVT

??

RFC

PCFT

??

MDR-3

Blood Fig. 103.1  Membrane transporters involved in the absorption of dietary water-soluble vitamins in the small intestine. The diagram shows localization of transporters for water-soluble vitamins at the BBM and BLM domains of polarized enterocytes. GLUT, glucose transporter; MDR-3, multidrug-resistance protein-3; PCFT, proton-coupled folate transporter; RFC, reduced folate carrier; RFT-1, riboflavin transporter-1; RFT-2, riboflavin transporter-2; SMVT, Na+-dependent multivitamin transporter; SVCT-1, Na+-dependent vitamin C transporter-1; SVCT-2, Na+-dependent vitamin C transporter-2; THTR-1, thiamine transporter-1; THTR-2, thiamine transporter-2.

Cell Biology Aspects Confocal imaging using live human intestinal epithelial cells and human SVCT-1 fused to yellow fluorescent protein (hSVCT1YFP) has shown that the hSVCT-1 protein is expressed at the apical membrane domain of these cells. The second transporter protein SVCT-2 appears to be expressed at the BLM domain of the polarized intestinal epithelial cells.8 The molecular determinants that influence targeting of the human Na+-dependent multivitamin transporter (hSMVT) protein to the BBM of intestinal epithelial cells are located in the cytoplasmic tail of the SMVT polypeptide.9–11 Mobility of these structures depends on the temperature and existence of an intact intracellular microtubule network.11 Studies involving co-localization, in-vitro knockdown, and in-vivo knockout (KO) approaches have also shown that Rab8a (a small recycling GTPase protein) is important for physiologic function and BBM delivery of hSVCT-1 in intestinal epithelial cells.12  Regulatory Aspects A variety of extracellular and intracellular factors and conditions regulate intestinal uptake of ascorbate; thus changes in extracellular ascorbate levels result in intestinal adaptation whereby AA supplementation leads to down-regulation in intestinal AA absorption associated with a decreased expression of hSVCT-1 mRNA.13,14 Other studies have used senescence marker protein-30/gluconolactonase KO mice, which are incapable of synthesizing AA in vivo to demonstrate that feeding a vitamin C-deficient diet leads to induction of SVCT-1 mRNA expression in the intestine.15 

Biotin (Vitamin B7) Metabolic Role and Effect of Deficiency Biotin is a carboxyl carrier and cofactor for 5 carboxylase enzymes, which are involved in essential pathways of intermediate metabolism (e.g., fatty acid synthesis, β-oxidation, gluconeogenesis, catabolism of odd-carbon fatty acids and branched-chain amino acids). It also plays a role in regulating gene expression, intracellular cyclic guanosine monophosphate levels, immune function, and cell proliferation. Biotin deficiency leads to growth retardation, neurologic disorders, and dermatologic abnormalities. Animal studies have shown that biotin deficiency during pregnancy may lead to growth retardation, congenital malformations, and death.16 Deficiency and low levels of biotin have been reported in several conditions, including inborn errors of biotin metabolism, inflammatory bowel diseases, long-term therapy with anticonvulsant drugs, long-term parenteral nutrition, and chronic alcohol use disorder. 

Sources and Recommended Daily Allowance Physiologic Aspects Biotin is obtained from dietary sources and is also produced by colonic microbiota. Biotin is found in many foods, although at a lower concentration than other water-soluble vitamins. Good sources of biotin include egg yolks, liver, nuts, legumes, and vegetables such as cauliflower. Precise data on biotin requirements

CHAPTER 103  Digestion and Absorption of Micronutrients

GFP

112

103

Colon BLM

Colon AMV

Colon BLM

Colon AMV

Colon AMV 195

Colon BLM

I II III hSMVT Ab Secondary Ab Ab+peptide

Z

hSMVT-GFP

XY

1659

hSMVT

58 -actin

A

B

30

Fig. 103.2  Cellular distribution of human sodium-dependent multivitamin transporter protein.  A, XY and Z confocal image showing human intestinal epithelial Caco-2 cells expressing hSMVT fused to GFP (hSMVTGFP) and dsRed (a cytoplasmic dye) 48 h post-transfection. Lower panels show the distribution of GFP alone. B, Western blot analysis showing expression of hSMVT protein at native human colonic apical (but not BLM) membrane. Colonic tissue was obtained from organ donors. AMV, Apical membrane vesicles; BLM, basolateral membrane; GFP, green fluorescent protein; hSMVT, human Na+-dependent multivitamin transporter. (Adapted from Subramanian VS, Marchant JS, Boulware MJ, et al. Membrane targeting and intracellular trafficking of the human sodium-dependent multivitamin transporter in polarized epithelial cells. Am J Physiol 2009; 296:C663-71.)

in humans are not available, but the recommended safe and adequate daily oral intake of biotin in adults is estimated to be between 30 and 35 μg/day.  Digestion and Absorption Dietary biotin exists in free and protein-bound forms; the latter cannot be absorbed and must first undergo digestion by intestinal proteases and peptidases to biocytin (biotinyl-l-lysine) and biotin-short peptides, which are then converted to free biotin by the enzyme biotinidase. Human biotinidase has been cloned, and a number of clinical mutations have been identified in patients with biotinidase deficiency.17,18 Those affected by this autosomal recessive disorder display seizures, vision problems, alopecia, developmental delay, and hearing loss. These individuals cannot use dietary protein-bound biotin owing to the fact that they are unable to convert biocytin and biotin-short peptides to absorbable free biotin. Biotinidase deficiency also precludes the recycling of endogenous biocytin and biotin-short peptides, which arise from catabolism of cellular protein-bound biotin to free biotin.19 Pharmacologic supplementation with high doses of free biotin improves clinical outcomes in patients affected by biotinidase deficiency.18,19 Free biotin is negatively charged at physiologic pH and is absorbed in the intestine via a carrier-mediated Na+-dependent process, which is most active in the proximal small intestine. Functional, immunologic, and confocal imaging studies have localized the Na+-dependent carrier-mediated system to the apical BBM domain of the polarized intestinal epithelial cells (Fig. 103.2). Biotin exits enterocytes across the BLM via a Na+ independent carrier-mediated process.20 Of note, the Na+-dependent process through which biotin is absorbed also transports 2 other functionally unrelated micronutrients: pantothenic acid and lipoate, which is a potent intracellular and extracellular antioxidant. This uptake system is therefore referred to as the SMVT. The normal colonic microbiota generates biotin predominantly in the free form, which is readily available for absorption through colonic epithelium via the SMVT.1 The combination of this efficient carrier-mediated process for biotin uptake in the colon and the significant duration that luminal contents remain in that region suggest that microbiota-generated biotin

contributes to host biotin, and especially to the local needs of colonocytes. Molecular Aspects The SMVT system is expressed throughout the intestinal tract. It has been cloned in several species, including humans, and its functionality has been characterized following expression in a number of cellular systems.20 SMVT encodes a protein of 635 amino acids that is predicted to have 12 transmembrane domains (TMD) and is N-glycosylated at positions Asn 138 and Asn 489. Glycosylation appears to be important for the function of hSMVT.21 In addition, a number of potential phosphorylation sites were predicted in the SMVT polypeptide, of which Thr286 has been experimentally shown to be involved in mediating the protein kinase C (PKC)-mediated regulation of intestinal biotin uptake.21 It has been postulated that there is an alternative biotin uptake system that functions in cells outside of the GI tract, (e.g., peripheral blood mononuclear cells, keratinocytes); however, experiments in an intestinal-specific (conditional) SMVT KO mouse model suggest that the SMVT is the only biotin uptake system that operates in the intestine.22 In these studies, complete inhibition of intestinal biotin and pantothenic acid uptake was observed in the KO mice compared with their sex-matched wild-type littermates. Interesting phenotypes were also observed in these KO animals.22 First, two thirds of the animals died before reaching the age of 2.5 months owing to acute peritonitis. Second, all KO mice, which had decreased biotin levels compared with same-sex control littermates, showed severe growth retardation and decreased bone density and length. Third, the KO mice had evidence of shortened and dysplastic villi in the small intestine and chronic active inflammation with dysplasia in the colon (Fig. 103.3). The mechanisms mediating the intestinal inflammation seen in the KO mice are unclear, but may be related to the role played by biotin in maintaining normal innate and adaptive immune functions.23 For example, biotin is essential for activity of intestinal natural killer cells,24 which play an important role in maintaining intestinal epithelial homeostasis and promoting antipathogen response.25 Activity of these cells and biotin levels are both decreased in patients with Crohn disease (see Chapter 115).24–27 

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PART X  Small and Large Intestine Small Intestine Histology

Cecum Histology

A

D

B

E Length of Villi

Dysplasia

1.5 1.0

*

50

*

25

0.5 KO

WT

KO

WT

Neutrophils (#/10 hpf)

Length of Villi (mm)

75

Dysplasia (%)

2.0

0.0

C

100

0

F

50

*

100 75

40 30

*

50

20 25

10

*

0

0 KO WT

KO WT

KO WT

Dysplasia/LP Edema (% area)

2.5

Dysplasia LP Edema

Neutrophils

Fig. 103.3  Histology of the small intestine (A-C) and cecum (D-F ) of intestinal-specific (conditional) Na+dependent multivitamin transporter knockout (KO) mice and their sex-matched wild-type (WT ) littermates. A, Normal small intestinal morphology of WT littermates. B, Shortening of villi and focal dysplastic changes (B insert). C, Small intestinal villi length in mm (left y-axis) and total area of dysplasia as a percentage (right y-axis). (*P < 0.01, n = 5). D, Representative section of WT cecum. E, Small intestine of the KO mouse showing significant submucosal edema (open arrow) and acute inflammation involving surface (closed arrows) and crypts. F, Number of neutrophils in 10 high-power fields (×400) (left y-axis), and total area of dysplasia and submucosal edema as a percentage (right y-axis). (*P < 0.01, n = 5). LP, Lamina propria. (Adapted from Ghosal A, Lambrecht NW, Subramanya SB, et al. Conditional knockout of the Slc5a6 gene in mouse intestine impairs biotin absorption. Am J Physiol Gastrointest Liver Physiol 2013; 304:G64-71.)

Cell Biology Aspects The SMVT system is exclusively expressed at the apical membrane domain of polarized enterocytes, and the molecular determinants that dictate the targeting of the hSMVT protein to the apical membrane are located in the cytoplasmic tail of the SMVT polypeptide.20,28 Distinct trafficking vesicles are involved in the intracellular movement of the hSMVT protein, and this process requires an intact microtubule network.28 Studies have identified a PDZ-containing protein, namely PDZD11, that interacts with hSMVT at a sequence in the

cytoplasmic tail of the latter (Fig. 103.4); this interaction influences the function and cell biology of hSMVT. Co-expression of PDZD11 with hSMVT leads to an increase in biotin uptake, whereas knocking down PDZD11 leads to an inhibition in uptake.29 Regulatory Aspects A variety of extracellular and intracellular factors regulate the intestinal uptake of biotin. For example, the SLC5A6 gene encodes SMVT in human enterocytes.20,30 and intestinal uptake

CHAPTER 103  Digestion and Absorption of Micronutrients

1661

103 hTHTR1

hRFC

hSMVT

Tspan1 PDZD11

Dynein light chain road block

Fig. 103.4  Accessory proteins that interact with human intestinal thiamine, biotin, and folate membrane transporters. Depicted are the interactions between recently identified accessary proteins and specific transporters of water-soluble vitamins in human intestinal epithelium. hRFC, Human reduced folate carrier; hSMVT, human Na+-dependent multivitamin transporter; hTHTR-1, human thiamine transporter-1; PDZD11, PDZ-containing protein-11; Tspan1, tetraspanin protein-1. (See text for details.)

is adaptively regulated by extracellular biotin availability.20,31 Biotin deficiency leads to a specific and significant up-regulation in intestinal carrier-mediated biotin uptake through increased transcriptional activity of the SLC5A6 gene, which induces expression of the hSMVT protein and mRNA.31 Studies have identified the region in the SLC5A6 promoter that responds to biotin deficiency as a 103-bp stretch that contains the ciselement, gut-enriched, Kruppel-like factor. Mutational analysis studies have established the role of the gut-enriched, Kruppellike factor site in mediating the upregulatory response seen in biotin deficiency.31 In early life, animal studies have shown that the preferential site of biotin uptake during the suckling period is the ileum and with maturation it transitions to the jejunum.20,32 This alteration is associated with parallel changes in the transcriptional activity of the SLC5A6 gene and expression of the SMVT protein and mRNA.32 Finally, intestinal biotin absorption is under the regulation of an intracellular PKC-mediated pathway that appears to affect activity and/or number of carriers, thereby influencing the Vmax of the uptake process.33 The PKC appears to act through Thr286 of the hSMVT polypeptide; mutation of this phosphorylation site leads to a significant reduction in the PKC-mediated effect on hSMVT function.21 

Clinical Pathophysiology of Intestinal Biotin Uptake Lower plasma biotin levels are seen in people with chronic alcohol use disorder.34 Animal models that are chronically fed alcohol have shown that this results, at least in part, from inhibition of intestinal biotin absorption. This decreased biotin uptake is associated with a significant reduction in expressed SMVT protein, mRNA, and heterogenous nuclear RNA levels, as well as a decrease in the activity of the SLC5A6.35 Chronic alcohol feeding also caused a significant inhibition of biotin uptake in the colon, which would limit the absorption of bacterially generated biotin. Similar findings were observed in studies using human intestinal epithelial cells that were chronically exposed to alcohol.35 Chronic alcohol use also inhibits renal biotin reabsorption via similar transcriptional mechanisms.36 Other drugs have been found to decrease intestinal biotin uptake, such as the anticonvulsant medications carbamazepine and primidone.

Cobalamin (Vitamin B12) Metabolic Role and Effect of Deficiency Cobalamin (Cbl, vitamin B12) refers to cyanocobalamin and all other forms of vitamin B12 that have biologic activity. Cbl in its active coenzyme forms (i.e., 5′-deoxy-adenosyl-Cbl [Ado-Cbl, the most abundant natural form of Cbl] and methyl-Cbl [MetCbl]) plays an essential role in the catabolism of fatty acids in mitochondria and in the conversion of homocysteine to methionine (and, hence, the production of S-adenosyl-methionine, the active methyl group donor) in the cytoplasm. Cbl deficiency leads to many conditions, including megaloblastic anemia, and, when prolonged, may lead to irreversible neurologic damage. Cbl deficiency is common and occurs in patients with restrictive diets, pernicious anemia (PA), atrophic gastritis, celiac disease, Crohn disease, and after significant bowel resection or surgery. In older adults, Cbl deficiency and suboptimal levels of Cbl are often caused by intestinal malabsorption.37 Cbl deficiency in patients who are capable of absorbing the vitamin can be supplemented with physiologic doses, whereas patients unable to absorb Cbl require lifelong therapeutic injections or high doses of the oral or nasal form of the vitamin.38 Mega doses of hydroxy-Cbl (OH-Cbl) are used to treat cyanide poisoning because cyanide displaces the hydroxyl group from OH-Cbl, leading to the formation of CN-Cbl, which is excreted in urine.39 

Sources and Recommended Daily Allowance Cbl is found in animal-derived foods in which the vitamin was produced by intestinal bacteria, then absorbed and accumulated in the animal’s tissues. Rich sources of Cbl include meat, poultry, eggs, and dairy products. Food of plant origin is virtually devoid of Cbl; however, some nutritional yeast products contain vitamin B12, as do fortified cereals. The RDA of Cbl is 2.4, 2.6, and 2.8 μg, respectively, for adults, during pregnancy, and during lactation. 

Digestion and Absorption Physiologic Aspects Dietary Cbl is bound to proteins, which is hydrolyzed to free Cbl during food preparation, mastication and by the proteolytic action of pepsin at the low pH of the gastric lumen (Fig. 103.5). In the stomach, free Cbl and other inactive derivatives of the

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Cbl-protein

Salivary haptocorrin



Cbl-Haptocorrin + IF Stomach

IF-Cbl

IF-Cbl Binds to cubam

Proximal intestine

Terminal ileum

Fig. 103.5  Digestion and luminal processing of dietary cobalamin.  Steps involved in processing protein-bound dietary cobalamin (Cbl) in the GI tract. After liberation of dietary protein-bound Cbl, the vitamin binds to haptocorrin (HC) secreted by salivary glands. HC is then enzymatically degraded in the upper small intestine by pancreatic enzymes, with the liberated Cbl then binding to intrinsic factor (IF), which is secreted by parietal cells in the gastric mucosa. The IF-Cbl complex then travels to the terminal ileum and is taken up by a specific receptor-mediated endocytosis. (See text for details.)

vitamin, called cobamides, bind to haptocorrin (rapid binder, HC), which is a glycoprotein synthesized predominantly by the salivary glands.40 The HC is resistant to digestion by gastric acid and pepsin and protects the Cbl molecule as it passes through the stomach. Cbl is released from HC in the upper small intestine by pancreatic trypsin and chymotrypsin, after which Cbl binds to intrinsic factor (IF) with high affinity (dissociation constant >10−12 mol/L). IF is a glycoprotein that is synthesized by gastric parietal cells and is resistant to the effect of the digestive enzymes present in the upper GI tract.41,42 Cbl binds preferentially to IF over inactive cobalamins, thereby insuring selective absorption of the bioactive molecule. In the terminal ileum, the IF-bound Cbl (IF-Cbl) binds to cubam, a specific receptor located at the apical BBM domain of ileal enterocytes, which facilitates endocytosis of the entire complex (Fig. 103.6).43–45 Following internalization, the cubam-IF-Cbl complex goes to endosomes where cubam is cleaved and recycled to the apical BBM. The IF-Cbl complex moves to the lysosomes where IF is degraded and the free Cbl is transported out of the lysosomes, likely via the lysosomal membrane protein LMBRD1.46 Cbl is then exported across the BLM via a process that involves the multidrug-resistance–associated protein-1 (see Fig. 103.6).47 Circulatory transcobalamin II carries Cbl to the liver for storage and use. Bacterial production of cobalamin analogues (cobamides), which deprives the host of usable B12, and competitive interference with binding of IF-Cbl to cubam by these analogues are part of the explanation for vitamin B12 deficiency in SIBO (see Chapter 105).

Molecular Aspects In humans, the IF gene is located on chromosome 11, and the protein has been cloned and characterized.45,48 IF is a 417amino acid protein that may disintegrate into 2 moieties, a 30-kd N-terminal portion and a 20-kd C-terminal portion. Each of these moieties can recognize Cbl, but when they exist together in solution the joint moieties bind only to 1 Cbl molecule.49 A 20- to 50-amino acid sequence in the C-terminal portion of IF appears to be important for the high-affinity binding to Cbl.50 Also, the carbohydrate moiety on this glycoprotein plays a role in protecting IF against enzymatic degradation. The IF receptor cubam is composed of 2 units: cubilin and amnionless. Cubilin is the unit that recognizes IF and is expressed in both ileal and renal proximal tubule epithelial cells. Cubulin consists of an N-terminal portion that does not span the membrane, followed by 8 epidermal growth factor repeats and 27 CUB domains.51 The N-terminal portion of cubilin is responsible for recognizing IF.52 Amnionless is a transmembrane protein that provides membrane anchorage and endocytic capacity via 2 sequence signals within its cytosolic domain (phenylalanineX-asparagine-proline-X-phenylalanine FXNPXF). These signals promote internalization of the entire complex via binding to the clathrin-associated sorting protein disabled-2 (Dab2).53 Mutations in amnionless have been identified in patients with ImerslundGräsbeck disease, which is characterized by Cbl malabsorption and proteinuria with affected individuals clustered in Norway and some Mediterranean regions.54 Amnionless is also believed to play a role in delivering cubilin to the cell membrane.55,56  Regulatory Aspects Cbl absorption in the intestine is under limited regulation compared with other water-soluble vitamins. The process appears to be dependent on the capacity of cubam, the intestinal IF-Cbl receptor. After ingestion of 2 to 4 μg of vitamin B12, the intestine cannot absorb a second dose of the vitamin with equal efficiency until 4 to 6 hours later. In healthy adults, fluctuation in the normal level of IF appears to have little effect on Cbl absorption, because the daily output of IF (≈20 nmol) is markedly higher than the few nanomoles needed to absorb ingested Cbl.57 Additionally, thyroid hormone has been reported to have a role in regulating Cbl absorption by influencing the expression of cubilin.58 

Clinical Pathophysiology of Intestinal Cobalamin Absorption PA is a well-recognized cause of Cbl malabsorption and deficiency. PA results from a lack of IF caused by autoimmune-mediated atrophic gastritis (see Chapter 52). PA is more common in older adults and those who suffer from other autoimmune disorders such as thyroid disease and type-1 diabetes.57 Other conditions associated with decreased levels of IF include patients who have undergone total gastrectomy, weight loss surgery,59 those with Helicobacter pylori infection, and those on long-term treatment with acid-reducing medications—usually PPIs.60–62 Intestinal absorption of Cbl is also influenced by conditions that affect the cubam receptor. Inherited defects in the cubilin and amnionless units of this receptor are rare.63 Intestinal disorders like Crohn disease, especially when there has been ileal resection, are well-recognized causes of Cbl malabsorption.64,65 Chronic or recurrent exposure to nitrous oxide (N2O), a commonly used inhaled anesthetic, may lead to oxidation of Cbl to an inactive form that can cause neurologic complications associated with Cbl deficiency, ranging from polyneuropathy to spinal cord degeneration.66 A number of phenomena combine to make SIBO an important cause of vitamin B12 (cobalamin) deficiency (see Chapter 105).67 These include consumption of cobalamin by anaerobes, bacterial production of cobalamin analogs called cobamides (with

CHAPTER 103  Digestion and Absorption of Micronutrients

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103

IF-Cbl

IF-Cbl IF-Cbl

IF-Cbl

IF-Cbl

IF-Cbl

IF-Cbl

Lumen Cubam

Endosomes Cubam

IF-Cbl

Lysosome

X

IF-Cbl LMBRD1

Cbl MRP1 Blood Fig. 103.6  Uptake of intrinsic factor–cobalamin by ileal enterocytes.  Intrinsic factor–cobalamin (IF-Cbl) binds to cubam, and the complex then undergoes endocytosis. In the endosomes, cubam-IF-Cbl dissociates into cubam (which recycles back to the apical membrane) and IF-Cbl; the latter then enters into lysosomes where IF is degraded (shown by X), and Cbl is transported out of lysosomes by lysosomal membrane protein (LMBRD1). Cbl is transported out of the ileal enterocytes across the BLM via multidrug-resistance-associated protein-1 (MRP1).

subsequent loss of the parent vitamin to the host), malabsorption of the vitamin at the ileal receptor as a result of competitive binding with cobamides, and, in instances of severe SIBO, mucosal injury that involves the cubulin-amnionless binding site. Finally, chronic use of metformin in patients with diabetes reduces Cbl levels via malabsorption, owing to a reduction in the levels of haptocorrin.68–70 

Folate (Vitamin B9) Metabolic Role and Effect of Deficiency Folate (vitamin B9) refers to a group of 1-carbon derivatives of folic acid required for the synthesis of pyrimidine and purine nucleotides (precursors of DNA and RNA, respectively) and metabolism of several amino acids, including homocysteine and serine. Cellular deficiency of folate leads to impairment in 1-carbon metabolism, DNA synthesis and methylation, incorporation of uracil into DNA, and in the metabolism of several amino acids. Suboptimal levels of folate lead to several clinical abnormalities that include megaloblastic anemia, growth retardation, and neural tube defects in the developing embryo. Folate deficiency is highly prevalent and results from a variety of causes, including impairment of the intestinal folate uptake system (e.g., hereditary folate malabsorption syndrome), intestinal diseases (e.g., celiac disease, tropical sprue), drug interactions (e.g., sulfasalazine, trimethoprim, pyrimethamine, diphenylhydantoin), and chronic alcohol use. 

