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11 TH
Sleisenger and Fordtran’s EDITION
Gastrointestinal
and Liver Disease
PATHOPHYSIOLOGY | DIAGNOSIS | MANAGEMENT
EDITORS ASSOCIATE EDITORS

MARK FELDMAN, MD RAYMOND T. CHUNG, MD
Chairman of Internal Medicine Director of Hepatology, Vice Chief, Gastroenterology
Texas Health Presbyterian Hospital Dallas Division of Gastroenterology
Clinical Professor of Internal Medicine Massachusetts General Hospital and Harvard Medical School
University of Texas Southwestern Medical School Associate Member, Broad Institute
Dallas, Texas Boston, Massachusetts
LAWRENCE S. FRIEDMAN, MD DAVID T. RUBIN, MD

Professor of Medicine Joseph B. Kirsner Professor of Medicine
Harvard Medical School Chief, Section of Gastroenterology, Hepatology, and Nutrition
Professor of Medicine Department of Medicine
Tufts University School of Medicine University of Chicago
Boston, Massachusetts Chicago, Illinois
The Anton R. Fried, MD, Chair
Department of Medicine
Newton-Wellesley Hospital C. MEL WILCOX, MD, MSPH
Newton, Massachusetts Division of Gastroenterology and Hepatology
Assistant Chief of Medicine University of Alabama at Birmingham
Massachusetts General Hospital Birmingham, Alabama
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
Elsevier
1600 John F. Kennedy Blvd.
Ste 1800
Philadelphia, PA 19103-2899
SLEISENGER AND FORDTRAN’S GASTROINTESTINAL AND LIVER DISEASE,

ELEVENTH EDITION ISBN: 978-0-323-60962-3
Volume 1: 978-0-323-76078-2
Volume 2: 978-0-323-76077-5
Copyright © 2021 by Elsevier, Inc. All rights reserved.
No part of this publication may be reproduced or transmitted in any form or by any means, electronic or
mechanical, including photocopying, recording, or any information storage and retrieval system, without
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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
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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
Printed in Canada
Last digit is the print number: 9 8 7 6 5 4 3 2 1

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 Bruce R. Bacon, MD William Bernal, MD

Senior Physician in Hepatology Professor of Internal Medicine Professor
Department of Gastroenterology Division of Gastroenterology and Liver Intensive Therapy Unit
Beth Israel Deaconess Medical Center Hepatology King’s College Hospital
Boston, Massachusetts, United States Saint Louis University School of London, United Kingdom
Medicine
Rakesh Aggarwal, MD, DM Adil E. Bharucha, MBBS, MD
St. Louis, Missouri, United States
Director Professor of Medicine
Jawaharlal Institute of Postgraduate William F. Balistreri, MD Division of Gastroenterology and
Medical Education and Research Director, Pediatric Liver Care Center Hepatology
Puducherry, India Gastroenterology, Hepatology, and Mayo Clinic
Nutrition Rochester, Minnesota, United States
Taymeyah Al-Toubah, MPH
Cincinnati Children’s Hospital Medical
Gastroenterology and Oncology Taft P. Bhuket, MD
Center
H. Lee Moffitt Cancer Center Associate Clinical Professor of Medicine
Cincinnati, Ohio, United States
Tampa, Florida, United States Division of Gastroenterology
Todd H. Baron, MD University of California, San Francisco
Jaime Almandoz, MD
Professor of Medicine San Francisco, California
Assistant Professor
Division of Gastroenterology and Chief of Gastroenterology and
Department of Internal Medicine,
Hepatology Hepatology
Division of Endocrinology
University of North Carolina Director of Endoscopy
University of Texas Southwestern
Chapel Hill, North Carolina, United Alameda Health System
Dallas, Texas, United States
States Oakland, California, United States
Ashwin N. Ananthakrishnan, MD, MPH
Bradley A. Barth, MD, MPH Yangzom D. Bhutia, DVM, PhD
Associate Professor of Medicine
Professor Assistant Professor
Harvard Medical School
Department of Pediatrics Cell Biology and Biochemistry
University of Texas Southwestern Texas Tech University Health Sciences
Massachusetts General Hospital
Dallas, Texas, United States Center
Boston, Massachusetts, United States
Lubbock, Texas, United States
Lee M. Bass, MD
Karin L. Andersson, MD, MPH
Associate Professor of Pediatrics J. Andrew Bird, MD
Assistant Professor of Medicine
Gastroenterology, Hepatology, and Associate Professor
Nutrition Pediatrics, Division of Allergy and
Hepatologist
Ann and Robert H. Lurie Children’s Immunology
Hospital of Chicago University of Texas Southwestern
Northwestern University Feinberg Medical Center
School of Medicine Director
Farshid Araghizadeh, MD, MBA Chicago, Illinois, United States Food Allergy Center
Colon and Rectal Surgeon Children’s Medical Center
Alex S. Befeler, MD
Texas Digestive Disease Consultants Dallas, Texas, United States
Professor of Internal Medicine
(TDDC) and The GI Alliance (TGIA)
Medical Director of Liver Boris Blechacz, MD, PhD
Dallas–Fort Worth, Texas, United States
Transplantation Clinical Associate Professor of Internal
Louis J. Aronne, MD Department of Internal Medicine Medicine
Sanford I. Weill Professor of Metabolic Saint Louis University Gastroenterology and Hepatology
Research St. Louis, Missouri, United States Palmetto Health—University of South
Department of Medicine Carolina
Mark Benson, MD
Weill Cornell Medicine Columbia, South Carolina, United States
New York, New York, United States
Section of Gastroenterology and Diego V. Bohórquez, PhD
Fernando Azpiroz, MD, PhD Hepatology Assistant Professor
Chief University of Wisconsin School of Departments of Medicine and
Department of Gastroenterology Medicine and Public Health Neurobiology
University Hospital Vall d’Hebron Madison, Wisconsin, United States Duke University Medical Center
Professor of Medicine Durham, North Carolina, United States
Universitat Autònoma de Barcelona
Barcelona, Spain
vi
Contributors vii
Jan Bornschein, MD Eugene B. Chang, MD Paul A. Dawson, PhD

