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Sleisenger and Fordtran’s Gastrointestinal and Liver Disease

PATHOPHYSIOLOGY | DIAGNOSIS | MANAGEMENT

EDITORS

MARK FELDMAN, MD

Chairman of Internal Medicine

Texas Health Presbyterian Hospital Dallas

Clinical Professor of Internal Medicine

University of Texas Southwestern Medical School Dallas, Texas

LAWRENCE S. FRIEDMAN, 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

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

ASSOCIATE EDITORS

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

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

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

Copyright © 2021 by Elsevier, Inc. All rights reserved.

ISBN: 978-0-323-60962-3

Volume 1: 978-0-323-76078-2

Volume 2: 978-0-323-76077-5

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

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

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

Todd H. Baron, MD

Professor of Medicine

Division of Gastroenterology and Hepatology

University of North Carolina Chapel Hill, North Carolina, United States

Bradley A. Barth, MD, MPH

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

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

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

Yangzom D. Bhutia, DVM, PhD

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

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

Marcello Costa, MD

Matthew Flinders Distinguished Professor and Professor of Neurophysiology

Physiology

Flinders University

Adelaide, South Australia, Australia

Thomas G. Cotter, MD

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

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

Flinders Medical Centre

Human Physiology

Flinders University

Adelaide, South Australia, Australia

J. Marcus Downs, 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

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

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

B. Joseph Elmunzer, MD, MSc

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

Charles O. Elson, MD

Professor of Medicine and Microbiology

Basil I. Hirschowitz Chair in Gastroenterology

University of Alabama at Birmingham Birmingham, Alabama, United States

Grace H. Elta, MD

Professor Emeritus

Formerly the H. Marvin Pollard

Collegiate Professor

Division of Gastroenterology

University of Michigan

Ann Arbor, Michigan, United States

Michael B. Fallon, MD

Professor of Medicine

Gastroenterology, Hepatology, and Nutrition

University of Arizona Chair

Department of Internal Medicine

University of Arizona—Phoenix

Phoenix, Arizona, United States

Geoffrey C. Farrell, MD

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

Mark Feldman, 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

Nielsen Q. Fernandez-Becker, MD

Clinical Associate Professor of Medicine

Division of Gastroenterology and Hepatology

Stanford University

Redwood City, California, United States

Paul Feuerstadt, 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

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

Alexander C. Ford, MBChB, MD

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

John S. Fordtran, MD

Internal Medicine, Division of Gastroenterology

Baylor University Medical Center

Dallas, Texas, United States

Chris E. Forsmark, MD

Professor and Chief

Division of Gastroenterology, Hepatology, and Nutrition

University of Florida

Gainesville, Florida, United States

Lawrence S. Friedman, 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, United States

Scott Fung, MD

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

Marc G. Ghany, MD, MHSc

Liver Diseases Branch

National Institute of Diabetes and Digestive and Kidney Diseases

National Institutes of Health

Bethesda, Maryland, United States

Pere Ginès, MD, PhD

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

Peter H.R. Green, MD

Phyllis and Ivan Seidenberg Professor of Medicine

Columbia University Medical Center New York, New York, United States

David A. Greenwald, MD

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

David J. Hass, MD

Associate Clinical Professor of Medicine

Division of Digestive Diseases

Yale University School of Medicine

New Haven, Connecticut, United States

David M. Hockenbery, MD Member

Clinical Research

Fred Hutchinson Cancer Research Center

Professor of Medicine

Division of Gastroenterology University of Washington Seattle, Washington, United States