Sources and Recommended Daily Allowance The human intestine is exposed to dietary folate and bacterial folate, which is generated by the normal colonic microbiota.1

Folate is widely distributed in food, and rich sources include green vegetables, liver, beans, and lentils. Since 1998, cereal products in the US and several other countries have been supplemented with folate and also represent a good source of the vitamin. The RDA for folate is 400 μg, which is the same dose recommended for women of child-bearing age to reduce the incidence of neural tube defects. 

Digestion and Absorption Physiologic Aspects Dietary folates exist in the free (i.e., folate monoglutamate) and predominant polyglutamate form. Conjugated folate polyglutamates cannot be absorbed because of their size and multiple negative charges. Prior to absorption, they must undergo hydrolysis to free folate by the enzyme folylpoly-γ-glutamate carboxypeptidase, which is also called folate hydrolase. There are 2 forms of this enzyme in intestinal absorptive cells: the first is expressed at the BBM domain of the cells, and the other is intracellular (localized in lysosomes).71,72 The BBM form of folate hydrolase is expressed mainly in the proximal part of the small intestine, and the intracellular form is expressed uniformly along the length of the small intestine. The membrane form of the enzyme has been cloned, and its activity appears to be adaptively upregulated in folate deficiency and during development.73–75 Intestinal absorption of the negatively charged dietary folate (pKa values of the α and γ carboxyl groups of the folate molecule are 3.5 and 4.8, respectively) occurs in the proximal half of the small intestine and involves a specific pH- (but not Na+-) dependent carrier-mediated process (see Fig. 103.1). In animal studies, resection of the proximal small intestine leads to a marked induction of carrier-mediated folate uptake in the ileum. The intestinal folate uptake process has similar affinities for reduced

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(e.g., 5-methyltetrahydrofolate, 5-formyltetrahydrofolate), oxidized (e.g., folic acid), and substituted (e.g., methotrexate) folate derivatives.76,77 Absorbed folate leaves the enterocytes across the BLM via another carrier-mediated process.78 A substantial portion of the folate synthesized by the normal microbiota exists in the absorbable free form, and the large intestine is capable of absorbing free folate via a highly efficient and specific carrier-mediated mechanism.79–81 Interferences with this mechanism may contribute to the development of localized folate deficiency and premalignant changes in colonic mucosa.82,83  Molecular Aspects Three specific systems are known to transport folate in mammalian cells: the transmembrane reduced folate carrier (RFC, the product of the SLC19A1 gene); the transmembrane protoncoupled folate transporter (PCFT, the product of the SLC46A1 gene); and the membrane-anchored (via a glycosyl phosphatidylinositol linkage) folate receptor.84–87 The first 2 systems (RFC and PCFT) are both expressed and functional in the intestinal tract, but the third is neither expressed nor functional under normal physiologic conditions.88 The human RFC (hRFC) operates optimally at a pH of 7.0 to 7.4. The hRFC polypeptide consists of 591 amino acids, and shares a high degree of sequence homology with the RFC system of other mammals (e.g., rodents, chimpanzees). RFC functions as an anion exchanger and moves the negatively-charged folate molecule against its concentration gradient in exchange for downhill movement of an anion.89 RFC mRNA is expressed along the length of the intestinal tract, with expression of the RFC protein at the apical membrane domain of the polarized small intestinal and colonic epithelia.78,90 The human PCFT (hPCFT) system operates optimally at acidic pH (5.8 to 6.0). The hPCFT polypeptide consists of 459 amino acids and is predicted to form 12 TMD.86,91 The PCFT functions electrogenically as a folate−:H+ symporter, transporting folate by the net movement of a positive charge (see Chapter 101).91 Folate is transported by this system against its concentration gradient using the energy generated by the downhill movement of protons. The inwardly directed proton gradient is provided by the intestinal surface acid microclimate, which has a pH of 5.8 to 6.0 at the proximal small intestine. The hPCFT mRNA is expressed mainly in the proximal small intestine, with less expression in the distal small intestine and the colon.86,89,92 Expression of hPCFT is restricted to the apical membrane domain of intestinal epithelial cells.93 Both the PCFT and RFC systems contribute to overall intestinal assimilation of exogenous folates. PCFT appears to be the predominant folate uptake system in the proximal small intestine, where the pH at the luminal surface is approximately 5.8 to 6.0.94 This belief is supported by the identification of individuals with hereditary folate malabsorption syndrome, a condition caused by mutations in hPCFT.79,86 The hRFC system operates in the distal small intestine and colon, where the pH at the luminal surface is near neutral.94 The folate transport system at the BLM domain of the intestinal absorptive epithelial cells is believed to be a member(s) of the MRPs.91 In recent years, knowledge of the structural features of the hPCFT and hRFC systems that are important for their function has evolved. The conserved histidine residues located at positions 247 and 281 of the hPCFT polypeptide appear to be critical for function of the transporter.95 In addition, clinical mutations identified in hPCFT in patients with hereditary folate malabsorption syndrome have implicated a role for the amino acid residues located at positions 65, 66, 113, 147, 318, 376, and 425 of the polypeptide.91 These mutations were shown to lead to a spectrum of consequences that include an early stop codon and a frame shift (both of which lead to absence of hPCFT protein), or to a

defective intracellular trafficking/membrane targeting of the protein and/or protein instability.91 Amino acid residues located at positions 45, 46, 104, 105, 127, 130, 297, and 309 as well as the intracellular loop between transmembrane 6 and 7 of the polypeptide appear to be important for the function of RFC.89,96  Cell Biology Aspects The molecular determinants that dictate targeting of the hRFC protein to the cell membrane appear to reside within the hydrophobic backbone of the polypeptide and not within its N- or C-terminal domains. Also, the integrity of the hRFC backbone is critical for exporting the polypeptide from the endoplasmic reticulum to the cell surface. Intracellular movement of RFC appears to involve trafficking vesicles, the mobility of which depends on an intact microtubule network (real-time movies can be viewed at: http://www.jbc.o rg/cgi/content/full/277/36/33325/DC1).97 Dynein light-chain road block-1, which is located in intestinal epithelial cells, interacts with hRFC and is important for its function (see Fig. 103.4).98 A beta-turn sequence between the second and third TMD of hPCFT appears to be essential for its targeting to the apical membrane of intestinal epithelial cells. Mutations in this sequence lead to retention of hPCFT in the endoplasmic reticulum. Again, cellsurface delivery of the hPCFT polypeptide appears to involve trafficking vesicles, which is microtubule dependent.93  Regulatory Aspects A variety of extracellular and intracellular factors regulate intestinal folate uptake. Globally, transcription of the SLC19A1 gene involves at least 6 alternative promoters and leads to the generation of many distinct 5′ untranslated regions, but with a common hRFC open reading frame. These promoters are regulated by both ubiquitous (SP, USF) and tissue-specific (e.g., AP1, C/ EBP) nuclear factors and by methylation.85,91,99 In the intestine, SLC19A1 promoter B appears to drive the transcription of hRFC.84,99 The minimal region required for basal activity of the hRFC promoter B in intestinal epithelial cells is encoded in a sequence between −1088 and −1043.100 The minimal promoter required for basal activity of SLC46A1 has been mapped to a region 157 bp upstream of the ATG and contains putative GC-box sites as well as enhancer elements (YY1 and AP1) that appear to be important for function.101 Intestinal folate uptake undergoes differentiation-dependent regulation; thus a significant upregulation in carrier-mediated folate uptake occurs as intestinal epithelial cells move from the undifferentiated stage to the differentiated stage. This increase in uptake with differentiation was associated with a marked increase in the level of expression of hRFC and hPCFT at the protein, mRNA, and promoter levels. The latter finding suggests that this mode of regulation in intestinal folate uptake is, at least in part, mediated via transcriptional mechanisms.102 Intestinal folate uptake is also regulated by extracellular folate levels; folate deficiency leads to an induction in intestinal folate uptake via an increase in the level of expression of RFC and PCFT mRNA.74,100,103,104 For the hRFC, this induction appears to be, at least in part, transcriptionally mediated, with the folatedeficient responsive region being encoded in a sequence between −2016 and −1431 of the hRFC promoter B.74,100,103,104 Intestinal folate uptake undergoes developmental regulation during the early stages of life.105 A progressive decrease in folate uptake occurs with maturation (i.e., from suckling to weanling to adult). This is associated with a parallel decrease in the level of expression of RFC and in the transcription rate of the SLC19A1 gene (changes in level of PCFT were not examined in these studies). Finally, intestinal folate uptake appears to be under the regulation of intracellular protein tyrosine kinase- and cAMP-mediated pathways that function by affecting the Vmax of the folate uptake process.81,106

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Intestinal folate digestion is also adaptively regulated by the substrate level in the diet, with significant induction in folylpolyγ-glutamate carboxypeptidase activity occurring in folate deficiency.74 Furthermore, the folate digestive process undergoes developmental regulation during the early stages of life.75 

Clinical Pathophysiology of Intestinal Folate Absorption It is well recognized that chronic alcohol use is associated with folate deficiency. A variety of factors contribute to the development of this deficiency, including inhibition in intestinal absorption of folate.107,108 Chronic alcohol consumption affects both the initial hydrolysis of dietary folate polyglutamates to free folate and subsequent absorption free folate.107–109 The latter effect is via inhibition of folate transport across the BBM and BLM domains of the absorptive epithelial cells and is associated with a marked reduction in level of expression of RFC.110,111 Other investigations have reported impairment in the activity of the intestinal folylpolyγ-glutamate carboxypeptidase (folate hydrolase) in disease conditions that affect the intestinal mucosa (e.g., celiac disease, tropical sprue) and as a result of long-term use of sulfasalazine.112–118 

Niacin (Vitamin B3, Nicotinic Acid) Metabolic Role and Effect of Deficiency Niacin, also known as nicotinic acid, nicotinamide, or vitamin B3 serves as a precursor for nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide phosphate, which are cofactors that play an important role in energy metabolism such as glycolysis. Niacin deficiency leads to pellagra, a disease characterized by inflammation of mucous membranes, skin lesions, colitis with resultant diarrhea, and dementia.119–121 There are some data to suggest that niacin supplementation may protect against Alzheimer disease and age-related cognitive decline, whereas pharmacologic doses are highly effective for increasing HDL although do not seem to reduce all-cause mortality, myocardial infarction, or stroke in patients already receiving statin therapy.119–121,122 

Sources and Recommended Daily Allowance Humans acquire niacin from both endogenous and exogenous sources. Endogenous niacin is provided by the metabolic conversion of tryptophan to niacin (60 mg of tryptophan yields approximately 1 mg of niacin) and as a byproduct from normal colonic microbiota, whereas exogenous niacin is obtained through dietary consumption. Rich dietary sources include meat, fish, bread, and yeast.123,124 Establishing an accurate RDA of niacin is quite challenging because of endogenous synthesis; however the recommended dietary intake in most adults ranges between 14 and 18 mg/day. 

Intestinal Absorption Niacin is absorbed primarily in the stomach and small intestine. The presence of food does not seem to influence niacin absorption and pharmacologic-range doses appear to be absorbed by passive diffusion. Specific factors that influence intestinal absorption of dietary niacin remain unclear but seem to be temperature and pH-dependent.125 Both niacin insufficiency and deficiency occur in persons with alcohol use disorder and those with IBD or Hartnup syndrome. Individuals with the latter disease have mutations in the membrane transporter of the amino acid tryptophan, which is the endogenous precursor of niacin (see Chapter 102). Cell Biology Aspects The regulation of intestinal niacin absorption is not well understood. Studies using jejunal and colonic epithelia from organ donors have helped to elucidate the mechanisms of niacin

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absorption in humans, including the presence of transporters at these sites.125 Intestinal uptake of physiologic concentrations of nicotinic acid involves a specific high-affinity acidic pH- (not Na+-) dependent, carrier-mediated mechanism (see Fig. 103.1).126 The molecular identity of the niacin uptake system has not been well defined, but the human organic anion transporter-10 (hOAT-10) has been suggested to play a role.127  Regulatory Aspects This specialized, acidic pH-dependent, carrier-mediated system of niacin uptake by human intestinal epithelial cells operates in the physiologic micromolar range of niacin concentration and appears to be regulated by an intracellular protein tyrosine kinase-mediated pathway.125 

Pantothenic Acid (Vitamin B5) Metabolic Role and Sources Pantothenic acid, also known as vitamin B5, is the functional moiety of coenzyme A and plays a critical role in energy-yielding metabolic reactions including carbohydrate, fat and, to a lesser extent, protein metabolism. Owing to the fact that pantothenic acid has a ubiquitous distribution in foodstuff, it is quite rare to develop pantothenic acid deficiency in humans. Indeed, its name derives from the Greek pantothen, meaning “from everywhere,” and small amounts of pantothenic acid are found in nearly every food. Recommended dietary intake has not been established; however adequate intake for adults is approximately 5 mg/day. 

Intestinal Digestion and Absorption Cell Biology Aspects Free pantothenic acid is absorbed in the small intestine via a Na+dependent carrier-mediated process that involves SMVTs that also allow for cellular uptake across the blood brain barrier and help maintain proper brain function.20,22,128 The same process also operates in the large intestine to absorb the pantothenate generated by colonic bacteria. There is no information about how absorbed pantothenic acid leaves the intestinal epithelial cells across the BLM, although it is thought to involve another SMVT.  Regulatory Aspects Humans acquire pantothenic acid from both exogenous and endogenous sources, the latter produced by normal colonic bacteria.1 Dietary pantothenic acid exists mainly in the form of coenzyme A, which is hydrolyzed to the absorbable form of free pantothenic acid in the intestinal lumen.129At low luminal concentrations, there is active transport of pantothenic acid via SMVT in exchange for protons on the apical membrane of the epithelial brush border. At higher concentrations, passive diffusion of pantothenic acid occurs and it appears that the alcohol form, panthenol (oxidized to pantothenic acid), diffuses more readily than the acid form. 

Pyridoxine (Vitamin B6) and Derivatives Metabolic Role and Effect of Deficiency Vitamin B6 refers to the 3 compounds pyridoxine, pyridoxal, pyridoxamine and their phosphorylated forms. Vitamin B6 plays a vital role in amino acid and carbohydrate metabolism and is involved in modulating the action of steroid hormones and in gene expression regulation. Pyridoxal 5′-phosphate is the most biologically active form of this vitamin. Vitamin B6 deficiency leads to a variety of clinical abnormalities that include, but are not limited to, neurologic disorders and anemia. Vitamin B6

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deficiency more commonly occurs in persons with alcohol use disorder, those with diabetes mellitus or celiac disease, and those on long-term therapy with isoniazid or penicillamine. Patients with vitamin B6-dependent seizures (an autosomal recessive disorder thought to result from impairment in vitamin B6 transport into cells) also display suboptimal levels of this vitamin.130,131 

Sources and Recommended Daily Allowance Humans acquire vitamin B6 exogenously via dietary intake; it is also produced by colonic bacteria. Vitamin B6 is abundantly found in foodstuff. Rich sources include meat, fish, starchy vegetables like potatoes, and noncitrus fruits. The RDA for vitamin B6 is 1.5 to 2 mg/day for adults. 

Intestinal Absorption Cell Biology Aspects Both dietary and bacterial sources of vitamin B 6 are bioavailable to the host, although their relative contribution to total body homeostasis of vitamin B 6 is not well defined. Dietary vitamin B 6 exists in free and phosphorylated forms; the latter is hydrolyzed by intestinal phosphatases to its free form prior to absorption. 130 Absorption of free vitamin B 6 in the small and large intestine occurs via a specific high-affinity, acidic pH-dependent, Na +-independent, carrier-mediated mechanism, Interestingly, the diuretic amiloride has the ability to inhibit intestinal and renal absorption of this vitamin and this may interfere with normal vitamin B 6 homeostasis. (see Fig. 103.1). 132–136 Regulatory Aspects Little is known about the regulation of intestinal pyridoxine uptake in mammals, but some data suggest a specialized carriermediated mechanism by intestinal epithelial cells that is pH dependent, amiloride sensitive, and under the regulation of an intracellular PKA-mediated pathway.132,136 Vitamin B6 deficiency leads to a specific and significant upregulation in uptake via transcriptional mechanisms.133 

Riboflavin (Vitamin B2) Metabolic Role and Effect of Deficiency Riboflavin, also known as vitamin B2, exists as 2 metabolically active coenzyme forms, flavin mononucleotide and flavin adenosine dinucleotide, which play an important role as an intermediary for the transfer of electrons in biological oxidation-reduction reactions. These reactions are involved in macronutrient metabolism, as well as in the conversion of folic acid and vitamin B6 to their active forms. Riboflavin deficiency can occur in those with IBD, alcohol use disorder, mitochondrial disorders, and in patients with Brown-Vialetto-Van Laere syndrome, which is a rare neurologic disorder associated with sensorineural deafness, bulbar palsy, and respiratory compromise, thought to be caused by a mutation in riboflavin transporter-2. Riboflavin deficiency can lead to a variety of clinical abnormalities, which include degenerative changes in the nervous system, endocrine dysfunction, skin disorders, and anemia.137 There are some data to suggest that riboflavin supplementation may improve neurologic motor function in those with multiple sclerosis because of its role in myelin formation.138 Riboflavin’s neuroprotective role is also demonstrated in those with Parkinson disease and migraine headache disorders via several proposed mechanisms, which include homocysteine metabolism, and reduction of oxidative stress and neuro-inflammation.139–141

Sources and Recommended Daily Allowance Riboflavin is found widely in foods, with higher levels in dairy products, eggs, meat, green leafy vegetables, and legumes. The RDA for healthy adults ranges between 1.3 and 1.6 mg/day. 

Intestinal Digestion and Absorption Physiologic Aspects As with other water-soluble vitamins, the human intestine is exposed to exogenous and endogenous sources of riboflavin. Exogenous dietary intake is absorbed in the small intestine via a highly efficient uptake system, whereas endogenous sources are produced by normal colonic microbiota in quantities believed to be several-fold more than what is consumed in the diet.1,142,143 Dietary riboflavin exists in free and conjugated forms. Conjugated forms are broken down by intestinal phosphatases prior to absorption.144 Absorption of free riboflavin in the small and large intestine occurs via a specific Na+-independent carriermediated mechanism located at the apical BBM domain of the polarized epithelial cells, which then leaves the cell across the BLM via another specific carrier-mediated mechanism (see Fig. 103.1).20 Molecular Aspects Both of the riboflavin transporters (RF transporter [RFT]-1 and 2) are expressed in the small and large intestine.145–147 The level of expression of hRFT-2 and its activity as a riboflavin transporter is significantly higher than that of hRFT-1. These findings imply that hRFT-2 has a prominent role in intestinal riboflavin uptake, a theory supported by the significant inhibition in riboflavin uptake by intestinal epithelial cells treated with gene-specific hRFT-2 siRNA.147 There are more than 10 mutations discovered in the RFT-2 transporter in patients with Brown-Vialetto-Van Laere Syndrome and, as such, there are various disease phenotypes depending on the particular mutation. This disorder is characterized by progressive pontobulbar plasy, which is typically preceded by sensorineural deafness.137,148–150  Cell Biology Aspects Confocal imaging studies in living cells have shown that the hRFT-1 protein is mainly expressed at the BLM domain of intestinal absorptive cells, whereas the expression of hRFT-2 is exclusively confined to the apical membrane domain (see Fig. 103.1).147,151 Also, an essential role has been demonstrated for the COOH-terminal sequence of TFT-2 in dictating cell surface expression of the protein, with a specific role for the conserved cysteine residues (C463 and C467).151 Furthermore, intracellular trafficking of hRFT2 was found to involve distinct vesicular structures, motility of which is dependent on an intact microtubule network.151 Regulatory Aspects A variety of extracellular and intracellular factors and conditions regulate the intestinal riboflavin uptake process, which is adaptively regulated by the host’s vitamin level;152–154 thus, riboflavin deficiency leads to a significant upregulation in intestinal riboflavin uptake, whereas excess supplementation results in downregulation of riboflavin intestinal absorption. These adaptive changes in intestinal riboflavin uptake by substrate levels appear to involve transcriptional regulatory mechanisms, which are developmentally regulated during the early stages of life.155 The intestinal riboflavin uptake process appears to be under the regulation of an intracellular PKA- and Ca2+/calmodulin-mediated signaling pathways.156 Interestingly, in laboratory studies, the intestinal riboflavin uptake process appears to be sensitive to the inhibitory

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effect of the Na+/H+ exchanger amiloride and to the tricyclic phenothiazine drug chlorpromazine which shares structural similarity with riboflavin).152,157,158 Whether these pharmacologic agents also affect intestinal riboflavin absorption in vivo is still unknown. 

Thiamine (Vitamin B1) Metabolic Role and Effect of Deficiency Thiamine, also known as vitamin B1, was the first water-soluble vitamin to be described. Thiamine deficiency was first referenced in Chinese medical literature more than 4000 years ago when clinical manifestations of thiamine deficiency (beriberi) were first described. The pyrophosphate form of thiamine, thiamine pyrophosphate (TPP), is the most abundant form of this vitamin in mammals. TPP is critical for oxidative energy metabolism and ATP production in the mitochondria via its role as a co-factor for multiple enzymes including transketolase, pyruvate dehydrogenase, α-ketoglutarate dehydrogenase, and branched-chain ketoacid dehydrogenase.159 Thiamine also plays an important role in decreasing cellular oxidative stress by maintaining the normal cellular redox state;159,160 thus, low intracellular thiamine levels lead to impairment in oxidative energy metabolism and result in an increased propensity for oxidative stress and alterations in mitochondrial structure and function.159–161 Thiamine triphosphate, which is another form of thiamine, influences regulation and function of membrane chloride channels and acts as a phosphate group donor to proteins. Thiamine deficiency in humans leads to 2 distinct clinical entities, beriberi and Wernicke encephalopathy. Beriberi has 3 different phenotypes: (1) dry beriberi is a symmetrical ascending peripheral polyneuropathy that usually affects older individuals and may be associated with cardiac involvement; (2) wet (or edematous) beriberi involves the heart and leads to lower extremity edema; and (3) acute “fulminating” beriberi, also known as shoshin beriberi, occurs mainly in infants and is associated with heart failure and metabolic abnormalities. Wernicke encephalopathy and Korsakoff psychosis are most commonly associated with alcohol use disorder and can manifest synchronously as WernickeKorsakoff syndrome. Wernicke encephalopathy is associated with neurologic abnormalities (nystagmus, extraocular palsy, ataxia, confabulation, coma) and anatomic lesions (hemorrhagic lesions in the thalamus, pontine tegmentum and mammillary bodies, with severe damage to astrocytes, neuronal dendrites, and myelin sheaths). Korsakoff psychosis typically develops as Wernicke symptoms start to resolve and manifests as confusion and shortterm memory loss that can lead to permanent brain damage. Thiamine deficiency is a significant problem in both developing and developed countries, and mainly results from inadequate dietary intake. In developed countries, alcohol use disorder is the leading cause although deficiency can also occur in those with diabetes, IBD, celiac disease, and renal disease, and from the use of chronic diuretic therapy.162–164 For unclear reasons, thiamine deficiency has also been reported in older adults, despite an average daily intake that exceeds their recommended requirement. Also recognized in more recent years is localized, tissue-specific thiamine deficiencies that occur despite the presence of normal plasma thiamine levels; examples include thiamine-responsive megaloblastic anemia (TRMA), which is autosomal recessive, and thiamine-responsive Wernicke’s-like encephalopathy. TRMA is characterized by megaloblastic anemia, sensorineural deafness, and insulin-requiring hyperglycemia. It is caused by mutations in the human thiamine transporter-1 (hTHTR-1), a product of the SLC19A2 gene.165–168 Thiamine-responsive Wernicke-like encephalopathy is characterized by seizures, ophthalmoplegia, nystagmus, and ataxia and is believed to occur because of mutations in hTHTR-2, a product of the SLC19A3 gene.169 In both

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disorders, oral administration of thiamine at pharmacologic doses result in significant improvements in many of the clinical symptoms. 

Sources and Recommended Daily Allowance Thiamine is ubiquitous in foods and, in particular, dried baker’s yeast, whole grain cereal, rice bran, nuts, and dried legumes. Poor sources of thiamine include highly processed foods such as polished rice, oils, and refined sugar. It is important to note that the existence of several dietary antagonists affect thiamine availability from dietary consumption. Sulfite, which is a food preservative, and heat-stable polyhydroxyphenolic compounds which exist in ferns, blueberry, red chicory, red beetroot, black currant, brussel sprouts, and red cabbage, can cleave the thiamine molecule. Certain food products and micro-organisms also contain thiamine-degrading enzymes, thiaminease I and II. Thiaminease I is present in a variety of microorganisms (e.g., Bacillus thiamineolyticus), plants (e.g., fern), fish (e.g., carp), and insects (e.g., African silkworm Anaphe spp.), and catalyzes a reaction between the thiamine molecule and a variety of bases. Such a reaction not only depletes thiamine but also leads to the generation of by-products that act as thiamine antagonists. Thiaminease II is relatively rare and exists in a small number of microorganisms such as intestinal B. thiamineolyticus and Clostridium thiamineolyticum. The RDA for thiamine is 1.4 mg/day for men, 1.1 mg/day for women, 1.5 mg/day during pregnancy, and 1.6 mg/day for women who are lactating. 

Intestinal Absorption Physiologic Aspects As with other water-soluble vitamins, there are 2 sources of thiamine: dietary and bacterial, the latter generated from normal colonic microbiota.1 Dietary thiamine from animal sources exists mostly in the phosphorylated form, whereas that from plant sources exists as a mixture of free and phosphorylated forms. Phosphorylated dietary thiamine is hydrolyzed to free thiamine by the action of intestinal phosphatases, which are abundantly expressed in the small intestine.170 Free thiamine is then absorbed mainly in the proximal small intestine via a specific pH- dependent and electroneutral carrier-mediated mechanism (see Fig. 103.1).171,172 Once absorbed in the proximal small intestine, thiamine exits the enterocyte across the BLM via a specific carriermediated mechanism.173 The normal colon microbiota synthesizes a considerable amount of thiamine in both free and phosphorylated forms via enzymes involved in the synthesis of TPP.174,175 Colonocytes possess little or no alkaline phosphatase activity compared with the epithelial cells of the small intestine. Identification of a TPP uptake system in these cells suggests that this form of thiamine is also bioavailable to humans.176–178 Collectively, the presence of efficient uptake mechanisms for free and phosphorylated thiamine suggest that bacterially-synthesized thiamine contributes significantly to the overall thiamine load in the host and has an important role in maintaining cellular nutrition of the colonocyte itself.  Molecular Aspects The 2 known thiamine transport systems THTR-1 and THTR2, which have been identified in humans and other mammals, are both expressed in the small and large intestine.166–169,179 The human THTR-1 functions in the micromolar range and hTHTR-2 functions in the nanomolar range.180 The THTR-1 protein is expressed at both the apical and the BLM domains of polarized enterocytes, whereas expression of the THTR-2 protein is restricted to the apical BBM domain of absorptive cells (see Fig. 103.1).181,182

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More than 16 missense and nonsense mutations have been found in THTR-1 in patients with TRMA. These mutations lead to impairment in the function of the protein via changes in stability, membrane targeting, and transport activity.183,184 A number of mutations have also been found in THTR-2 in patients with thiamine-responsive Wernicke-like encephalopathy that lead to functional impairment.169 Other mutations in THTR2 have been reported in patients with biotin-responsive basal ganglia disease; however, it is unclear how mutations in a specific thiamine transporter lead to pathologic conditions that respond to biotin, because THTR-2 is not a biotin transporter.185,186  Cell Biology Aspects Confocal imaging of living human intestinal epithelial cells show that THTR-1 protein fused to green fluorescent protein targets to both the apical and BLM domains of the polarized cells, and that the signals that dictate membrane targeting of the protein are embedded within its N-terminal and backbone.182,187 Furthermore, intracellular trafficking of THTR-1 involves numerous trafficking vesicles, and movement of these vesicles is temperature-dependent and requires an intact microtubule network (real-time movies can be viewed at: http://www.jcb.org/cg i/content/full/278/6/3976/DC1). More recent studies have also shown that THTR-1 interacts with a member of the tetraspanin family of proteins (Tspan-1) in intestinal epithelial cells, and this interaction is important for stability of the thiamine transporter (see Fig. 103.4).188 Living cell confocal imaging has shown that the THTR-2 protein is expressed exclusively at the apical membrane domain of the polarized intestinal absorptive epithelial cells, and this membrane targeting is dictated by the transmembrane backbone of the protein.187 Similarly, intracellular trafficking of this protein depends on the existence of an intact microtubule network.187  Regulatory Aspects Intestinal thiamine uptake undergoes differentiation-dependent regulation, with upregulation in carrier-mediated thiamine uptake as intestinal epithelial cells differentiate.189,190 This upregulation is associated with a significant increase in the level of expression of hTHTR-1 protein and mRNA, hTHTR-2 protein and mRNA, and in the activity of the SLC19A2 and SLC19A3 promoters. Intestinal thiamine uptake is adaptively regulated by the coinciding substrate level.191,192 Thiamine deficiency in humans leads to an increase in intestinal thiamine uptake via changes in the Vmax and Km of the uptake process.191 Similar adaptive upregulation in intestinal thiamine uptake occurs in mice and is associated with a significant increase in the level of expression of THTR-2 (but not THTR-1) protein, mRNA, and activity of the SLC19A3 promoter.192 These data provide evidence that adaptive upregulation in the intestinal thiamine uptake process in thiamine deficiency is mediated via an induction in the level of expression of THTR-2, and that induction is, at least in part, mediated via transcriptional mechanisms. Intestinal thiamine uptake undergoes developmental regulation during early stages of life. The intestine is more effective at absorbing thiamine during the suckling period than in adulthood, and is associated with a greater expression of THTR-1 and THTR-2 and more activity of their respective promoters earlier in life.193 Therefore developmental regulation of intestinal thiamine uptake appears to be mediated by transcriptional mechanisms. Finally, intestinal thiamine uptake appears to be under the regulation of an intracellular Ca2+/calmodulin (CaM)-mediated pathway.175,194 The same pathway appears to regulate thiamine uptake in other cell types (e.g., pancreatic beta cells, renal epithelial cells, retinal pigment epithelial cells) and suggests a wide distribution of this intracellular signaling pathway in the regulation of thiamine uptake.195,196 

Clinical Pathophysiology of Intestinal Thiamine Absorption Chronic heavy alcohol consumption leads to impaired intestinal thiamine absorption and thiamine deficiency.197 Animals chronically fed alcohol develop significant inhibition of carrier-mediated thiamine transport across both the BBM and BLM domains of the polarized enterocytes, which is mediated via transcriptional mechanisms.193 Inhibition of intestinal thiamine uptake was noticeable as early as 2 weeks after initiation of alcohol exposure.198 Chronic alcohol feeding also inhibited carrier-mediated thiamine uptake in the large intestine, which suggests that absorption of bacterially synthesized thiamine is also impaired by chronic alcohol consumption.198 Infection with the Gram-negative enteropathogenic Escherichia coli (EPEC), a food-borne pathogen (see Chapter 111), severely inhibits intestinal thiamine uptake.180 Interestingly, EPEC infection of the host does not cause a generalized inhibition of micronutrient absorption, and uptake of neither of the watersoluble vitamins riboflavin or folate is affected. Furthermore, EPEC inhibition of thiamine uptake is associated with a significant decrease in membrane expression of hTHTR-1, hTHTR-2, and in activity of the SLC19A2 and SLC19A3 promoters. These findings suggest that EPEC infection rapidly affects expression of the thiamine transporters at the enterocyte cell membrane, followed by a more prolonged effect that is mediated via inhibition of SLC19A2 and SLC19A3 transcriptional activities. 

FAT-SOLUBLE VITAMINS Vitamins A, D, E, and K are polar, nonswelling, insoluble lipids (Fig. 103.7). There are considerable differences, however, among these vitamins, and only vitamin E is an obligate dietary constituent. Their respective fat solubility influences their absorption, metabolism, excretion, and storage. Although their chemical structures are known, the retention of a letter naming system to distinguish them is useful because each consists of a number of closely related compounds with similar properties.199

Vitamin A Hippocrates (466-377 bc) first suggested the functional role of a liver-derived nutrient, but vitamin A was only confirmed by Moore as a dietary vitamin in 1957. The complexity surrounding its dietary sources, requirement, and availability reflects the existence of both retinyl esters ([preformed], previtamin A) and carotenoids (provitamin A), both requiring metabolic change to become active. Such complexity is further complicated by differences in their properties, regulatory functions, and potential clinical applications.200

Metabolic Role and Effect of Deficiency Preformed vitamin A is found in the diet in a number of forms, including retinol (vitamin A1) and retinal (3-dehydroretinol [vitamin A2]), predominantly as palmitate retinyl esters. The basic unit of activity is termed a retinol equivalent. Carotenoids have 2 primary roles in humans: macula pigments and natural precursors to vitamin A. Carotenoids include carotenes, with provitamin A capability and others, such as lycopene, lutein, and zeaxanthin, without this capability.201,202 Despite significant global variability in the food sources of carotenoids, there is limited evidence of populations that are specifically carotenoiddeficient. In contrast, retinoids have a critical role in the mammalian life cycle. Vitamin A deficiency can cause vision defects such as nightblindness and immune dysfunction, the latter notably affecting childhood mortality associated with measles and diarrheal illnesses via a putative role in regulating T-cell–mediated immunity,

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Fig. 103.7  Chemical structures of fat-soluble vitamins A, D, E, and K.

intestinal mucosal integrity and immunoglobulin (IgA) production.200,203,204 Deficiency of vitamin A differs between developing and developed countries, which highlights the dependency on pro- and preformed vitamin A from a well- balanced diet. Adequate availability of vitamin A is required for normal development and embryogenesis; however, vitamin A excess can cause teratogenesis in the first trimester of pregnancy.205 In addition, mortality caused by acute vitamin A toxicity has been reported in hunters in the Arctic regions after ingestion of polar bear liver, which is very rich in vitamin A. 

Sources and Recommended Daily Allowance Preformed dietary vitamin A is found in meat products, dairy, egg yolk, liver, fish oils, and is fortified in margarine. Provitamin A is found in yellow, orange and green vegetables such as spinach, carrots, mango, and papaya, with fortification through food colorings that contain β-carotene.206 Of the carotenoids, β-carotene has the greatest biologic activity compared with β-cryptoxanthin and α-carotene.207 In western diets, provitamin A from plant

sources provides less than 30% of vitamin A, with the remainder from animal sources; in developing countries, plant sources provide more than 70% as provitamin A.208 Historical studies suggest that vitamin A deficiency rarely occurs in populations subjected to starvation owing to the availability of carotenes in vegetables, green plants, herbs and grasses, which are consumed in times of food shortages. Among Key’s Minnesota experiments on healthy subjects given semi-starvation vegetable diets, there was no evidence of vitamin A deficiency either biochemically, clinically, or on dietary analysis.209 The RDA for vitamin A is age dependent and altered in pregnancy, lactation, and childhood. For adults, it is equivalent to 900 μg in men and 700 μg in women.210 The necessary intake of carotenoids remains unclear, but 2 to 4 mg/day is recommended, particularly where dietary intake of preformed vitamin A is considered insufficient.206 Dietary intakes of vitamin A among the US population recorded in the National Health and Nutrition Examination Survey was estimated at approximately 500 μg/day; the RDA is commonly achieved through vitamin supplementation.211 

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Clinical Pathophysiology of Intestinal Absorption of Vitamin A Provitamin A carotenoids are isoprenoid compounds, which contain up to 15 conjugated double bonds and are synthesized in certain plants, fungi and bacteria.200 Only approximately 50 of the 600 known carotenoids are found in the human diet, 10 of which have been measured in significant amounts in humans. Of these, only 3 are provitamin A precursors: α-carotene, β-carotene, and β-cryptoxanthin. β-carotene has twice the activity of the other carotenes because it contains 2 β-ionone structures, which have the capacity to form 2 vitamin A1 molecules.212 Recent data, however, suggest other carotenoids may have greater activity than initially considered.213 The dietary absorption of β-carotene is approximately 17% from a mixed diet. Preformed and pro-forms of vitamin A are absorbed differently in the small intestine, and absorption also varies in the fed and fasted state. Preformed vitamin A is absorbed more efficiently than carotenes in the small intestine. Aside from differing degrees of absorption, there are also variances in regulatory mechanisms, postabsorption activity and metabolism.214,215 Dietary retinal (vitamin A aldehyde) esters are first hydrolyzed to retinol in the intestinal lumen before absorption. Vitamin A is a fat-soluble dietary constituent and is better absorbed in the presence of pancreato-biliary secretions when incorporated into lipid micelles.216 Retinyl ester hydrolysis is required prior to absorption, but precise understanding of this mechanism remains uncertain. Diffusion and transport-dependent mechanisms have been noted, with co-consumption of fat leading to rapid uptake of retinol forms and secretion because retinyl esters are solubilized into chylomicrons. In the absence of dietary lipid, retinol is absorbed via a nonlipoprotein-dependent mechanism with secretion across the intestinal cell; thus absorption of vitamin A occurs in the form of both retinyl esters and free retinol. Absorption of carotenoids is variable and influenced by the complexity of the food matrix, preparation, dose, co-consumption of fiber, fat, preformed vitamin A and other carotenoids.212 Like the retinyl esters, carotenoids are solubilized into micelles with other lipids and absorbed across the luminal interface. There appears to be both concentration-dependent passive diffusion and a saturable active transporter mechanism, predominantly based on β-carotene. In the latter case, activity of the transporter may be dependent on the cis-transisomeric form that may compete for the transport mechanism.216 Following dietary consumption of previtamin A and retinyl esters, or ingestion of carotenoids that are converted to retinol in the enterocytes, retinol is re-esterified by lecithin, and retinol acyltransferase with palmitic acid. These esters are then incorporated into chylomicrons with other dietary lipids, which enter the systemic circulation via the lymphatic system. Although a small proportion of retinyl ester is removed by muscle, adipose, and other tissues, the larger proportion remains in the chylomicron remnant, which enters the hepatocytes via an apolipoprotein E-dependent pathway.217 Within the hepatocytes, these esters undergo hydrolysis and the majority of vitamin A is then stored within hepatic stellate cells, whereas a smaller proportion remains within the hepatocytes. Vitamin A, primarily palmitate retinyl esters, constitutes approximately 40% of the stellate cell’s lipid content and accounts for most of the body’s retinoid stores. How vitamin A is transported from the hepatocyte to the stellate cell remains unknown. It is released into the systemic circulation, depending on physiologic requirement, as determined by the ratio of retinol-bound to retinol-binding protein (RBP). RBP is a 21-kd protein with a single retinol-binding site. It is produced in hepatocytes and other tissues and is responsible for transporting vitamin A to peripheral tissues from the liver. RBP is bound as a 1:1 complex with transthyretin, which also plays a role in the transport of thyroxine. RBP levels are tightly regulated and

this contributes to the systemic bioavailability of retinol. RBP is a specific transport protein for retinol and other retinoids, and is responsible for the reprocessing of retinol between hepatic stellate cells and the periphery.218,219 More than 95% of retinol in the plasma is bound to RBP and the remainder is found as retinyl esters in lipoproteins released from the liver. 