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

Hyman Professor of Medicine

Division of Gastroenterology

University of Tennessee Health Science Center

Memphis, Tennessee, United States

Patrick A. Hughes, PhD

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

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

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

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

Lawrence A. Mark, MD, PhD

Associate Professor of Clinical Dermatology

Department of Dermatology

Indiana University School of Medicine

Indianapolis, Indiana, United States

Paul Martin, MD, FRCP, FRCPI

Chief, Division of Gastroenterology and Hepatology

University of Miami

Miami, Florida, United States

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

Stephen A. McClave, MD

Professor and Director of Clinical Nutrition

Department of Medicine

University of Louisville School of Medicine

Louisville, Kentucky, United States

Shilpa Mehra, MD

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

Pediatric Gastroenterology Fellow

Department of Pediatric Gastroenterology

University of Texas Southwestern Medical Center

Dallas, Texas, United States

Joanna M.P. Melia, MD

Assistant Professor of Medicine

Johns Hopkins University School of Medicine

Baltimore, Maryland, 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

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

Department of Internal Medicine

Division of Hematology and Oncology

Texas Health Presbyterian Hospital

Dallas

Dallas, Texas, United States

John Magaña Morton, MD, MPH, MHA

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

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

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

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

Mark L. Norris, BSc (Hon), MD

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

Stephen J. Pandol, MD Professor Medicine

Cedars-Sinai Medical Center

Los Angeles, California, United States

John E. Pandolfino, MD, MSCI

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

Patrick R. Pfau, MD

Professor, Chief of Clinical Gastroenterology

Section of Gastroenterology and Hepatology

University of Wisconsin School of Medicine and Public Health

Madison, Wisconsin, United States

Angela K. Pham, MD

Clinical Assistant Professor

Gastroenterology, Hepatology, and Nutrition

University of Florida

Gainesville, Florida, United States

Kimberly L. 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

Gastroenterologist

Gastroenterology and Hepatology

Mayo Clinic Rochester, Minnesota

Michael Quante, PD, Dr Technische Universität München II Medizinische Klinik Klinikum rechts der Isar München, Germany

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

Christopher K. Rayner, MBBS, PhD

Professor

Adelaide Medical School

University of Adelaide

Consultant Gastroenterologist

Department of Gastroenterology and Hepatology

Royal Adelaide Hospital

Adelaide, South Australia, Australia

Ahsan Raza, MD

General and Colorectal Surgery

Rapides Surgical Specialists

Alexandria, Louisiana, United States

Miguel D. Regueiro, MD

Chair and Professor of Medicine

Department of Gastroenterology and Hepatology

Cleveland Clinic, Digestive Disease and Surgery Institute

Cleveland, Ohio, United States

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

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

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

George S. Sarosi Jr., MD

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

Vijay H. Shah, MD

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

G. Thomas Shires, MD

John P. Thompson Chair

Surgical Services

Texas Health Presbyterian Hospital

Dallas

Dallas, Texas, United States

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

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

David C. Whitcomb, MD, PhD Professor Medicine, Cell Biology and Molecular Physiology, and Human Genetics

University of Pittsburgh and UPMC Pittsburgh, Pennsylvania, United States

C. Mel Wilcox, MD, MSPH Division of Gastroenterology and Hepatology

University of Alabama at Birmingham Birmingham, Alabama, United States

Christopher G. Willett, MD Professor and Chairman Radiation Oncology

Duke University Durham, North Carolina, United States

Joseph C. Yarze, MD

Assistant Professor of Medicine

Harvard Medical School

Associate Physician

Division of Gastroenterology

Massachusetts General Hospital Boston, Massachusetts, United States

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

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.

The Sleisenger and Fordtran Editors

Editions 5-11

Editions 7-11

Editions 8-11

Editions

Editions 5-6

Mark Feldman, MD
Lawrence S. Friedman, MD
Lawrence J. Brandt, MD
Raymond T. Chung, MD Edition 11
David T. Rubin, MD Edition 11
C. Mel Wilcox, MD Edition 11
Marvin H. Sleisenger, MD
Editions 1-7
John S. Fordtran, MD
1-5
Bruce F. Scharschmidt, MD

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 disorders discussed—a first for a medical textbook. Since the auspicious 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.

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.

Lawrence

Lawrence

Mark Feldman, MD
S. Friedman, MD
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.

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

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

Biology of the Gastrointestinal Tract PART I

Cellular Growth and Neoplasia

CHAPTER OUTLINE

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

G1/S checkpoint

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

Cyclin B
Cyclin A
Cyclin D/E
CDK2
Cyclin A

Death Receptors (TNFR1, Fas, etc.)

Cellular Stress (Radiation, chemotherapy, etc.)

Mitochondria

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

Caspase-8

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

genesis. In the absence of a Wnt signal (left top), cytosolic β-catenin is regulated by the destruction complex, Fig. 1.3 The Wnt signaling pathway is an important regulator of intestinal epithelial cell proliferation and tumori-

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 cyto-

plasmic 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.

GSK-3β

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

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

Chromosomal

Microsatellite instability

APC COX2 overexpression

Normal Hyperproliferative epithelium Early Serrated Polyp

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

Sessile Serrated Adenoma

Mutations in genes with polynucleotide tracks

MLH1 promoter methylation and silencing (˜10%)

Normal Hyperproliferative epithelium Early Serrated Polyp Late Sessile Serrated Adenoma

or BRAF mutations

CpG island methylation and silencing of tumor suppressor genes IGF2R, BAX, TGFB2R, etc. Carcinoma

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

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