Vitamin D Vitamin D is part of the secosterol family of compounds and is unique because it can be produced endogenously by ultraviolet B wavelength sunlight exposure. This exposure is conditional, and dietary supplementation may be necessary to avoid deficiency. The vitamin D group includes vitamin D3 (cholecalciferol) and D2 (ergocalciferol). The originally identified vitamin D1 was subsequently recognized as a mixture of different sterols.220 Another unique aspect of vitamin D is its dependence on structural modification to become its active form, 1,25αdihydroxycholecalciferol (1,25α-[OH]2D3), through a series of organ-specific enzyme-dependent metabolic steps that requires it to circulate through the body.221

Metabolic Role and Effect of Deficiency The principal function of vitamin D is related to its effect on calcium and phosphate homeostasis, although there is increasing evidence of its importance in other areas such as cellular proliferation, diabetes, and immunomodulation. Vitamin D exerts its effects via the vitamin D receptor (VDR), which is a member of the steroid hormone superfamily. This leads to transcriptional regulation of target genes, including upregulation of osteocalcin and receptor activator of nuclear factor kappa-Β ligand and down-regulation of parathyroid hormone (PTH).222 VDR is noted in high levels in the intestinal epithelial cells, where it modulates calcium absorption; renal tubular epithelial cells and collecting ducts where calcium resorption occurs; bone tissue, including osteoblasts; and parathyroid tissue. VDR is also noted in high concentrations in pancreatic beta cells and immune cells, which include activated T lymphocytes and the monocyte/macrophage line, for which it influences differentiation. Vitamin D, as 1,25α-(OH)2D3, influences calcium absorption through both transcellular and paracellular transport mechanisms.223 In the former, it is suggested that there are modulator effects on the TRPV6 calcium receptor, the calcium-binding protein that facilitates cytosolic diffusion. These transport mechanisms, however, are thought to be critical only in the setting of calcium deficiency and are only a subset of alternative mechanisms for transcellular calcium transport through the intestinal epithelium. Paracellular transport of calcium is considered to occur by passive absorption, which depends on the electrochemical gradient between the intestinal lumen and extracellular environment as well as the integrity of the intercellular tight junctions. This transport mechanism is influenced by 1,25α-(OH)2D3-induced expression of claudins that facilitate calcium transport and inhibit cadherin and aquaporin protein expression. Finally, it is suggested that 1,25α-(OH)2D3 regulation of tight junction proteins have a role in protecting against mucosal injury and maintaining the integrity of the bowel mucosa.224 Limited animal model data suggest that the effect on expression of transporter proteins via a transcriptional mechanism may also extend to phosphate absorption (NaPi-IIb).225 1,25α-(OH)2D3 influences renal calcium resorption through a number of mechanisms, including an indirect effect on increasing calcium absorption, a synergistic effect with PTH to increase the efficiency of calcium resorption by increasing mRNA of both PTH and PTHrp receptors, enhancement of calcium absorption in the distal tubules consistent with localization of VDR, and

CHAPTER 103  Digestion and Absorption of Micronutrients

increased expression of the PMCa pump for calcium transport at the BLM of distal renal tubular cells.222,226 Vitamin D deficiency is associated with metabolic bone disease through altered calcium and phosphate regulation, effects on PTH formation and release, and a direct effect on bone tissue. Rickets in children and osteomalacia in adults develop as a consequence of impaired bone mineralization along with associated hypocalcemia and a physiological increase in PTH with subsequent bone breakdown; this is associated with skeletal malformations in children and risks of fracture in all age groups. Vitamin D deficiency is associated with a range of other conditions, including cardiovascular disease, immune deficiency, diabetes, hypertension, and cancer.227,228 

Sources and Recommended Daily Allowance Vitamin D is present in food as a natural constituent and an additive. The richest sources of vitamin D are fish, including salmon, tuna, and mackerel, which ingest vitamin D from dietary plankton; and from oils extracted from fatty fish, such as cod liver oil.199,229 Vitamin D is also found in eggs and liver. Human breast milk contains sufficient vitamin D to prevent rickets, but unfortified cow’s milk is a poor source of vitamin D. Dairy products, orange juice, margarine, and cereals are frequently fortified with vitamin D.221 Dietary intake is complementary to the vitamin D that is produced endogenously through skin exposure to UVB (290 to 320 nm) light. It is suggested that for populations between the ages of 4 and 64 years, summer sunlight exposure is sufficient to provide adequate vitamin D. The value of sunlight depends on the geographic location and dose of UVB light, which is reduced by sunscreen, clothing and other barriers.230–232 Accordingly, seasonal variations are noted in populations from temperate climates, with serum concentrations of vitamin D falling in winter and spring. Vitamin D production in the skin is also affected by pigmentation, and populations with fairer skin tones generate more vitamin D from sunlight exposure. RDA varies depending on age, but is 600 IU/day in adults including pregnant and breastfeeding women. Higher amounts may be of value in the maintenance of bone health.233,234 

Intestinal Absorption Vitamin D is absorbed from the small intestine via a process of passive diffusion that depends upon the presence of fat and bile salts for the formation of micelles.234a ( The duodenum and the distal segments of the small intestine play an important role in vitamin D absorption, but the majority of absorption appears to occur in the distal small intestine where the transit time is greater. Intestinal absorption of vitamin D is disrupted in those with intestinal resections, malabsorptive weight loss surgeries or inflammatory states affecting these regions of the small intestine.235 Physiologic Aspects As with vitamin A, vitamin D absorption occurs by passive diffusion in the small intestine and it appears that bile salts are not necessary for this process.236 Luminal pH influences absorption, which is reduced at neutral pH and increased in an acidic milieu.237 Most of the absorbed vitamin D passes unchanged in chylomicrons into the lymphatic system.  Metabolic Aspects The metabolic pathway for vitamin D is well defined. UVB exposure converts 7-dehydrocholesterol, a cholesterol-like compound in the skin, to secosterol previtamin D3, which rearranges to vitamin D3, cholecalciferol. Vitamin D3 is subsequently transported in the circulation by vitamin D–binding protein to the liver.238

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In the liver, both vitamins D2 and D3 are converted to 25(OH)2D3 through P450 cytochrome vitamin D 25-hydroxylase.239 25(OH)2D3 is transported in the blood to the proximal renal tubule where it is further hydroxylated to convert to the active 1,25α-(OH)2D3 by renal 1α-hydroxylase, CYP27B1, which is found predominantly in the kidney, although activity has been noted in some extra-renal tissues.240 This 1α-hydroxylation appears to be the most essential step in the vitamin D pathway.241  Regulatory Aspects Regulation of the availability of active 1,25α-(OH)2D3 includes 2 key processes. First, the production of competing low-activity forms through reduction in available precursor 25(OH)2D3 to 24,25(OH)2D3 by 24-hydroxylase or conversion of 1,25α-(OH)2D3 to 1,24,25(OH)2D3, and second, through negative feedback loops involving inhibition of 1α-hydroxylase activity, transcription by PTH, and 24-hydroxylase transcription.242 These negative feedback mechanisms work to modulate 1α,25(OH)2D3 function and availability to prevent overactivity and metabolic dysregulation of calcium. 

Vitamin E Vitamin E represents 2 families of natural antioxidants derived from plant chlorophyll and tyrosine. The tocopherols have a chromanol ring with a saturated 15-carbon tail, and the tocotrienols have an unsaturated isoprenoid 16-carbon side chain.242 Each of these includes 4 isomers (α, β, γ, δ), depending on the position of a methyl group, which modulates bioavailability and biologic activity. Interest in vitamin E has been principally with α-tocopherols, but there is increasing evidence that clinical benefits, particularly related to supplementation, are seen more commonly with tocotrienols (see Fig. 103.7).243

Metabolic Role and Effect of Deficiency The principal role of vitamin E is as a lipid-soluble membranebound potent peroxyl radical scavenger. Vitamin E restricts the propagation of free radical breakdown of membrane lipids, specifically polyunsaturated fatty acids, which otherwise can lead to further free radical release and self-propagating membrane injury.244 Free radicals preferentially react with vitamin E as tocopherol, leading to the formation of a tocopherol-free radical complex that is “recycled” by reducing agents (including vitamin C), which restores its antioxidant properties.245 Animal studies indicate that tocotrienols may exhibit antioxidant activity through induction of antioxidant enzymes (e.g., superoxide dismutase, glutathione peroxidase).246,247 The effectiveness of vitamin E supplementation, however, may depend on in-situ antioxidant availability. Furthermore, it is suggested that Vitamin E may also modify vitamin K metabolism and exert an inhibitory effect on the clotting cascade.244 In addition to their antioxidant properties, tocotrienols have transcriptional, translational, and post-translational effects.248 Such targets include growth factors such as transforming growth factor-β, which modulates proliferation, caspase-8 and other signaling pathways involved in apoptosis, and suppression of angiogenesis through inhibition of vascular endothelial growth factor and receptor signaling. Studies evaluating the role of vitamin E in the inflammatory cascade have produced mixed results. One hypothesis for this is owing to the contrasting effects of the various isoforms of vitamin E, which may have competing and opposing influences on the inflammatory pathway.249 This is demonstrated by stimulatory and inhibitory effects on the vascular adhesion molecule, VCAM-1, by α-tocopherol and γ-tocopherol, respectively. More specifically, VCAM-1–dependent lymphocyte transmigration demonstrates direct antagonizing effects following

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supplementation. Tocopherols demonstrate additional immunomodulatory effects involving the regulation of signal transduction of protein inflammatory mediators (PKC, protein tyrosine kinases), regulatory enzymes in the eicosanoid pathways (5-, 12-, and 15-lipoxygenases, cyclooxygenase-2, phospholipase A2), and modulation of protein-membrane interactions.250 Additionally, tocopherol isomers have been shown to modulate inflammation in models of asthma, without an effect on cytokines or other recognized inflammatory mediators.251,252 Vitamin E deficiency can occur in those with poor dietary intake or inherited metabolic conditions. Neurologic consequences of vitamin E deficiency include cerebellar ataxia, which is presumed to occur because of uncontrolled oxidative stress and cellular membrane damage, although it remains unclear why the cerebellum is most likely affected These clinical manifestations can also be seen in those with congenital metabolic deficiencies such as chylomicron retention disease or deficiencies of α-tocopherol transfer protein owing to gene mutation.253,254 Although deficiency of vitamin E as a result of poor dietary intake is rare, it may result from fat malabsorption and after bariatric surgery.255 The clinical benefits of vitamin E in regards to its antioxidant and membrane-protective properties have produced conflicting results in studies when evaluating cardiovascular risk. There are also some data to suggest that tocotrienols may have a cancer-preventative role via antiproliferative inhibitory effects on the cell cycle and apoptosis.256 A potential benefit has been demonstrated in prostate cancer risk with α-tocopherol supplementation; however, there was accompanying evidence of an increase of colorectal adenomas. 

Sources and Recommended Daily Allowance The RDA for vitamin E is 15 mg/day (22.4 IU), with lower levels recommended in childhood and increased levels recommended in lactating women.257 Vitamin E, mainly as α-tocopherol, is found in a range of lipid-rich plant seeds, oils, and vegetables, which include wheat germ, sunflower, almond, hazelnuts, peanuts, corn, margarine, soya bean, broccoli, tomato, and spinach. Of note, breast milk contains a higher level of vitamin E than cow’s milk. 

Intestinal Absorption Physiologic Aspects Vitamin E is absorbed passively across the intestinal mucosa.258 The ester form, in which many vitamin preparations are presented, is hydrolyzed by pancreatic and duodenal esterases prior to absorption, but the ester can be absorbed intact.259 After vitamin E is incorporated into micelles, it is transported across enterocytes and merged into chylomicrons for transfer into the lymphatics. Vitamin E absorption is affected by concurrent dietary fat intake.260 Results comparing supplementation of the isoforms of both tocopherol and tocotrienols in healthy human subjects suggest that marked increases in plasma α-tocopherol levels occur after supplementation, with negligible increases in all other isoforms. Supplementation with supra-high levels of tocotrienol (up to 300 mg/day) lead to a marked increase in plasma levels, suggesting a dose-dependent response.261 

Clinical Pathophysiology of Intestinal Vit E Absorption The biologic activity of α-tocopherol is based on a metabolic response and is thought to be secondary to a process of selective retention in the liver that is mediated by α-tocopherol transfer protein, which incorporates α-tocopherol into lipoproteins prior to its return to the circulation. Incorporation of α-tocopherol into lipoproteins occurs at the expense of other forms of vitamin E that demonstrate a lower binding affinity, which are then degraded and excreted. Although the antioxidant properties are

similar, the biologic properties are highest for α-tocopherol.262 Through the above mechanism, the liver plays a significant role in regulating circulating levels of α-tocopherol. Radio-labeled studies suggest that the half-life of natural α-tocopherol is less than 60 hours in the circulation There is rapid recirculation between the liver and systemic circulation with almost daily replacement of the vitamin E pool.263,264 Tocopherols are metabolized by cytochrome P450 side-chain degradation/oxidation and are excreted by the biliary system. 

Vitamin K Similar to other fat-soluble vitamins, vitamin K is acquired from both exogenous and endogenous sources. This family of compounds has structures similar to chlorophyll, from which phylloquinone is derived, but differs in the nature of their side-chain structure.220 Dietary sources include phylloquinone (K1) and endogenous sources are from bacterial synthesis in the colon and include menaquinones (K2). Menaquinones may also be absorbed in small quantities from the diet and can be synthesized from dietary phylloquinone in certain tissues. The role of vitamin K has primarily focused on the coagulation pathway, although additional roles have been discovered for menaquinones.

Metabolic Role and Effect of Deficiency The traditionally recognized function of vitamin K is vitamin K-dependent (VKD) protein carboxylation for intracellular activation of VKD proteins. VKD carboxylase is an endoplasmic reticulum membrane bifunctional enzyme that catalyzes both the oxygenation of vitamin K hydroquinone to vitamin K epoxide and carboxylation of multiple glutamate residues to γ-carboxyglutamate (Gla) on VKD proteins. These steps are essential in the synthesis of clotting factors II, VII, IX, and X within the liver.265,266 VKD carboxylase has also been identified in tissues other than the liver including lung, kidney, spleen, testis, and bone, and, therefore, serves additional roles beyond those associated with hemostasis.267 Deficiency of vitamin K is rare but may occur in the setting of fat malabsorption (fecal loss of vitamin K), antibiotic exposure (antibiotics are cidal to vitamin K–producing bacteria) and/or following ingestion of high doses of vitamin E. The effects of Vitamin E on homeostasis in humans have not been fully elucidated, but in rat models it seems to be secondary to increased vitamin K metabolism and excretion as a result of elevated hepatic α-tocopherol concentrations after vitamin E supplementation.268 Adequate vitamin K absorption is required for bone health because it is involved in matrix Gla protein and osteocalcin, both of which are involved in bone calcification. Chronically low levels of vitamin K are associated with metabolic bone disease and increased risk of fracture.269 

Sources and Recommended Daily Allowance Vitamin K1, phylloquinone, is derived from chlorophyll, which is present in green vegetables, including broccoli, spinach, lettuce, herbs, and kale. Absorption and bioavailability depends on a variety of factors including the nature of the food matrix and the fat content of the meal. Studies suggest that absorption from raw vegetables is markedly low (3 mm) and dilatation of the bowel loops (>2.5 cm) have been suggested to be the most sensitive markers.106 A hyperechoic appearance of the bowel wall may be suggestive for Whipple disease (Fig. 104.7), AIDS enteropathy, or mycobacterial infections,107 and the presence of intraluminal abscesses in the ileocecal region for intestinal TB.108 IV and oral contrast agents have been used for better differentiation of small intestinal alterations on US examination.105 

Other Studies A plain film of the abdomen may be helpful to detect pancreatic calcifications if exocrine pancreatic insufficiency is suspected, although morphologic signs of chronic pancreatitis alone do not prove a pancreatic cause of malabsorption, because the function of the exocrine pancreas must be severely impaired before malabsorption becomes evident. A plain film of the abdomen can also document dilated loops of intestine; dilated loops predispose to SIBO or suggest the presence of an obstruction. ERCP can help establish the cause of pancreatic insufficiency (see Chapter 59). It can also help distinguish chronic pancreatitis from pancreatic tumor and can document pancreatic duct stones. ERCP and EUS are the methods of choice for documenting various causes of biliary obstruction. MRCP is increasingly being used to replace diagnostic ERCP. If a neuroendocrine tumor (e.g., gastrinoma, somatostatinoma) is the suspected cause of malabsorption, an indium-111 octreotide scintigraphic scan, PET, or an EUS examination of the pancreas may be helpful in establishing the diagnosis or demonstrating the extent of disease (see Chapter 34). 

Noninvasive Evaluation of GI Digestive and Absorptive Function Some conditions that cause malabsorption can be diagnosed by noninvasive testing, although, as illustrated in Table 104.8, diagnostic accuracy may be limited, and further tests may be necessary to identify underlying diseases or differentiate primary and secondary causes. Apart from providing a diagnosis, tests that evaluate GI absorptive and digestive function may be helpful in evaluating complex disease presentations. For most or all of the following tests, the potential benefits with regard to the costs of workup or to patient acceptability have not been established.

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TABLE 104.8  Malabsorptive Diseases or Conditions in Which Noninvasive Tests Can Establish Malabsorption or Provide a Diagnosis Disease or Condition

Diagnostic Test(s)*

Comment(s)

Bile acid malabsorption

Measurement of serum levels of C4, FGF19, SeHCAT test, 14C-TCA test

Do not differentiate between primary and secondary causes Tests involving radioactive substances should be avoided where they are still available

Exocrine pancreatic insufficiency

Quantitative fecal fat determination

Used to establish malabsorption in chronic pancreatitis

Fecal elastase or chymotrypsin, tubeless tests (see Chapters 56 and 59)

Variable sensitivity and specificity, depending on the type of test and stage of the disease

Incomplete fructose absorption

Fructose hydrogen breath test

This test is neither useful nor required for starting treatment; for this, a validated symptom assessment after ingestion of fructose is required

Lactose malabsorption

Lactose hydrogen breath test Lactose tolerance test

Tests do not differentiate between primary and secondary lactose malabsorption These tests are neither useful nor required for starting treatment; for this, a validated symptom assessment after ingestion of lactose is required

SIBO (see Chapter 105)

Glucose or lactulose hydrogen breath test Lactulose methane breath test

A predisposing factor should be sought if tests is positive

Vitamin B12 malabsorption

Serum Vitamin B12 level

Schilling test is no longer available in most countries but was performed without intrinsic factor and, depending on the result with intrinsic factor, with antibiotics or pancreatic enzymes (see text). Further tests are necessary if SIBO, terminal ileal disease, or pancreatic disease is suspected

*See text for diagnostic accuracy of the different tests listed. C4, 7α-hydroxy-4-cholesten-3-one; FGF19, fibroblast growth factor 19; SeHCAT, Selenium-75-homotaurocholic acid test; TCA, taurocholic acid.

20

Fat Malabsorption

15

Quantitative Fecal Fat Analysis The van de Kamer method is the quantitative titration of fatty acid equivalents in which results are expressed as fecal output of fat in grams per 24 hours. This method is considered the gold standard for fecal fat analysis.110 Modifications in which the extracted fats are weighed rather than titrated111 have an excellent correlation with the results of the original van de Kamer method. The stool must be mixed before a sample is obtained for analysis. Fecal fat excretion of less than 7 g/day with a fat intake of 100 g/ day usually is considered normal. The volume effect of diarrhea by itself, however, may increase fecal fat output to levels of up to 14 g/ day (secondary fat malabsorption) (Fig 104.8).112 With significant diarrhea, a fecal fat excretion of 14 g/day should be used as the upper limit of normal. Diet is important in considering causes of steatorrhea; for example, elevated fecal fat values can be observed in patients consuming a diet rich in the fat substitute olestra.111 Quantitative fecal fat analysis is routinely available now in only a few centers. Reasons for its limited clinical use are: (1) If the main symptom of malabsorption is chronic diarrhea, measurement of fecal fat might not influence the subsequent evaluation, because the diagnostic tests performed to establish the etiology of diarrhea are similar to the tests for the workup of steatorrhea. (2) An elevated fecal fat level usually cannot differentiate biliary, pancreatic, and enteric causes of malabsorption. (3) In many patients with severe steatorrhea, the stools have a very foul smell and a characteristic porridge-like appearance, and quantitative studies are not necessary to establish fat malabsorption. (4) Fat absorption may be normal despite malabsorption of other nutrients, so a normal fat balance does not imply normal absorptive function of the GI tract. (5) Finally, accuracy depends on quantitative stool collections for 48 to 72 hours, adherence

Fecal fat (g/day)

Because test procedures and analytical methods can vary among laboratories,109 each laboratory should establish its own reference values for these tests.

10

5

0 0

400

800

1200

1600

2000

Fecal weight (g/day) Fig. 104.8  Graph showing fecal fat output (average of a 3-day stool collection) plotted as a function of fecal weight from normal subjects (open circles) and subjects with induced diarrhea (closed circles). The washout effect of diarrhea increases fecal excretion of fat to levels above the upper limit of normal (7 g/day). With significant diarrhea, a fecal fat excretion of 14 g/day should be used as the upper limit of normal. (From Fine KD, Fordtran JS. The effect of diarrhea on fecal fat excretion. Gastroenterology 1992; 12:1936-9.)

to a diet that contains 80 to 100 g of fat daily, and a diet diary to determine fat intake. Science aside, quantitative fecal fat analysis has never been popular among patients, physicians, or laboratory personnel performing the test. Despite the limitations of quantitative fecal fat analysis, it, nevertheless, is still useful in several clinical circumstances: to establish malabsorption and avoid nutritional deterioration when overt features of intestinal or pancreatic disorders are lacking, as

CHAPTER 104  Maldigestion and Malabsorption

in some cases of osteoporosis, osteomalacia, anemia, or weight loss; to monitor treatment in patients with established malabsorptive disorders, such as exocrine pancreatic insufficiency or short bowel syndrome; to estimate fecal calorie loss in patients with severe malabsorption syndromes; and to quantitate fecal fat excretion in patients with diarrhea who have undergone ileal resection, thereby distinguishing steatorrhea due to BA deficiency from secretory diarrhea caused by BA loss.113  Semi-Quantitative Fat Analysis For the acid steatocrit (AS) test,114 a sample of stool is diluted 1:3 with distilled water in a test tube. The diluted stool is homogenized, and a 500-μL aliquot is pipetted into a tube. Then 100 mL of 5M HClO4 is added to allow better fat extraction and separation of the lipid layer. An aliquot of the diluted stool-HClO4 mixture is put into a nonheparinized microcapillary tube and sealed on one end. After centrifugation of this aliquot at 13,000 rpm for 15 minutes, the fatty layer and the solid layer are measured, and the AS is determined according to the following equation: [ ] FL AS ( % ) = × 100 (FL + SL) An AS of less than 31% is normal. In a small study, the AS for random spot stool samples had a high sensitivity and specificity for detection of steatorrhea, compared with the van de Kamer method, which is performed on a 72-hour stool collection. A linear correlation was also found between results obtained with the AS and those of the van de Kamer method, although results were quite divergent in some patients.114 Because quantitative fecal fat measurements are based on 48- to 72-hour stool collections (to minimize the effect of day-to-day variability in fecal fat excretion), the AS cannot be expected to replace quantitative measurement of fat output in borderline cases or cases where exact measurement of fecal fat loss is required.  Qualitative Fecal Fat Analysis Although fat analysis by microscopic examination of random stool samples might provide a clue to the presence of steatorrhea, it cannot be used to exclude steatorrhea; its sole advantage is its ease of performance. A sample of stool is placed on a glass slide to which several drops of glacial acetic acid and Sudan III stain are added. Acidification of stool samples improves fat extraction and separation of the lipid layer.114 The slide is held over a flameburner, and the acidified mixture is heated to boiling then examined while still warm for the presence of orange fat globules. A count of up to 100 globules, each with a diameter less than 4 mm, per high-power field is normal.10 Results of qualitative fat analysis by this method and of quantitative fat analysis do not correlate very well.115 In a small study, Sudan staining of spot stool samples had a sensitivity of 78% and a specificity of 70% for the detection of steatorrhea.114 A quantitative microscopic method of counting and measuring fat globules using the Sudan stain has been shown to correlate well with chemically measured fecal fat output.116  Breath Tests for Fat Malabsorption The principle of the 14C-triolein breath test is to measure 14CO in the breath after ingestion of a triglyceride that has 2 been radiolabeled with 14C. Fat malabsorption results in decreased pulmonary excretion of 14CO2.117 Because of erroneous results in a variety of metabolic and pulmonary diseases, lack of sensitivity in mild malabsorption, radiation exposure to the patient, cost of the substrate, and the need for expensive equipment, this test has not found widespread acceptance for clinical use. The nonradioactive isotope 13C is used to label triglycerides instead.

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Carbohydrate Malabsorption The HBT is a noninvasive test that takes advantage of the fact that in most people bacterial metabolism of carbohydrate results in accumulation of hydrogen, which then is absorbed by the colonic mucosa and excreted in the breath. Using different carbohydrates, such as lactose or fructose, the HBT can be used to detect malabsorption of these carbohydrates. Measurement of breath hydrogen excretion after ingestion of lactulose has been used to assess orocecal transit time, and glucose has been used as a substrate to detect SIBO, although sensitivity and specificity are poor (see Chapter 105).118 Unfortunately, up to 18% of people are hydrogen nonexcretors,119 and in these persons, HBT results may be falsely negative because hydrogen is further metabolized by bacteria to methane. Such limitations and pitfalls of breath hydrogen testing have to be taken into account when test results are interpreted.120 The diagnosis of lactose malabsorption is established if an increase in breath hydrogen concentration of greater than 20 ppm over baseline occurs after ingestion of 20 to 50 g of lactose. An increase within the first 30 minutes after ingestion of lactose is disregarded because it may be due to bacterial degradation of lactose in the oral cavity. Up to 4 hours may be required for the increase in breath hydrogen concentration to occur. Breath hydrogen measurements obtained before and at 30, 60, 90, 180, and 240 minutes after ingestion of 50 g of lactose provide the best diagnostic yield with the fewest possible measurements.119 The lactose HBT is still performed by most clinicians for evaluating lactose malabsorption, but this test can miss the disorder in hydrogen nonexcretors. In these patients, a combined measurement of hydrogen and methane excretion in breath or a lactose tolerance test—measurement of blood glucose levels before and 30 minutes after ingestion of 50 g of lactose—can be used. An increase in glucose concentration of less than 20 mg/ dL over baseline within 30 minutes of ingestion of 50 g of lactose indicates lactose malabsorption. The lactose tolerance test has a lower sensitivity than the lactose HBT for diagnosing lactose malabsorption.119 Lactase deficiency in acquired primary lactase deficiency (adult-type hypolactasia) is not caused by mutations in the gene coding for intestinal lactase (lactase-phlorizin hydrolase [LPH] gene). It has been shown, however, that a single-nucleotide polymorphism (SNP), either the C or T nucleotide−13910 upstream of the LPH gene, is involved in regulating intestinal lactase expression.121 A CC genotype at−13910 C/T is associated with acquired primary lactase deficiency (adult-type hypolactasia), whereas TC and TT genotypes are linked with lactase persistence.121,122 This polymorphism can be used as a diagnostic test for adult-type hypolactasia.122,123 This SNP is only associated with adult-type hypolactasia in whites; other SNPs are linked to adult-type hypolactasia or lactase persistence in Africans.124 In patients with diarrhea, a stool test to detect a fecal pH less than 5.5 can serve as a qualitative indicator of carbohydrate malabsorption.125 In the research setting, fecal carbohydrates can be determined by the anthrone method, which measures carbohydrates on a weight basis. By contrast, the reducing sugar method gives results on a molar basis and provides information about the osmotic activity of malabsorbed carbohydrates.19 Total and individual SCFAs and lactic acid, which are the products of bacterial carbohydrate metabolism, can be measured in stool by several methods including titration, gas chromatography-mass spectrometry, and high performance liquid chromatography.126 Tests for lactose malabsorption or lactase deficiency do not address the clinically important question whether abdominal symptoms such as bloating, flatulence, or diarrhea are caused by lactose ingestion, for which the term lactose intolerance should be reserved. Only the proof of lactose intolerance, for example by recording symptoms after ingestion of lactose for a period of

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several hours, but not of lactose malabsorption or lactase deficiency, is sufficient to recommend dietary restrictions or oral supplementation of lactase (see below). 

Protein Malabsorption The classic test to quantify protein malabsorption, measurement of fecal nitrogen content in a quantitatively collected stool specimen,13 is rarely used today. For research purposes, a combined 14C-octanoic acid–13C-egg white breath test, accompanied by measurement of the urinary output of phenol and p-cresol, has been used to assess the effect of gastric acid on protein digestion.127 In this method, labeling of the 13C-egg protein test meal with 14C-octanoic acid allows simultaneous measurement of protein assimilation and gastric emptying rate. Phenol and p-cresol are the quantitatively most important phenolic compounds in feces and urine and are specific metabolites of tyrosine that are produced by bacterial fermentation in the colon. They result from protein that has escaped digestion and absorption in the small intestine and are rapidly absorbed in the colon, detoxified, and excreted in urine. In the study of this test, recovery of higher amounts of urinary phenols after omeprazole treatment indicated an increased availability of protein in the colon.

Vitamin B12 (Cobalamin) Malabsorption Schilling Test Historically, the Schilling test has been the classic test used clinically to distinguish between gastric and ileal causes of vitamin B12 deficiency; it is rarely performed today, because the IF used in the Schilling test is of bovine origin, and is, therefore, no longer commercially available in most countries. Because both IF and hydrochloric acid are produced by parietal cells in humans, alternative approaches to diagnosing PA are to document atrophic gastritis by endoscopy and biopsy; to confirm achlorhydria by acid secretion analysis (also rarely performed today) and increased serum gastrin levels; and to look for antibodies in the serum directed against parietal cells or IF.28,128  Serum Test for Vitamin B12 and Folate Deficiency Measurements of serum cobalamin and folate concentrations are commonly used to detect deficiency states of these vitamins. The sensitivity and specificity of these tests are unknown because no gold standard test has been established and because serum levels do not always correlate with body stores.26 Furthermore, results of vitamin B12 levels vary with different commercial tests.129 Several causes of misleading serum cobalamin levels have been established. Serum vitamin B12 levels can be normal despite depleted body stores in SIBO (as a result of production of inactive cobalamin analogs by the bacteria), liver disease, myeloproliferative disorders, congenital transcobalamin II deficiency, and with high levels of IF antibodies. In contrast, oral contraceptives, pregnancy, and folate deficiency can cause low serum cobalamin levels despite normal body stores.128 Therefore, if there is a high suspicion, especially for cobalamin deficiency, parenteral replacement with monitoring of the clinical response is recommended.129 Measurement of methylmalonic acid, homocysteine, and holotranscobalamin are of limited clinical use in establishing vitamin B12 deficiency.129 Serum folate concentrations decrease within a few days of dietary folate restriction even if tissue stores had been normal immediately prior to restriction. Feeding also influences serum folate levels; therefore determination of folate in the fasting state is recommended. Measurement of red blood cell folate concentration has been considered a better estimate of folate tissue stores than serum folate levels by some authors.128 Elevation of serum folate levels may be seen in SIBO as bacteria produce folate, but

it has insufficient diagnostic accuracy to be of significant value in the detection of SIBO. 

Small Intestinal Bacterial Overgrowth Tests for the diagnosis of SIBO are covered in more detail in Chapter 105. Briefly, tests used to diagnose SIBO are the quantitative culture of a small intestinal aspirate (which is considered to be the gold standard diagnostic test), measurement of deconjugated BAs or vitamin B12 analogs in intestinal aspirates, measurement of serum folate, and several breath tests, including the 14C-glycocholate breath test, the 14C-d-xylose breath test, the lactulose HBT, and the glucose HBT. The rationale for the breath tests is the production by intraluminal bacteria of volatile metabolites (i.e., 14CO2 or H2), from the administered substances, which can be measured in the exhaled breath. 

Exocrine Pancreatic Insufficiency Pancreatic function tests are discussed in detail in Chapters 56 and 59. Invasive pancreatic function tests require duodenal intubation and measurement of pancreatic enzyme, volume, and bicarbonate output after pancreatic stimulation by a liquid test meal (the Lundh test) or by injection of CCK or secretin. Noninvasive tests include measurement of fecal chymotrypsin or elastase concentration, the fluorescein dilaurate test, and the N-benzoyl-l-tyrosyl para-aminobenzoic acid (NBT-PABA) test. Elastase has a higher sensitivity than chymotrypsin for detecting exocrine pancreatic insufficiency,130 but the specificity of elastase is low.131 Measurements of pancreatic enzymes and components of pancreatic fluid in duodenal aspirates obtained during endoscopy and after IV stimulation with secretin and CCK have an excellent correlation with the more classic intubation tests for secretory function.132 Secretin-enhanced MRCP has also been used to assess exocrine pancreatic function; its results correlate best with changes of severe pancreatitis, but this method is too insensitive for assessment of mild pancreatic insufficiency.133 

Bile Acid Malabsorption Intestinal absorption of BAs occurs through a combination of passive diffusion throughout the small intestine and active absorption in the terminal ileum, resulting in less than 5% of BAs entering the colon.3 When ileal uptake of BAs is insufficient, an increased amount reaches the colon, where pro-secretory BAs such as chenodeoxycholic acid and deoxycholic acid induce the secretion of water and electrolytes.3 Along with an increase in colonic contractions, this may lead to symptoms of diarrhea. The presence of 2 α-hydroxyl groups at the 3, 7, or 12 positions is responsible for the secretory effects of chenodeoxycholic acid and deoxycholic acid.134 In the past, diarrhea resulting from BA malabsorption (BAM) had been considered a rare occurrence, limited to patients with extensive ileal resections or inflammatory conditions. More recent studies have suggested BAM also occurs in patients with chronic functional diarrhea or IBS without evidence of ileal morphologic alterations. In a systematic review, BAM was reported in 32% of patients with unexplained chronic diarrhea,135 leading the authors to suggest the existence of a subtype of BAM (idiopathic BAM) with defective BA uptake or feedback inhibition of BA synthesis in these patients. BAM is also found in various other GI conditions including after cholecystectomy or with intake of particular drugs. Therefore classification of BAM according to different etiologies has been proposed136: T •  ype 1: BAM caused by ileal disease or resection • Type 2: BAM without ileal morphologic abnormalities (idiopathic BAM)

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• T  ype 3: BAM induced by drugs (e.g., biguanide drugs) or other diseases (e.g., pancreatitis, previous cholecystectomy, vagotomy, microscopic colitis) In patients with steatorrhea due to ileal disease or resection, BAM usually is present, but measurement of BAM is of limited clinical value. In patients with diarrhea and no steatorrhea, BAM may be present in the absence of overt ileal disease, and in such cases, measurement of bile salt absorption is helpful. Measurement of Fecal Bile Acid Output In the past, testing for BAM has been cumbersome, involving radioactive isotopes, repeated measurements requiring the patient to stay on-site, or stool collections, all of which limited their general availability beyond highly specialized centers. The most widely used diagnostic tools were the75 selenium homotaurocholic acid test (SeHCAT) or measurement of fecal BA quantity, both of which require the ingestion of radiolabeled BAs and repeated measurements of whole-body radioactivity136 or stool collections over a course of at least 48 hours. Therefore, in clinical practice, treatment response to BA sequestrants (e.g., cholestyramine or colesevelam) has been widely used as an indirect indicator of BAM playing a causal role in diarrhea. A therapeutic trial with cholestyramine requires high doses of BA binders that patients may not tolerate because of poor palatability and side effects (borborygmi, flatulence, and abdominal pain). Thus such a therapeutic trial may be falsely negative, compromising the ability to diagnose BAM. In addition, the therapeutic trial is not specific for BAM, because BA binders may also bind and inactivate other diarrheagenic agents including Clostridioides difficile toxin,137 resulting in a false-positive treatment trial. Recently, less cumbersome and less time-consuming serum tests for BAM have been introduced and have led to increasing detection rates of BAM; these tests result from improved understanding of ileal BA absorption and hepatic BA production. BAs are recycled via the liver up to 10 times every day.135 In case of intestinal losses, hepatic BA synthesis is up-regulated via a tightly regulated feedback mechanism. The serum concentration of a hepatic intermediary product of BA synthesis, 7α-hydroxy-4-cholesten-3-one (abbreviated as C4), reflects the rate of BA synthesis in humans and is elevated in clinical conditions associated with BAM.135 The clinical performance of the C4 assay demonstrated a sensitivity of 90%, specificity of 79%, negative predictive value of 98%, and positive predictive value of 74% compared with the SeHCAT test.138 The ability of serum fibroblast growth factor 19 (FGF19) to serve as a screening test for BAM also has been explored.139 FGF19 is released by enterocytes in response to BA uptake and provides feedback inhibition of BA synthesis via down-regulation of cholesterol 7α-hydroxylase.140 In a study of 258 patients, sensitivity and specificity of FGF19 at a serum concentration of less than 145 pg/mL for detecting a C4 level greater than 60 ng/mL (denoting high BA synthesis) were 74% and 72%, respectively.139 Concentrations of FGF19 can be measured by ELISA, whereas C4 measurement requires a more elaborate high-performance liquid chromatography (HPLC ) method. Elevated fecal BA concentrations or output can indicate intestinal BAM.141 Under steady-state conditions, the increased fecal BA output reflects increased hepatic synthesis of BAs.142 In severe BAM, fecal BA output can be reduced if hepatic synthesis of BAs becomes impaired. Measurement can be performed by enzymatic methods or by gas chromatography. This test requires a quantitative stool collection, and the analytic techniques are time-consuming and require considerable expertise. Enzymatic methods may be unreliable in severe steatorrhea.143

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14Carbon-Taurocholate Bile Acid Absorption Test The 14C-taurocholate BA absorption test requires a 72-hour stool collection after ingestion of radioactively labeled BA. The rate of intestinal BA absorption is calculated from the fecal recovery of 14C-labeled taurocholic acid. Normal values for this test have been established in normal persons with laxative-induced diarrhea, because diarrhea by itself can increase fecal losses of BAs,142 presumably because of accelerated intestinal transit.144 Clinical limitations of this test are that it requires substantial analytical work, access to a gamma camera, and a time-consuming stool collection. 

Selenium-75-Labeled Homotaurocholic Acid Test The radioactive taurocholic acid analog used for this test is resistant to bacterial deconjugation. After it has been administered orally, the patient undergoes serial gamma scintigraphy to measure whole-body BA retention or, as suggested by some authors, BA retention in the gallbladder.145 This test has several limitations. First, normal values for BA retention, which are used to compare normal and abnormal BA absorption, were obtained for SeHCAT only in healthy persons without diarrhea146; secondary BA malabsorption, however, can be induced by diarrhea itself and is proportional to the stool weight, as shown by the 14C-labeled taurocholic acid test.142,144 For this test to be clinically useful, normal values have to be established for patients with diarrhea. Second, this test is very time-consuming because BA retention must be measured either 4 or 7 days (depending on the protocol) after the BA administration. 

D-xylose Test Absorption of the pentose d-xylose is facilitated by passive diffusion. Approximately 50% of the absorbed d-xylose is metabolized, and the remainder is excreted in urine. After an overnight fast, a 25-g dose of d-xylose is ingested, and the patient is encouraged to drink sufficient volumes of fluid to maintain good urine output; urine is collected for the next 5 hours. As an alternative, 1 hour after ingestion of d-xylose, a venous sample may be obtained.147 Less than 4 g (16% excretion) of d-xylose in the urine collection or a serum xylose concentration below 20 mg/dL indicates abnormal intestinal absorption. The traditional urine test appears to be more reliable than the 1-hour blood test. False-positive results occur if the duration of urine collection is too short or if the patient is dehydrated or has renal dysfunction, significant ascites, delayed gastric emptying, or portal hypertension. d-Xylose absorption may be normal in patients with only mild impairment of mucosal function or with predominantly distal small intestinal disease. Because d-xylose is susceptible to bacterial metabolism, absorption is diminished in patients with SIBO, although the test has a poor sensitivity for detecting SIBO.148 The test is of limited clinical value today and mostly has been replaced by small intestinal biopsy. 

Intestinal Permeability Tests Intestinal permeability tests mostly are used in studies of the pathophysiology of intestinal disorders; they do not provide a specific diagnosis.149 Most current permeability tests are based on the differential absorption of mono- and disaccharides. Damage to the mucosa can result in increased permeability for disaccharides and oligosaccharides, and this can result in decreased permeability of monosaccharides secondary to reduction of mucosal surface area. Absorption is measured by urinary excretion. Expression of results as the ratio of monosaccharide absorption to disaccharide absorption minimizes the influences of gastric emptying, intestinal transit, renal and hepatic function, and variations in time of urine collections.150

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In celiac disease, the finding of considerably increased permeability is a sensitive marker for advanced disease (see Chapter 107). Permeability tests have also been used to judge response to a gluten-free diet151 or to screen first-degree relatives for celiac disease. Elevated serum aminotransferase levels in patients with celiac disease correlate with increased intestinal permeability.152 Disturbances of intestinal permeability also have been documented in users of NSAIDs, and patients with Crohn disease and diabetic diarrhea.  13Carbon

Breath Tests

The increasing availability of stable isotopes has raised interest in replacing radioactive 14C with nonradioactive 13C for breath tests.118 For malabsorptive diseases, 13C-labeled substrates have been evaluated in the diagnosis of steatorrhea, SIBO, and exocrine pancreatic insufficiency153 and in the evaluation of the digestibility of egg protein. Because of concerns about diagnostic accuracy, cost, and limited availability, these tests have not gained widespread acceptance. 

MALABSORPTION IN SPECIFIC SITUATIONS AND DISEASE STATES Lactose Malabsorption Deficiency of the intestinal brush border enzyme lactase can lead to lactose malabsorption. Malabsorption of lactose can be diagnosed by the measurement of hydrogen and methane excretion in the breath after a provocative testing dose of lactose. For this purpose 25 to 50 g of lactose have been used in the past, with the current suggestions leaning toward a testing dose of 25 g. Sampling every 30 minutes for up to 4 hours has been suggested, and a rise in hydrogen of greater than 20 ppm or of methane of greater than 10 ppm is considered positive.154,155 The pathogenesis of lactose intolerance, i.e., bloating, flatulence, abdominal cramps, and diarrhea after ingestion of lactose, must be looked at separately from lactose malabsorption and, therefore, malabsorption testing by breath tests has to be accompanied by intolerance testing, i.e., symptom assessment; results of breath testing without simultaneous assessment of symptoms are not clinically useful.156 In the future, intolerance testing may possibly replace malabsorption testing. The pathophysiologic mechanisms resulting in lactose intolerance are currently unclear and may be related to milk protein allergy or fat intolerance on ingestion of nonlactose sugars with the lactose or to functional GI disorders.53 Unlike other intestinal disaccharidases, which develop early in fetal life, lactase levels remain low until the 34th week of gestation.157 Transient lactase deficiency in premature infants can lead to symptoms of lactose malabsorption, such as diarrhea, until normal intestinal lactase activity develops. In rare cases, enzyme deficiency is manifest at the time of birth is permanent, and congenital lactase deficiency (OMIM #223000)* is ultimately diagnosed. Reversible lactase deficiency can occur at all ages as a result of transient small intestinal injury associated with acute diarrheal illnesses. Acquired primary lactase deficiency (adult-type hypolactasia, OMIM #223100) is the most common form of lactase deficiency worldwide. Most populations lose considerable lactase activity in adulthood which explains why adult mammals are unable to digest lactose and most refuse to drink milk.158 This decline in lactase activity is a multifactorial process that is regulated at the gene transcription level and leads to decreased biosynthesis, *The Online Mendelian Inheritance in Man (OMIM) system assigns numbers to specific diseases according to a continuously updated catalog of human genes and genetic disorders (http://www.ncbi.nlm.nih.gov/ omim/).

BOX 104.4 Ethnic Groups With High and Low Prevalence Rates of Acquired Primary Lactase Deficiency (Adult-Type Hypolactasia) LACTASE DEFICIENCY–PREDOMINANT ETHNIC GROUPS (60%-100% OF POPULATION IS LACTASE DEFICIENT) Middle East and Mediterranean: Arabs, Israeli Jews, Greek Cypriots, southern Italians Asia: Thais, Indonesians, Chinese, Koreans Africa: South Nigerian, Hausa, Bantu North and South America: Alaska Natives, Canadian and U.S. Native Americans, Chami Indians LACTASE PERSISTENCE–PREDOMINANT ETHNIC GROUPS (2%-30% OF POPULATION IS LACTASE DEFICIENT) Northern Europeans Africa: Hima, Tutsi, Nomadic Fulani India: Indians from Punjab and New Delhi areas Data from Johnson JD. The regional and ethnic distribution of lactose malabsorption. In: Paige DM, Bayless TM, editors. Lactose digestion. Clinical and nutritional implications. Baltimore: Johns Hopkins University Press; 1981. p 11.

retardation of intracellular transport, or maturation of the enzyme lactase-phlorizin hydrolase. In whites, a SNP—13910 T/C upstream of the gene that codes for LPH gene has been found to be involved in regulation of the enzyme.121 The CC genotype of the SNP—13910 T/C upstream of the LPH gene is associated with adult-type hypolactasia; TC and TT genotypes are linked with lactase persistence, and, hence, the ability to consume lactose without adverse effect.159 In other populations (e.g., some African and sub-Saharan African populations), the SNP—13910*T polymorphism is not associated with lactase persistence.124 Because it is present in most of the adult human population, this form of lactase deficiency has to be considered normal rather than abnormal. Lactase deficiency usually produces symptoms only in adulthood, although lactase levels in affected persons start to decline during childhood.160 Lactase activity persists in most adults of Western European heritage (Box 104.4).161 Even in this group, however, the activity of lactase is only about half the activity of sucrase and less than 20% of the activity of maltase.160 Accordingly, in these persons, lactase activity is much more susceptible to a reduction in function with acute or chronic GI illnesses. In patients with lactose malabsorption, it may be unclear whether the condition results from acquired primary lactase deficiency or is a consequence of another small intestinal disorder. Therefore, in the individual patient who demonstrates lactose malabsorption, especially if there is an ethnic background associated with a low prevalence of acquired primary lactase deficiency, it may be necessary to exclude other malabsorptive disorders such as celiac disease. The main symptoms of lactose intolerance are bloating, abdominal cramps, increased flatus, and diarrhea. Development of bloating and abdominal cramps is presumably associated with increased perception of luminal distention by gas,162 because no clear relation has been observed between the amount of lactose ingested and the severity of symptoms.163 Ingestion of as little as 3 g of lactose may induce symptoms in persons with lactose malabsorption.164 GI symptoms, including diarrhea, have been shown to be more severe in adults with shorter small intestinal transit time,165 but no such relation between intestinal transit and symptoms is observed in children.166 Also, in pregnant women and in thyrotoxic patients

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H2 concentration (ppm × 10), symptoms

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reduce symptoms of lactose intolerance, presumably as a result of prolonged gastric emptying. Alternatively, supplementation of dairy products with lactase of microbiologic origin can be suggested.172 The results of controlled studies on the use of lactose-reduced products or lactase capsules are inconsistent.170 Furthermore, because many carbohydrates other than lactose are incompletely absorbed by the normal small intestine,55,173 and because dietary fiber also may be metabolized by colonic bacteria, persistence of some symptoms while the patient is on a lactose-free diet is not uncommon. It must also be kept in mind that symptoms arising after ingestion of dairy products may be from milk protein allergy or fat intolerance rather than lactose intolerance.

Fructose Malabsorption and Intolerance

Lactose malabsorption without intolerance

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Fig. 104.9  Graphs illustrating the role of symptoms in determining the clinical importance of lactose malabsorption. Assessment of the clinical relevance of an abnormal lactose hydrogen breath test is made by monitoring abdominal symptoms (bloating, cramps, pain) during the test. Breath hydrogen concentration in parts per million (ppm) and GI symptoms using an arbitrary scoring system for 2 different patients are plotted on the graphs. The patient in (A) has symptoms associated with an increase in breath hydrogen concentration and, therefore, can be considered to have lactose intolerance. The patient in (B) has no increase in symptoms, although the breath hydrogen concentration increases considerably, so the patient has lactose malabsorption without lactose intolerance.

with Graves disease, changes in intestinal motility play a role in the clinical manifestation of lactose malabsorption.167 To make a diagnosis of lactose intolerance, and in view of the poor correlation between lactose malabsorption and lactose intolerance, it is very important to monitor symptoms during a lactose HBTest and to confirm that any symptoms experienced by the patient during the test are truly those the patient complains of and that they are associated with a significant increase in breath hydrogen levels (Fig. 104.9). Adult-type hypolactasia may also be a risk factor for developing osteoporosis and bone fractures, either owing to patients’ avoidance of dairy products168 or interference with calcium absorption.169 Patients in whom a clear association can be established between symptoms and lactose ingestion (with or without proven lactose malabsorption) should be educated about lactose-reduced or lactose-free diets. Patients should be informed that the commonly ingested doses of lactose (e.g., up to a cup of milk) usually do not cause symptoms when ingested with a meal. Dietary instructions may help the large majority of lactoseintolerant subjects. Daily consumption of lactose-containing food may be better tolerated than intermittent consumption.170 Yogurt may be tolerated by such patients171 and provides a good source of calcium. Consuming whole milk or chocolate milk rather than skim milk, and drinking milk with meals can

Fructose is found in modern diets either as a constituent of the disaccharide sucrose or as the monosaccharide, both of which are used as sweeteners in a variety of food items. Around the world, the average daily intake of fructose varies from 11 to 54 g.174 Fructose as a constituent of sucrose is absorbed by a dosedependent and limited capacity absorptive system that integrates enzymatic hydrolysis of the disaccharide sucrose by sucrase and transfer of the resulting 2 monosaccharides, glucose and fructose, through the apical membrane of the epithelial cell (see Chapter 102).175 Our understanding of the mechanisms of intolerance to incomplete fructose absorption, however, is still incomplete.176 The absorptive capacity for fructose that is not accompanied by glucose, however, is relatively small. Healthy subjects have the capacity to absorb up to 25 g of fructose, but normal absorption of fructose also depends on other ingested nutrients and is not well understood; many individuals will have malabsorption and intolerance with intake of 50 g of fructose.176 Ingesting food that contains fructose in excess of glucose can result in symptoms such as abdominal bloating or diarrhea176 and especially can provoke symptoms in patients with IBS.177 It has been suggested that as little as 3 g of fructose can precipitate symptoms in patients with functional bowel disorders. Women might complain more often of fructose-associated symptoms and exhibit more fructose malabsorption than men. There is no adaptation to regular consumption of fructose.178 Fructose malabsorption usually is identified by a positive result on a HBT after ingestion of 25 to 30 g of fructose.155 Just as discussed earlier for lactose, the relation between fructose malabsorption and fructose intolerance is unclear in adults and children, and may be related to co-occurrence of functional GI disorders.53,54 In a study of children and adolescents with functional abdominal pain in which a validated symptom questionnaire was used before and during a fructose breath test, symptoms induced by ingestion of fructose correlated with the abdominal symptoms these patients had before the tests. In contrast, there was no relation between abdominal symptoms and results of the hydrogen breath measurements. This suggested that visceral hypersensitivity, rather than malabsorption per se, is correlated with symptoms. Obtaining information on fructose malabsorption using a HBT did not provide any valuable clinical information regarding the role of fructose ingestion in clinical symptom severity.54 Clinical decisions regarding dietary treatment should, therefore, be based on the results of a structured and validated assessment of symptoms after ingestion of fructose.54 Because the fructose content in fruit and soft drinks usually is less than 8 g per 100 g of fruit or drink, the amounts of fructose used in the HBT are not physiologic, and no data are available on how many otherwise asymptomatic people would have a positive test result with these larger doses. Fructose contents of 30 to 40 g per 100 g are present in some chocolate, caramel, and praline products.179

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In a group of patients with isolated fructose malabsorption, no defect of the gene that encodes the luminal fructose transporter (GLUT5) could be detected.180 It is, therefore, unlikely that patients who present with GI symptoms have a true defect of intestinal fructose absorption. Rather, it is more likely that they belong to a subset of people in whom ingestion of fructose-rich foods provokes symptoms related to other disorders (e.g., IBS) or as a result of unique but not necessarily abnormal colonic bacterial activity. The latter is suggested by a study in asymptomatic and symptomatic persons with fructose malabsorption in whom it was demonstrated that the disappearance rate of fructose in anaerobic, but not aerobic, stool cultures was significantly elevated in the symptomatic group compared with the asymptomatic group.181 A placebo-controlled study on patients with incomplete fructose absorption showed that ingestion of the enzyme xylose isomerase, which catalyzes the reversible isomerization of glucose and fructose, decreased pain, nausea, and the area under the breath hydrogen curve after ingestion of a watery fructose load.182 It is unclear whether this effect is also present during ingestion of carbohydrate mixtures or food containing fructose and whether it persists over a lengthy observation period. 

Other Poorly Absorbable Carbohydrates The rapid increase in the prevalence of obesity and the recent guidelines which suggest limiting the consumption of simple sugars has resulted in increased interest for alternative sweeteners.183 Some of these are poorly absorbed carbohydrates, such as sorbitol, xylitol, and trehalose, which may result in similar symptoms as with ingestion of fructose or lactose. In case of persistence of bloating, abdominal cramps, flatulence, or diarrhea after dietary treatment of lactose or fructose intolerance, the contribution of these sugars to the pathogenesis of symptoms should be considered. 

Bile Acid Malabsorption BAM is usually present in patients who have undergone ileal resection or bypass operations or who have severe disease of the ileum, where specific BA transport proteins are located. The clinical consequences of BAM depend on whether BA loss can be compensated by increased hepatic synthesis.184 Ileal resection of greater than 100 cm usually results in severe BAM that cannot be compensated by increased hepatic synthesis; in such cases, steatorrhea results from impaired micelle formation due to decreased luminal concentrations of conjugated BAs.3,184 With ileal resections of less than 100 cm, BAM usually can be compensated by increased hepatic synthesis, and malabsorbed BAs cause secretory diarrhea rather than steatorrhea.3,184 Secretory diarrhea caused by or associated with BAM is discussed in detail in Chapter 16. Knowledge of the differing pathophysiology of steatorrhea and of secretory diarrhea from BAM is important not only for understanding the clinical presentation, but also for choosing the appropriate therapy. In patients with compensated BAM, binding of BAs in the lumen of the intestine by cholestyramine reduces diarrhea. By contrast, in decompensated BAM, cholestyramine further depletes the BA pool, thereby worsening steatorrhea. In several cases of decompensated BAM after extensive ileal resections, intestinal fat absorption was improved markedly by oral administration of conjugated BAs.113 Cholylsarcosine in a dose of 2 to 3 g per meal has been reported to enhance fat absorption and nutritional status in patients with short bowel syndrome who have residual colon113,185; natural conjugated BAs lessen severity of steatorrhea in such patients to a smaller extent. Improved fat absorption also was associated with decreased urinary oxalate excretion.185 A syndrome of primary BAM with normal ileal morphology has been reported in children who, at birth, develop severe

diarrhea, severe steatorrhea, and failure to thrive and who have reduced plasma cholesterol levels. In the index case, this type of BAM was shown to be caused by mutations in the ileal sodiumbile acid co-transporter gene (SLC10A2).4 Adult-onset BAM is not caused by SLC10A2 mutations,186 and although its exact pathophysiology is unknown, accelerated intestinal transit may be a causative factor.187 

Amyloidosis Malabsorption has been reported in AL-type amyloidosis, AA-type amyloidosis, and hereditary amyloidosis (see Chapter 37). Malabsorption occurs in 5% to 13% of patients with AL or AA amyloidosis188,189 and was present in 58% of Swedish patients with familial amyloidosis.190 Fecal fat excretion can reach levels of 60 g/day.190 GI absorption of d-xylose and vitamin B12 can be reduced,190,191 and protein-losing enteropathy can develop.192 Amyloid deposits are found in the muscle layers, the stroma of the lamina propria and the submucosa, the wall of mucosal and submucosal blood vessels in the GI tract, and in enteric and extraenteric nerves.193 In many patients with amyloidosis who have diarrhea or malabsorption, or both, symptoms suggesting autonomic neuropathy are present.144,190 Autonomic neuropathy can cause rapid intestinal transit, which in turn can lead to severe diarrhea and malabsorption despite normal transport capacity of the intestinal mucosa.144 Other suggested mechanisms of malabsorption in amyloidosis are chronic mesenteric ischemia, decreased absorption from a physical barrier effect of amyloid deposits,193 and SIBO, which also might be a consequence of autonomic neuropathy and delayed GI transit.191 BAM is found in many patients with amyloidosis associated with autonomic neuropathy194 and is caused by rapid intestinal transit rather than impaired absorptive transport in the terminal ileum.144 Diarrhea in these patients usually fails to respond to BA-binding agents.144 The endoscopic appearance of the GI mucosa may show a fine granular appearance, polypoid protrusions, erosions, ulcerations, atrophic changes, and mucosal friability, but in many patients, no macroscopic changes are evident.193 Histologic examination demonstrates amyloid deposits in 72% of esophageal, 75% to 95% of gastric, 83% to 100% of small intestinal, and 75% to 95% of colorectal biopsy specimens.189,193 Subcutaneous fat pad aspiration or biopsy is another diagnostic approach. Amyloid deposits might not be seen with routine histologic stains but become more evident with Congo red staining. Therapy of diarrhea in patients with amyloidosis includes attempts to prolong intestinal transit time with opioids or octreotide and to avoid further amyloid deposition in the tissue by treatment of the underlying disorder in AA amyloidosis, the plasma-cell dyscrasia in AL amyloidosis, and by administration of colchicine to patients with familial Mediterranean fever.

Drugs and Food Supplements Table 104.9 lists drugs and food supplements reported to induce malabsorption of vitamins, minerals, or nutrients, as well as the suggested pathophysiologic mechanisms by which this occurs.

Angiotensin II Receptor Blockers The administration of ARBs has been associated with the occurrence of a sprue-like enteropathy leading to villous atrophy, diarrhea, and generalized malabsorption.195,196 This form of enteropathy was initially described for olmesartan, but also occurs, albeit less frequently, with other ARBs.195,196 The pathogenetic

CHAPTER 104  Maldigestion and Malabsorption

1699

TABLE 104.9  Drugs and Dietary Products That Cause Malabsorption Substance

Substrate Malabsorbed

Suggested Mechanism

Reference(s)

Acarbose

Carbohydrate

Inhibition of α-glucosidase

308

Angiotensin II Receptor Blockers (especially Olmesartan)

Generalized malabsorption

Immune mediated enteropathy with villus atrophy

195, 196

Antacids

Phosphate, iron, vitamin A

Luminal binding of substrates

309

Azathioprine

Generalized malabsorption

Villus atrophy

310

Biguanide (metformin)

Cobalamin, folate, glucose

Reduced ileal absorption of intrinsic factor (IF)-cobalamin 309, 311, 312 complex; inhibition of intestinal glucose or folate absorption

Carbamazepine

Folate

Inhibition of intestinal folate absorption

313

Cholestyramine

Fat, fat-soluble vitamins, bile acids

Binding of conjugated bile salts

309

Colchicine

Fat, xylose, nitrogen, cobalamin, carotene

Mucosal damage and villus atrophy at high doses (impaired processing of IF-cobalamin receptor [the cubilin-amnionless complex])

26, 309, 314

Contraceptives, oral*

Folate

Inhibition of pteroylpolyglutamate hydrolase (folate conjugase)

309

Ethanol

Xylose, fat, glucose, nitrogen, thiamine, cobalamin, folate

Mucosal damage; decreased disaccharidase activity; decreased pancreatic exocrine function and bile secretion

34, 309

Fiber, phytates

Iron, calcium, magnesium, zinc

Chelation

315

Glucocorticoids

Calcium

Inhibition of calcium absorption

23

H2RAs

Cobalamin

Impaired release of food-bound B12 owing to reduced gastric acid and pepsin secretion (and reduced IF secretion)

316

Laxatives, irritant type (phenolphthalein, bisacodyl, anthraquinones)

Fat, glucose, xylose

Washout effect; toxic effect on mucosa

112, 309

Methotrexate

Folate, fat, cobalamin, xylose

Mucosal damage; inhibition of intestinal folate transport

309, 315

Methyldopa†

Generalized malabsorption

Mucosal damage

317

Neomycin

Fat, nitrogen, fat-soluble vitamins, cobalamin, mono- and disaccharides, iron

Mucosal damage; disruption of micelle formation

309, 315

Olestra*

Fat-soluble vitamins

Binding of fat-soluble vitamins

318

Orlistat

Fat, fat-soluble vitamins

Inhibition of pancreatic lipase

308

Para-aminosalicylate

Fat, cobalamin, folate

Unknown

26, 309

Phenytoin

Folate, calcium

Inhibition of folate and calcium absorption owing to luminal alkalinization; impaired vitamin D metabolism

23, 317, 319

PPIs*

Cobalamin, calcium?, magnesium? Impaired release of food-bound cobalamin by pepsin owing to reduced gastric acid secretion; SIBO

27, 320

Pyrimethamine

Folate

Competitive inhibition of intestinal folate absorption

321

Somatostatin analogs (e.g., octreotide)

Fat

Inhibition of hepatobiliary bile acid secretion; inhibition of pancreatic enzyme secretion; inhibition of CCK release

322, 323

Sulfonamides and sulfasalazine

Folate

Inhibition of pteroylpolyglutamate hydrolase and folate transport

128, 315

Tetracycline

Calcium

Precipitation of luminal calcium

324

Thiazides

Calcium

Decreased 1,25 dihydroxyvitamin D synthesis

325

Triamterene*

Folate

Competitive inhibition of intestinal folate absorption

321, 326

*Malabsorption usually does not result in deficiency states. †Findings in case reports.

mechanism is not fully established, but the immunologic findings in the small intestinal mucosa are similar to those in celiac disease.197 Risk factors for this side effect of ARBs are the use of olmesartan, older age, and therapy of more than 1 year.195 Enteropathy subsides after the discontinuation of ARBs and is the treatment of choice.196 

Gastric Resection or Bariatric Surgery Gastric Resection Severe steatorrhea after total and partial gastric resections has been a long-observed complication of these operations. Fecal fat excretion rates after such operations usually are between

104

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PART X  Small and Large Intestine

15 and 20 g/day,1 but values of up to 60 g/day have been reported.198 Suggested mechanisms for steatorrhea include defective mixing of nutrients with digestive secretions, lack of gastric acid and gastric lipase secretion, decreased small bowel transit time, SIBO, and pancreatic insufficiency.1,199 Studies have shown, however, that pancreatic enzyme supplements200 and antibiotic therapies199 neither improve fat absorption nor relieve symptoms after gastric resection. Total and partial gastric resections also can result in significant protein malabsorption, whereas absorption of carbohydrates does not seem to be significantly impaired. Nutrient malabsorption in these patients also can result in GI symptoms such as diarrhea and severe weight loss.201 Vitamin E deficiency can occur if food does not pass through the duodenum. The differential diagnosis of neurologic symptoms in postgastrectomy patients should include hypovitaminosis E.202 Loss of parietal cells after total gastric resection results in diminished IF secretion, which in turn leads to malabsorption of vitamin B12 and, in approximately 30% of patients, vitamin B12 deficiency. SIBO and lack of release of food-bound cobalamin secondary to diminished gastric acid and pepsin secretion have been implicated as additional pathogenic factors. Iron malabsorption with resultant iron deficiency anemia is also commonly present in patients who have undergone gastric resection, although the mechanisms for iron malabsorption are not fully established. Lack of acid secretion with resultant decreased solubilization of iron salts and bypass of the duodenum have been suggested as a possible causes. Calcium absorption can be severely impaired in patients with gastric resections and result in reduced bone density.203 The mechanisms for calcium malabsorption probably are several, including decreased solubilization of calcium salts because of loss of gastric acid secretion, rapid intestinal transit, low calcium intake secondary to milk intolerance, and malabsorption of vitamin D. Studies in rats after gastrectomy have suggested that diminished calcium absorption results mainly, if not entirely, from decreased calcium solubilization.204 By contrast, studies in humans have shown that calcium absorption is normal in patients with atrophic gastritis and in persons in whom acid secretion was inhibited by acid-inhibiting drugs.205 Treatment for patients who have undergone gastric resection should include adequate supplementation of malabsorbed vitamins and minerals to prevent serious long-term complications.206 

Bariatric Surgery The number of patients undergoing bariatric surgery is increasing; indications for such surgery and details of the various procedures are described in Chapter 8. These patients need to be monitored for long-term problems such as changes in bone metabolism. Risks of malabsorption can increase beyond those that might be expected from the procedure over time because of poor compliance with supplementation or inadequate intake. Malabsorption plays only a minor role in reducing average net intestinal energy absorption after long-limb Roux-en-Y gastric bypass. In a study of 9 severely obese patients, gastric bypass reduced fat absorption in every patient, although the severity of malabsorption varied widely and was correlated with the length of the biliopancreatic limb. Bypass caused protein malabsorption in some patients but did not cause carbohydrate malabsorption in any patient. Intestinal absorption of combustible energy averaged 3505 kcal/day before bypass, 1318 kcal/day 5 months after bypass, and 1914 kcal/day 14 months after bypass. The vast majority of the reduction in energy absorption after bypass was explained by reduced intake rather than malabsorption (e.g., at 5 months, reduction in intestinal energy absorption by malabsorption was 135 kcal/day vs. 2052 kcal/day from reduced intake).207

Long-term GI problems from bariatric surgery depend on the type of surgical procedure performed. Restrictive procedures and Roux-en-Y gastric bypass have only a mild component of noncaloric malabsorption compared with other procedures such as biliopancreatic diversion, which was used more extensively in the past, and which can result in severe malnutrition.208 Roux-en-Y gastric bypass can result in deficiency of proteins, iron, calcium, folate, vitamin B12, and vitamin D. Deficiencies in vitamin B1 are rare but potentially serious.209,210 Iron deficiency after gastric bypass can develop for several reasons, such as intolerance to red meat, diminished gastric acid secretion, and exclusion of the duodenum. Menstruating or pregnant women may be particularly predisposed to iron deficiency after gastric bypass surgery. Postoperatively, oral iron and vitamin C supplementation should be prescribed because once iron deficiency has developed, it may be refractory to oral treatment.211 In Roux-en-Y gastric bypass, colonization of both gastric chambers with aerobic and anaerobic bacteria has been demonstrated, resulting in a positive HBT in 41% of subjects; no clinical symptoms such as diarrhea, malabsorption, or pneumonia could be attributed to this bacterial overgrowth.212 It has been suggested that after bariatric surgery, patients should have yearly measurements of a basic metabolic panel, magnesium, complete blood cell count, iron studies, vitamin D, parathyroid hormone, and bone density.208 Routine and lifelong use of multivitamins is considered necessary.213 An updated guideline for the perioperative support has been published.214 

Aging Malabsorption in older adults should not be ascribed to the aging process; it should be evaluated just like malabsorption that occurs in younger patients. In healthy older adults, small bowel histologic features are normal despite a decline in cell turnover and continual cell renewal.215,216 Malabsorption of fat has rarely been described in chronic heart failure217 and chronic intestinal ischemia (see Chapter 118), but this is not due to aging per se. Older adults may be more susceptible to GI insult and subsequent decompensation of GI function.218 Changes in pancreatic anatomy and secretion occur with advanced aging, but only rarely do they result in overt pancreatic insufficiency.219 Deficiencies of some nutrients, however, presumably caused by malabsorption, may be present in older adults with no overt GI disease. An increased risk of folate and vitamin B12 deficiency despite adequate intake of these vitamins has been reported in older adults.220 Malnutrition in older adults can contribute significantly to morbidity and mortality, although it may be difficult to ascertain whether weight loss results from altered appetite, increased catabolism, or malabsorption. SIBO in older adults with gastric hypochlorhydria from atrophic gastritis or treatment with a PPI is usually not associated with clinically significant malabsorption,221 but an improvement in nutritional status after antibiotic treatment has been described in some older adults.222 An increased prevalence of lactose malabsorption in older adults may be the result of clinically unapparent SIBO.223 

Connective Tissue Diseases PSS The GI tract is involved to a variable degree in most patients with PSS. Early pathologic changes are characterized by vasculopathy, which results in ischemia and progressive organ dysfunction. Typical histologic findings include atrophy of the muscle layers with increased deposition of elastin and collagen in the submucosa and serosa and between smooth muscle bundles of the muscularis

CHAPTER 104  Maldigestion and Malabsorption

externa.224 Small intestinal biopsy specimens might reveal an increased number of plasma cells within the lamina propria and collagen deposits around and between lobules of Brunner glands in the submucosa of the duodenum.225 Malabsorption in PSS usually results from SIBO secondary to ineffective motility in the small intestine, but other factors (e.g., decreased mucosal blood flow) can also contribute.224 Malabsorption and SIBO are not limited to patients with diffuse disease; they can also occur in patients with long-standing limited cutaneous sclerosis.226 Elevated serum concentrations of motilin and CCK have been described in patients with PSS and fat malabsorption, but are thought to result from myogenic or neurogenic disturbances of intestinal or gallbladder contraction.227 In addition to antibiotic treatment of SIBO, low doses of octreotide (50 μg subcutaneously every evening for 3 weeks) have been shown to induce intestinal migrating motor complexes, reduce bacterial overgrowth, and relieve abdominal symptoms.224,228 

SLE and Other Connective Tissue Diseases Excessive fecal fat excretion associated with abnormalities of d-xylose breath testing may be found in some patients with SLE; these findings may be accompanied by flattened and deformed villi with an inflammatory infiltrate seen on duodenal biopsy specimens.229 Furthermore, there is an increased prevalence of celiac disease in patients with SLE.230 Malabsorption that resolved after treatment with prednisolone has also been described in association with hypereosinophilic syndrome in SLE.231 Malabsorption is an uncommon feature of mixed connective tissue disease and polymyositis.232,233 

Congenital Defects Table 104.10 lists congenital intestinal diseases that result in malabsorption of specific substrates or in a generalized malabsorption syndrome.

Amino Acid Transport Defects AAs are absorbed by the enterocyte as oligopeptides, dipeptides, and free AAs. In several inborn errors of metabolism, transport defects for different groups of AAs have been identified in the intestine and kidney (see Table 104.10). In iminoglycinuria, Hartnup disorder, and cystinuria, the intestinal transport defect seems to be of no or only minor clinical significance, because the AAs affected by the transporter defects still can be absorbed as oligopeptides and dipeptides, and protein malnutrition can be avoided.234-236 Manifestations in these diseases, therefore, are mainly due to AA transport defects in the kidney. In Hartnup disorder, oral administration of nicotinamide and a high-protein diet have been shown to relieve symptoms to some extent.234 In lysinuric protein intolerance, however, the transport defect is located on the basolateral membrane of the enterocyte and leads to malabsorption of cationic AAs in both their monopeptide and dipeptide forms. Patients with lysinuric protein intolerance, therefore, cannot tolerate high-protein foods and are prone to develop protein malnutrition. Malabsorption of lysine with resultant deficiency of this essential AA is thought to be important to the development of several disease manifestations in these patients.237 Treatment consists of protein restriction and supplementation with oral citrulline. 

Disaccharidase Deficiency and Transport Defects for Monosaccharides In sucrase-isomaltase deficiency, affected infants usually become symptomatic after weaning when starch and sucrose

1701

are introduced to the diet. Symptoms and signs include osmotic diarrhea, failure to thrive, excess flatus, and occasional vomiting. Diagnosis can be established by an oral sucrose absorption test or the absence or markedly reduced sucrose activity in duodenal biopsies. Treatment includes avoidance of dietary starch and sucrose and enzyme replacement therapy with oral administration of sacroidase.238 In patients with this disease, symptoms tend to resolve spontaneously with age.238 Patients with glucose-galactose malabsorption suffer from severe diarrhea that leads to dehydration in the first days of life. The diarrhea stops only if glucose and galactose are eliminated from the diet. Older children and adults tolerate the offending carbohydrates better, but the transport defect is lifelong. Diagnosis can be established with an oral glucose tolerance test or by in vitro glucose absorption tests performed on intestinal biopsy specimens. Therapy consists of a fructose-based diet free of glucose and galactose. After the age of 3 months, addition of foods containing low quantities of glucose or galactose such as vegetables, fruits, and cheese is considered safe.239 

Congenital Disorders of Lipid Absorption Abetalipoproteinemia is a disorder of autosomal recessive inheritance characterized by triglyceride accumulation in the enterocyte. This disease seems to be caused by mutations in the gene for microsomal triglyceride transfer protein (MTP), with resultant defective assembly of triglyceride-rich lipoproteins.9 Familial hypobetalipoproteinemia, a disorder of autosomal dominant inheritance, has clinical manifestations similar to those of abetalipoproteinemia when in the homozygous state. This disease seems to be caused by mutations of the apolipoprotein B gene in most cases.9 Chylomicron retention disease and Anderson disease are caused by defective release of chylomicrons by enterocytes. The distinction between the 2 conditions derives from differences in the partitioning of lipid between membrane and cytoplasmic compartments, although both diseases are due to a defect in the same gene (SAR1B). General treatment measures in abetalipoproteinemia, hypobetalipoproteinemia, chylomicron retention disease, and Anderson disease include replacement of triglycerides that contain long-chain fatty acids with medium-chain triglycerides and dietary supplementation with tocopherol.9 Wolman disease and the milder late-onset cholesteryl ester storage disease are seemingly caused by mutations in different parts of the LIPA gene, resulting in infiltration of intestinal mucosa with foam cells and intestinal damage. 

Congenital Disorders of Cobalamin Absorption Several congenital diseases can result in vitamin B12 malabsorption. Absence of IF synthesis is the most common cause of congenital cobalamin deficiency; abnormal results on Schilling tests normalize with the co-administration of IF.26 In some patients, an abnormal (nonfunctional) IF is secreted that has decreased affinity for cobalamin, decreased affinity for the ileal IF-cobalamin receptor (cubilin-amnionless complex), or increased susceptibility to proteolysis.26,31,240 Imerslund-Gräsbeck syndrome is a congenital disease characterized by malabsorption of the cobalamin-IF complex despite normal ileal morphology. This syndrome can be caused by mutations in either of 2 genes that code for the cubilin and AMN proteins, which are co-localized in the ileal mucosa and form the IF-cobalamin receptor.31 In transcobalamin II deficiency, serum levels of cobalamin commonly are normal, although in most patients intestinal cobalamin absorption is abnormal.240 Diagnosis is established by demonstrating the absence of transcobalamin II in the plasma. All

104

1702

TABLE 104.10  Congenital Disorders of the Gastrointestinal Mucosa That Result in Malabsorption327 Disorder

Causative Gene

Suggested Mechanism of Malabsorption

AR

Neutral amino acids (tryptophan, leucine, methionine, phenylalanine, tyrosine, valine, ?histidine, ?lysine)

Clinical Features

Reference(s)

Decreased intestinal absorption of free neutral amino acids

Most patients are asymptomatic; some patients have photosensitive skin rash, intermittent ataxia, psychotic behavior, mental retardation, diarrhea

234

Cystinuria (types A, B, AB) OMIM#220100

Type A: SLC3A1 Type B: SLC7A9

AR (type A) and incomplete AR (type B)

Cystine and/or dibasic amino acids (lysine, ornithine, arginine)

Decreased intestinal absorption of specific free amino acids owing to a defective amino acid transporter at the brush border membrane Type A: no transport of cystine, lysine, or arginine Type B: reduced or normal cystine transport and reduced or no lysine and arginine transport

Aminoaciduria, cystine stones in the urinary tract

235

Lysinuric protein intolerance OMIM#222700

SLC7A7

AR

Dibasic amino acids (lysine, ornithine, arginine)

Defect of the basolateral transporter (y+LAT-1) for dibasic amino acids (also malabsorption of di- and oligopeptides)

Sparse hair, hyperammonemia, nausea, vomiting, diarrhea, protein malnutrition, failure to thrive, aversion to protein-rich food

237

Isolated lysinuria*

?

?

Lysine

Decreased intestinal absorption of lysine Mental retardation, malnutrition, failure 237 to thrive

Iminoglycinuria OMIM#242600

SLC6A20 SLC6A19 SLC36A2

AR

l-Proline

Impaired intestinal absorption of l-proline in a subgroup of subjects

Aminoaciduria; benign disorder

236

Blue diaper syndrome* OMIM#211000

?

AR

Tryptophan

Intestinal tryptophan absorption defect

Blue discoloration of diapers, failure to thrive, hypercalcemia, nephrocalcinosis

328

Methionine malabsorption syndrome* (Oasthouse syndrome) OMIM#250900

?

AR

Methionine

Intestinal methionine absorption defect

Mental retardation, convulsions, 329 diarrhea, white hair, hyperpnea; urine has characteristic sweet smell of dried celery

Lowe oculocerebral syndrome OMIM#30900

OCRL1

XR

Lysine, arginine

Impaired intestinal lysine and arginine absorption

Aminoaciduria, mental retardation, cataracts, rickets, choreoathetosis, renal disease

330

AR

Lactose

Permanent very low lactase activity

Diarrhea, bloating, and dehydration in the first days of life

331

Malabsorption of Carbohydrates Congenital lactase deficiency LCT OMIM#22300 Sucrase-isomaltase deficiency OMIM#2229000

SI

AR

Sucrose, starch

Sucrase activity is absent; isomaltase activity is absent or reduced; reduced maltase activity

Osmotic diarrhea after starch or sucrose ingestion; failure to thrive

238, 331

Trehalase deficiency OMIM#612119

TREH

AR

Trehalose

Lack of intestinal trehalase activity

Diarrhea and/or vomiting after ingesting mushrooms

331

Glucose-galactose malabsorption OMIM#606824

SLC5A1

AR

Glucose, galactose

Defect of the brush border sodiumglucose cotransporter (SGLT1)

Neonatal onset of osmotic diarrhea, dehydration, intermittent or constant glycosuria

239

PART X  Small and Large Intestine

Malabsorption of Amino Acids Hartnup disorder SLC6A19 OMIM#234500

Suggested Mode of Malabsorbed Inheritance Substrate(s)

Disorder

Causative Gene

Suggested Mode of Malabsorbed Inheritance Substrate(s)

Suggested Mechanism of Malabsorption

Malabsorption of Fat Abetalipoproteinemia OMIM#200100

MTP

AR

Fat, fat-soluble vitamins

Defective lipoprotein assembly owing to a lack of MTP, resulting in TG accumulation in the enterocyte and no chylomicron formation

Familial hypobetalipoproteinemia OMIM#615558

APOB

Incomplete AD

Fat, fat-soluble vitamins

TG accumulation in the enterocyte in Homozygotes: clinical manifestations homozygotes owing to formation of a as for abetalipoproteinemia truncated apolipoprotein B Heterozygotes: fat absorption probably normal; hypolipidemia, neurologic manifestations

9

Chylomicron retention disease

SAR1B

AR

Fat

Defective chylomicron formation and accumulation in the enterocyte

Steatorrhea, failure to thrive, absence of chylomicrons and reduced LDL levels in the blood; neurologic symptoms in some patients

9, 332

AR

Fat

Deficient activity of hLAL, cholesteryl ester hydrolase, causing accumulation of cholesteryl esters and TGs in various body tissues; infiltration of intestinal mucosa with foamy cells, intestinal damage

Steatorrhea, hepatosplenomegaly, abdominal distention; failure to thrive, adrenal calcifications

333, 334

GIF

AR

Cobalamin (vitamin B12)

Defective synthesis of IF or synthesis of Megaloblastic anemia, neurologic an abnormal IF with either reduced symptoms, delayed development affinity for cobalamin or for the ileal IF receptor, or increased susceptibility to proteolysis

32

Imerslund-Gräsbeck syndrome (ileal B12 malabsorption, megaloblastic anemia type I) OMIM#261100

CUBN or AMN

AR

Cobalamin (vitamin B12)

Impaired ileal absorption of IFcobalamin complex owing to defects in the cubilin-AMN complex (IFcobalamin receptor)

Megaloblastic anemia, neurologic symptoms, proteinuria

26, 31

Transcobalamin II deficiency OMIM#275350

TCN2

AR

Cobalamin (vitamin B12)

Defective transport of cobalamin out of enterocytes into the portal blood owing to absence or malfunction of transcobalamin II

Vomiting, diarrhea, failure to thrive, anemia, immunodeficiency, neurologic symptoms

32, 240

Hereditary folate malabsorption OMIM#229050

SLC46A1

AR

Folate

Defective folate transport across the intestinal mucosa

Megaloblastic anemia, diarrhea, neurologic symptoms

335

SLC39A4

AR

Zinc

Defective zinc absorption in the small Diarrhea, scaling erythematous intestine owing to a defect in the zinc dermatitis, alopecia, transport protein (hZIP4) neuropsychiatric symptoms; onset after weaning

48

TRPM6

AR

Magnesium

Selective defect in intestinal magnesium Tetany, convulsion, diarrhea, absorption hypomagnesemia with secondary hypocalcemia

41

(Anderson disease) OMIM#246700 Cholesteryl ester storage disease LIPA (Wolman disease) OMIM#278000

Malabsorption of Vitamins Congenital IF deficiency (congenital pernicious anemia) OMIM#261000

Steatorrhea, diarrhea, neurologic symptoms, retinitis pigmentosa, failure to thrive, absence of chylomicrons and VLDL in the blood, acanthocytosis

9

Continued

1703

Isolated magnesium malabsorption (hypomagnesemia with secondary hypocalcemia [HOMG]) OMIM#602014

Reference(s)

CHAPTER 104  Maldigestion and Malabsorption

Malabsorption of Minerals Acrodermatitis enteropathica OMIM#201100

Clinical Features

104

1704

TABLE 104.10  Congenital Disorders of the Gastrointestinal Mucosa That Result in Malabsorption327—cont’d Causative Gene

Suggested Mode of Malabsorbed Inheritance Substrate(s)

Suggested Mechanism of Malabsorption

Clinical Features

Reference(s)

Menkes disease OMIM#309400

ATP7A

XR

Copper

General copper transport disorder; intestinal copper malabsorption with copper accumulation in the intestinal mucosa owing to a defective transmembrane copper-transporting ATPase (MNK)

Cerebral degeneration, diarrhea, abnormal hair, hypopigmentation, arterial rupture, thrombosis, hypothermia, bone changes

336

Occipital horn syndrome (X-linked cutis laxa) OMIM#304150

ATP7A

XR

Copper

Milder form of same defect as in Menkes disease; low levels of functional MNK

Inguinal hernias, bladder and ureteral diverticula, skin and joint laxity, chronic diarrhea, bone changes

336

Iron-refractory iron-deficient anemia OMIM#206200

TMPRSS6

AR

Iron

Intestinal iron transport disorder

Iron-deficient anemia that is unresponsive to oral iron supplementation

45

Hereditary selective deficiency of 1α,25(OH)2D (pseudo–vitamin D deficiency rickets) OMIM#264700

CYP27B1

AR

Calcium

Defective 25(OH)D 1α-hydroxylase, resulting in 1α,25(OH)2D deficiency and reduced intestinal calcium absorption

Bone pain, deformities and fractures, muscle weakness

337

Hereditary generalized resistance to 1α,25(OH)2D (vitamin D-resistant rickets) OMIM#277440

VDR

AR

Calcium

Malfunction of the vitamin D receptor owing to defective hormone binding, defective receptor translocation to nucleus, or defective receptor binding to DNA, resulting in malabsorption of calcium

Bone pain, deformities and fractures, muscle weakness, alopecia

337

PRSS7

AR

Protein, fat

Defective activation of pancreatic proenzymes owing to lack of intestinal enterokinase

Diarrhea, failure to thrive, hypoproteinemia, edema, anemia

15, 338

Congenital bile acid malabsorption OMIM#613291

SLC10A2

AR

Bile acids, fat

Defect of the ileal ASBT

Steatorrhea, diarrhea, failure to thrive

4

Microvillus inclusion disease OMIM#251850

MYO5B

AR

Carbohydrates, fat, cobalamin, electrolytes, water

Villus atrophy with microvillus inclusions in enterocytes, absent or shortened brush border microvilli

Severe watery diarrhea and steatorrhea requiring total parenteral nutrition

339

Hyperinsulinism, with enteropathy USH1C, ABCC8, and deafness or KCNJ11 OMIM#606528

AR

Generalized malabsorption

Enteropathy with villus atrophy and inflammation

Hyperinsulinism, profound congenital sensorineural deafness, enteropathy, renal tubular dysfunction

340

Immune dysregulation polyendocrinopathy and enteropathy, X-linked (IPEX) OMIM#304790

FOXP3

XR

Generalized malabsorption

Villus atrophy

Polyendocrinopathies, severe diarrhea, hemolytic anemia

250

Enteric anendocrinosis* OMIM#610370

NEUROG3

AR

Generalized malabsorption

Lack of enteroendocrine cells

Severe diarrhea, failure to thrive, type 1 diabetes mellitus

281

Other Defects Enterokinase deficiency OMIM#226200

PART X  Small and Large Intestine

Disorder

Suggested Mode of Malabsorbed Inheritance Substrate(s)

Suggested Mechanism of Malabsorption

Clinical Features

Reference(s)

Congenital proprotein convertase PCSK1 1/3 deficiency OMIM#600955

AR

Generalized malabsorption

Lack of functional hormone production by enteroendocrine cells

Severe diarrhea, polyendocrinopathies, failure to thrive, overweight in later age

282

Congenital tufting enteropathy OMIM#613217

EpCAM

AR

Generalized malabsorption

Intestinal epithelial cell dysplasia and villus atrophy

Severe diarrhea, failure to thrive

341

CHAPLE syndrome CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and protein-losing enteropathy OMIM#226300

CD55

AR

Protein losing enteropathy, vitamin and micronutrient deficiencies

Intestinal lymphangiectasia

Anemia, growth retardation, diarrhea, abdominal pain, hypoproteinemia, thrombosis

342

Disorder

Causative Gene

*Reported in only a few cases. % sign (in place of #) means that the gene causing the disease is unknown in this case. AD, autosomal dominant; AMN, amnionless; AR, autosomal recessive; ASBT, sodium bile acid co-transporter; CUBN, cubilin; hLAL, human lysosomal acid lipase; IF, intrinsic factor; LDL, low-density lipoprotein; MTP, microsomal TG transfer protein; 1α,25(OH)2D, 1α,25-dihydroxyvitamin D; 25(OH)D, 25-hydroxyvitamin D; VLDL, very-low-density lipoprotein; XR, X-linked recessive.

CHAPTER 104  Maldigestion and Malabsorption

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congenital disorders of cobalamin absorption are treated by the parenteral administration of cobalamin, although high-dose oral cobalamin or nasal cobalamin also might be effective. 

Intestinal Enterokinase Deficiency Enterokinase, an enzyme secreted by the intestinal mucosa, initiates activation of pancreatic proenzymes. Several patients have been reported to have an inborn deficiency of this enzyme, with resultant diarrhea, failure to thrive, and hypoproteinemia mainly from protein malabsorption. These patients respond well to pancreatic enzyme replacement, and some patients show a tendency to improve with age. Secondary enterokinase deficiency also has been reported in patients with villus atrophy, although patients with celiac disease seem not to be affected.15 

Primary Immunodeficiency Diseases Malabsorption commonly occurs in entities characterized by deficiencies in humoral or cellular immunity (see Chapter 2).241 The immunodeficiency syndromes most commonly associated with malabsorption are selective immunoglobulin (Ig)A deficiency, common variable immunodeficiency (CVID), and severe combined immunodeficiency. The etiology of the malabsorption varies for the different syndromes.

Selective Immunoglobulin a Deficiency Selective IgA deficiency is the most common primary immunodeficiency disorder and is characterized by a selective near-absence of secretory and serum IgA that renders one susceptible to respiratory, urogenital, and GI infections. Autoimmune and allergic diseases are also commonly seen in patients with this disorder. A 10- to 16-fold increased incidence of gluten-sensitive enteropathy has been reported in patients with IgA deficiency,242 and a subgroup of patients with selective IgA deficiency have sprue-like small intestinal lesions that lead to severe diarrhea and malabsorption but are unresponsive to a gluten-free diet.243 Improvement with immunosuppressive therapy has been described in one case report.244 PA, giardiasis, and secondary disaccharidase deficiencies are also seen with increased frequency in patients with selective IgA deficiency.243,245 

Common Variable Immunodeficiency CVID, or CVID-acquired hypogammaglobulinemia, is a clinically and genetically heterogeneous group of immunodeficiency disorders characterized by decreased serum IgG levels and variably decreased serum levels of other Ig subclasses with T-cell defects. Most cases are sporadic and 10% to 20% of CVID are familial. Onset of disease usually is in adulthood and manifests with recurrent respiratory and GI infections. Affected patients are also at increased risk for autoimmune and neoplastic diseases. Malabsorption and diarrhea occur in 9% to 40% of patients with CVID246; malabsorption involves dietary fat, carbohydrates, vitamin B12, and folate.241 Small intestinal biopsy specimens show either sprue-like features, including villus shortening with increased numbers of lymphocytes in the epithelium and lamina propria, or a pattern similar to that in graft-versus-host disease (see Chapter 36).246,247 Some specific histologic features, such as a near-absence of plasma cells, are observed. The disease responds to a gluten-free diet in a minority of patients, and it appears that the sprue-like syndrome in CVID is a distinct entity,248,249 sometimes referred to as “hypogammaglobulinemic sprue.” In some patients with CVID, foamy macrophages are present, as in Whipple disease, but in contrast to Whipple disease, the macrophages do not contain material that stains with periodic acid-Schiff.247 In addition,

nodular lymphoid hyperplasia can be detected in the GI tract of a high proportion of CVID patients, although it does not correlate with the presence of malabsorption; other morphologic alterations found in CVID were not related to GI symptoms in a recent larger cross-sectional study.250 The incidence of small intestinal lymphoma is increased in CVID, and both disorders have to be considered as potential causes of malabsorption in these patients. Giardia organisms are often isolated from patients with CVID, and SIBO has been documented in a number of cases. Unfortunately, only some patients with malabsorption associated with CVID respond to antimicrobial treatment.247 Some patients with sprue-like intestinal changes have benefited from glucocorticoids,249 but the value of IV immunoglobulins is questionable.249 Improvement of enteropathy with infliximab has been described in case reports.251 Patients with CVID have a higher prevalence of atrophic gastritis with cobalamin malabsorption, although antibodies against parietal cells and IF are absent.246 

X-linked Infantile Agammaglobulinemia (Bruton Agammaglobulinemia) X-linked infantile agammaglobulinemia (Bruton agammaglobulinemia [OMIM #300755]) is an immunodeficiency disease characterized by lack of mature B lymphocytes and failure of Ig heavy chain rearrangement; it is caused by mutations in the gene for Bruton tyrosine kinase.252 This disease usually manifests after the first 6 months of life and is characterized by recurrent severe bacterial infections. Severe GI problems such as malabsorption and chronic diarrhea are less common than in CVID247; the prevalence of chronic gastroenteritis was 10% in one large series.253 In affected patients, the possibility of giardiasis and SIBO must be considered.247,253 

Immune Dysregulation-Polyendocrinopathy-Enteropathy– X-Linked Syndrome Immune dysregulation-polyendocrinopathy-enteropathy–Xlinked syndrome (IPEX [OMIM #304790]) is a disorder of early childhood characterized by protracted diarrhea, dermatitis, insulin-dependent diabetes mellitus, thyroiditis, thrombocytopenia, and hemolytic anemia. It is a disorder of X-linked recessive inheritance caused by mutations in the FOXP3 gene.254 Diarrhea and malabsorption are secondary to severe villus atrophy with inflammation. Antienterocyte antibodies are commonly present. The enteropathy usually does not respond to a gluten-free diet, but immunosuppressive therapy has been shown to be of some benefit. IPEX usually is fatal in childhood. Successful bone marrow transplantation with amelioration of enteropathy has been reported in some cases.255 

Other Congenital Immunodeficiency Syndromes In severe combined immunodeficiency (OMIM #300400), diarrhea and malabsorption are common. Symptoms are associated with stunting of intestinal villi or their complete absence. The pathophysiology of malabsorption is unknown, and the syndrome usually fails to respond to antimicrobial treatment.246,256 Malabsorption also has been reported in DiGeorge syndrome (thymic hypoplasia [OMIM #188400]) and chronic granulomatous disease of childhood (OMIM #306400), but little is known about its cause in these disorders.246 

Neurofibromatosis Type 1 (Von Recklinghausen Disease) Malabsorption can be an intestinal complication of neurofibromatosis type 1 (OMIM #162200). Mechanisms of malabsorption include peri-ampullary duodenal tumors, which are mainly

CHAPTER 104  Maldigestion and Malabsorption

somatostatin-containing neuroendocrine tumors, and pancreatic carcinomas with resultant pancreatic duct obstruction; tumors can cause exocrine pancreatic insufficiency and biliary obstruction.257 Duodenal somatostatinomas in von Recklinghausen disease usually do not increase plasma somatostatin levels, although one case of somatostatinoma syndrome has been reported.258 Infiltrating mesenteric plexiform neurofibromas and vascular damage caused by proliferation of nerves can cause lymphatic or vascular obstruction (or both), with resultant abdominal pain, protein-losing enteropathy, diarrhea or constipation, steatorrhea, and bowel ischemia.259,260 In patients with von Recklinghausen disease, an increased incidence of neuroendocrine tumors in other locations has been observed; gastrinomas with ZES have also been reported in some of these patients.261 

Autoimmune Enteropathy and Nongranulomatous Chronic Idiopathic Enterocolitis Nongranulomatous chronic idiopathic enterocolitis is an entity that is distinct from refractory celiac disease and IBD.262 The etiology of this disease is unknown, although chronic infection and an autoimmune cause have been suggested. Severe diarrhea and malabsorption occur as a result of diffuse villus atrophy, and ulcerations may be present in the small and large intestine. Small intestinal villus atrophy and neutrophilic inflammation of the mucosa with crypt abscesses may be seen in biopsy specimens from the small intestine and colon; the number of intraepithelial lymphocytes is not increased.262,263 Patients respond dramatically to glucocorticoids, and most require long-term low-dose maintenance therapy.262,263 Improvement with cyclosporine and longterm antibiotic therapy has been reported in one patient each.264 The condition is associated with a high mortality rate.262,263 Nongranulomatous chronic idiopathic enterocolitis shares several clinical and histologic features with adult autoimmune enteropathy and probably represents a subtype with this disease spectrum.263,265 In many patients with adult autoimmune enteropathy, antienterocyte antibodies, antigoblet cell antibodies, and alterations in regulatory T-cell function are present.265,266 This entity has been reported in children as well as adults, and other autoimmune disorders are frequently present in these patients. Although the name autoimmune enteropathy implies a causative autoimmune process, very little is known about the pathophysiology of this disease. Symptoms are chronic severe high-output diarrhea and malabsorption265; development of vitamin and mineral deficiencies are very common and patients commonly require TPN.267,268 Diagnosis relies on a combination of clinical and histologic findings. Proposed diagnostic criteria require the presence of chronic diarrhea and malabsorption; exclusion of other small intestinal diseases, such as celiac disease; histologic changes on intestinal biopsies such as partial or complete villus atrophy, deep crypt lymphocytosis, increased crypt apoptotic bodies, and minimal intra-epithelial lymphocytosis; and the presence of antienterocyte antibodies and antigoblet cell antibodies. Different histologic patterns are described, either as chronic active enteritis, celiac disease-like, graft-versus-host disease–like, or as mixed picture (Fig. 104.10).269 Colonic involvement is more common than in refractory celiac disease (see Fig. 104.10)267 Absence of antibodies does not exclude the diagnosis.265,267 The variety of histologic findings in the small and large intestine found in cases termed autoimmune enteropathy challenge the notion if this is really a uniform disease with a consistent pathophysiology. Therapy of autoimmune enteropathy is challenging, and some patients have been treated successfully with glucocorticoids and immunosuppressive drugs, such as cyclosporine A and tacrolimus. A recent case series reported an 85% response rate to open-capsule budesonide even in patients who had not responded to systemic steroids.267 Response to TNF-α blockers, abatacept270 or infusion of mesenchymal stromal cells271in individual patients was

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reported; a significant proportion of patients do not response to immunosuppressive therapy.272 

Endocrine and Metabolic Disorders Adrenal Insufficiency (Addison Disease) Some patients with adrenal insufficiency, independent of its etiology, have fat malabsorption, with fecal fat excretion of up to 30 g/day having been documented.273 Fat malabsorption is also observed in rats after adrenalectomy.274 The pathophysiologic mechanism of malabsorption in this disease is unknown, but fat absorption normalizes upon glucocorticoid replacement. Isolated autoimmune Addison disease has been associated with PA275 and celiac disease.276 An increased incidence of celiac disease and PA is also found in autoimmune polyglandular syndrome type 2 (Schmidt syndrome), which is characterized by the association of autoimmune Addison disease and other autoimmune endocrine disorders (except hypoparathyroidism).277

Enteroendocrine Deficiency Autoimmune Polyendocrinopathy, Candidiasis, Ectodermal Dystrophy (APECED) [OMIM #240300] also termed as autoimmune polyglandular syndrome type 1 (APS 1 [OMIM #240300]) is characterized by multiple endocrine organ failure (especially hypoparathyroidism and adrenal insufficiency) resulting from autoimmune destruction, with ectodermal dystrophy and susceptibility to chronic Candida infections.277 APECED is inherited as an autosomal recessive disorder and is caused by mutations in the AIRE gene.278 Severe malabsorption, which tends to be recurrent, develops in approximately 20% of patients with APECED. In one patient, malabsorption was caused by a transient and selective destruction of small intestinal enteroendocrine cells, leading to a temporary deficiency of enteroendocrine hormones (especially CCK);242 this has been confirmed by observations in subsequently reported patients.243,244 These patients have autoantibodies to tryptophan hydroxylase, which are directed against enteroendocrine cells (including CCK-producing cells).245 The long-known association of hypoparathyroidism or hypocalcemia and steatorrhea may be caused by the same mechanism, because in most reports of this association, patients fulfill the diagnostic criteria for APECED279,280 Selective absence of small intestinal enteroendocrine cells can be diagnosed by special immunohistochemical stains for these cells (e.g., immunohistochemical stains for chromogranin A or CCK [Fig. 104.11]) or by measurements of postprandial serum levels of the affected hormones. Patients with APECED also have an increased incidence of vitamin B12 malabsorption as a result of autoimmune gastritis.277 Lack of enteroendocrine cells also results in congenital malabsorption in 2 other described diseases resulting from mutations in the NEUROG3 gene (diarrhea 4; enteric anendocrinosis [OMIM #610370]) and PCSK1 gene (congenital proprotein convertase 1/3 deficiency [OMIM #600995]) (see Table 104.10).281,282 

Hyperthyroidisxm and Autoimmune Thyroid Disease Some reports suggest that up to 25% of hyperthyroid patients have at least some degree of fat malabsorption, but data from large series of patients are lacking. Fecal fat values in hyperthyroid patients can reach 35 g/day.283 The mechanism of steatorrhea in hyperthyroidism has not been established. Motility studies in hyperthyroid patients (including patients with and without diarrhea) have demonstrated accelerated small intestinal and whole-gut transit times284 ; fecal fat values were not reported in these patients. It can be hypothesized that more pronounced disturbances of intestinal transit can lead to decreased mixing of

104

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PART X  Small and Large Intestine

A

C

B

D Fig. 104.10  Duodenal biopsy specimen (A,B) from a patient with autoimmune enteropathy with a chronic enteric inflammation pattern (nongranulomatous chronic idiopathic enterocolitis). A, Histopathologic features include villus atrophy, diffuse infiltration of lamina propria with inflammatory cells, and crypt abscesses (arrow). B, High-power view demonstrates crypt infiltration by neutrophils (arrow). (H&E stain.). Colonic biopsies (C,D) showing a GVHD-like pattern of autoimmune enteropathy with a mixed inflammatory infiltrate, increased crypt epithelial apoptosis, and mild crypt architectural distortion. C, H&E stain D, immunohistochemical staining for caspase 3 highlighting apoptosis. (Courtesy Cord Langner, MD.)

food and digestive secretions and reduced intestinal absorption of nutrients. Some of the steatorrhea in hyperthyroid patients might result from hyperphagia with increased dietary intake of fat.285 An increased number of lymphocytes and plasma cells and some degree of edema in small intestinal biopsy specimens have been found in patients with steatorrhea and hyperthyroidism; villus architecture is normal.283 Absorption of glucose and d-xylose is normal in hyperthyroid patients with and without malabsorption.285 Fat malabsorption tends to normalize when patients attain a euthyroid state.283,285 In patients with autoimmune thyroid diseases, an increased prevalence of celiac disease276 and PBC,275 both of which can

result in fat malabsorption, has been recognized. The prevalence of celiac disease in patients with autoimmune thyroid disease is approximately 2% to 4%.276 Cobalamin malabsorption resulting from autoimmune gastritis is found in a considerable number of patients with autoimmune thyroid disease.28,275 

Diabetes Mellitus Chronic diarrhea is common in patients with diabetes mellitus, especially in those with long-standing diabetes mellitus type 1.286 Mild steatorrhea often is present in patients with diabetic diarrhea and also in diabetic patients who do not complain of diarrhea.287

CHAPTER 104  Maldigestion and Malabsorption

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104

A

B Fig. 104.11  Chromogranin A immunohistochemical staining of enteroendocrine cells in duodenal biopsy specimens obtained from a normal subject (A) and from a patient with malabsorption associated with APECED (B). In B, enteroendocrine cells are absent. See text for details.

Although the pathophysiologic mechanism of malabsorption and diarrhea in patients with diabetes mellitus is unknown, poor glycemic control is an important cofactor.288 Most of these patients have signs of autonomic neuropathy, such as orthostatic hypotension, impotence, bladder dysfunction, incontinence, inappropriate heart rate variability, and abnormal sweating.289 Therefore in some patients, diarrhea and malabsorption have been attributed to rapid gastric emptying and rapid intestinal transit, causing impaired mixing of nutrients with digestive secretions and decreased contact time between nutrients and the intestinal mucosa. The clinician has to be aware that certain treatable diseases, such as celiac disease,290 SIBO,289 and pancreatic insufficiency,291 can be associated with diabetes mellitus. In patients with diabetes mellitus type 1, a high prevalence (3% to 8%) of celiac disease has been reported from screening studies, but most of these patients are asymptomatic.292 Markedly reduced pancreatic exocrine function, as determined by fecal elastase measurement, has been reported in 30% of patients with type 1 diabetes and 17% with type 2 diabetes, compared with 5% of control subjects. In 40% of diabetic patients with reduced fecal elastase levels, fat malabsorption with fecal fat output of greater than 10 g/day was detected.293 GI symptoms and steatorrhea in these patients did not correlate with fecal elastase levels.291,293 In addition, the unresolved specificity of elastase raises the possibility that not all of these patients truly had pancreatic insufficiency.294 The presence of cobalamin malabsorption caused by autoimmune atrophic gastritis is increased three- to fivefold in patients with diabetes mellitus type 1 compared with the nondiabetic population.295 Ingested carbohydrates are malabsorbed in patients receiving acarbose as part of their diabetes treatment, which in turn can lead to symptoms of diarrhea and malabsorption. Foods recommended to diabetics because they contain poorly absorbable carbohydrates, such as fructose or sorbitol, can result in bloating and diarrhea. 

Metabolic Bone Disease Special consideration has to be given to osteoporosis and osteomalacia in malabsorptive diseases. Patients with these metabolic bone diseases usually do not present with suggestive symptoms or abnormalities either on physical examination or on routine laboratory examinations. Reduced bone mineral density is a common finding in patients with gastric resection,296 celiac disease,297 and lactose malabsorption.298 Osteoporosis has been suggested to result from calcium malabsorption or reduced calcium intake,

which leads to secondary hyperparathyroidism, which in turn increases bone turnover and cortical bone loss; vitamin D malabsorption is probably of lesser importance. Although up to one half of patients on a gluten-free diet have osteoporosis,298 some studies have shown significant improvement in bone mineral density 1 year after starting a gluten-free diet.299 In Crohn disease, which may be accompanied by malabsorption, other factors such as glucocorticoid use or testosterone deficiency300 may contribute to decreased bone mass. In addition to treating the underlying cause of malabsorption, calcium supplementation is needed to ensure a daily intake of 1500 mg of calcium. Vitamin D deficiency also must be corrected. If osteoporosis is present, bisphosphonate treatment is suggested.297 Nutritional management is discussed in more detail in Chapters 5 and 6. 

GENERAL APPROACH TO MANAGEMENT Treatment of malabsorptive diseases must be directed against the underlying condition if possible, and nutritional deficits must be corrected. The reader is referred to the relevant chapters of this book for discussion about treatment of specific diseases and their nutritional management. In patients with abdominal bloating and gas-related complaints due to sugar malabsorption, a diet with reduced content of poorly absorbable carbohydrates (e.g., fructose, sorbitol, fermentable dietary fibers) is an effective long-term therapy.301 Interest has recently surrounded the potential role of fermentable oligosaccharides, disaccharides, monosaccharides, and polyols in the treatment of patients with symptoms of IBS.173 In pancreatic insufficiency, disorders of intestinal fat absorption, and short bowel syndrome, medium-chain triglycerides can be used as a source of dietary calories. In patients with short bowel syndrome and some remaining colon, colonic salvage capacity can be used to regain calories from carbohydrates;302 these patients should consume a diet rich in carbohydrates and medium-chain triglycerides. Teduglutide, a glucagon-like peptide 2 analog, has been shown to reduce the amount of malabsorbed calories and the need for parenteral volume supplementation.303 The suggested mechanisms for the proabsorptive effects of teduglutide are increased growth of intestinal mucosa, reduced gastric emptying and secretion, and prolonged intestinal transit time.303,304 In BAM after extensive ileal resections, intestinal fat absorption can be improved markedly by oral administration of natural conjugated BAs or synthetic cholylsarcosine.113,185 Replacement of conjugated BAs also reduces urinary oxalate excretion and, therefore, should protect against development of kidney

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stones.185 Patients with cystic fibrosis or short bowel syndrome who are unable to absorb vitamin D from their diet may benefit from treatment with an ultraviolet lamp, which emits ultraviolet radiation similar to sunlight.305 In patients with malabsorption and an intact colon, fluid depletion must be avoided to prevent kidney stones associated with hyperoxaluria.306 In patients with malabsorption syndrome, special care should be given to the replacement of vitamins, iron, calcium, and trace elements to avoid deficiency syndromes (see Chapters 5 and 6).

In patients with diarrhea, symptomatic treatment with opiates or loperamide can increase the time available for absorption of nutrients. In patients on home parenteral nutrition, catheter-related bloodstream infections remain the major threat. A prevention strategy using taurolidine, which is a potent antimicrobial agent, has been shown to reduce the risk of these infections.307 Full references for this chapter can be found on www.expertconsult.com.

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