Translational Gastroenterology Unit Martin Boyer Professor Professor
John Radcliffe Hospital Department of Medicine Pediatrics— Gastroenterology,

Oxford University Hospitals University of Chicago Hepatology, and Nutrition
Oxford, United Kingdom Chicago, Illinois, United States Emory University
Atlanta, Georgia, United States
Christopher L. Bowlus, MD Joseph G. Cheatham, MD
Professor and Chief Associate Professor of Medicine Gregory de Prisco, MD
Division of Gastroenterology and Department of Medicine Diagnostic Radiologist
Hepatology Uniformed Services University Department of Radiology
University of California Davis Bethesda, Maryland Baylor University Medical Center
Sacramento, California, United States Program Director Director of Medical Education
Gastroenterology Fellowship American Radiology Associates
Lawrence J. Brandt, MD
Naval Medical Center San Diego Dallas, Texas, United States
Professor of Medicine and Surgery
San Diego, California, United States
Albert Einstein College of Medicine Jill K. Deutsch, MD
Emeritus Chief Shivakumar Chitturi, MD Clinical Fellow
Division of Gastroenterology Associate Professor Department of Internal Medicine
Montefiore Medical Center Australian National University Section of Digestive Diseases
Bronx, New York, United States Senior Staff Hepatologist Yale New Haven Hospital—Yale
The Canberra Hospital University School of Medicine
Robert Scott Bresalier, MD
Australian Capital Territory, Australia New Haven, Connecticut, United States
Professor of Medicine
Lydia and Birdie J Resoft Distinguished Daniel C. Chung, MD Kenneth R. DeVault, MD
Professor in GI Oncology Associate Professor of Medicine Professor of Medicine
Gastroenterology, Hepatology, and Harvard Medical School Mayo Clinic College of Medicine
Nutrition Division of Gastroenterology Jacksonville, Florida, United States
The University of Texas MD Anderson Massachusetts General Hospital
Adrian M. Di Bisceglie, MD
Cancer Center Medical Co-Director
Professor of Internal Medicine
Houston, Texas, United States Center for Cancer Risk Analysis
Department of Internal Medicine
Massachusetts General Hospital Cancer
Simon J.H. Brookes, PhD Saint Louis University
Center
Professor St. Louis, Missouri, United States
Human Physiology
John K. DiBaise, MD
College of Medicine, Flinders University Raymond T. Chung, MD
Adelaide, South Australia, Australia Director of Hepatology, Vice Chief,
Division of Gastroenterology and
Gastroenterology
Alan L. Buchman, MD, MSPH Hepatology
Professor of Clinical Surgery Mayo Clinic
Massachusetts General Hospital and
University of Illinois at Chicago Scottsdale, Arizona, United States
Medical Director
Associate Member, Broad Institute Philip G. Dinning, PhD
Intestinal Rehabilitation and Transplant
Boston, Massachusetts, United States Flinders Medical Centre
Center
Human Physiology
Chicago, Illinois, United States Marcello Costa, MD
Flinders University
Matthew Flinders Distinguished
Ezra Burstein, MD, PhD Adelaide, South Australia, Australia
Professor and Professor of
Professor
Neurophysiology J. Marcus Downs, MD
Departments of Internal Medicine and
Physiology Program Director
Molecular Biology
Flinders University Colon and Rectal Surgery
UT Southwestern Medical Center
Adelaide, South Australia, Australia Texas Health Resources
Clinical Professor of Surgery
Thomas G. Cotter, MD
Andres F. Carrion, MD Colon and Rectal Surgery
Gastroenterology Fellow
Assistant Professor of Clinical Medicine University of Texas Southwestern
Section of Gastroenterology,
Program Director, Transplant Medical School
Hepatology, and Nutrition
Hepatology Fellowship Dallas, Texas, United States
University of Chicago Medicine
Chicago, Illinois, United States Douglas A. Drossman, MD
Hepatology
Professor Emeritus of Medicine and
University of Miami Albert J. Czaja, MD
Psychiatry
Miami, Florida, United States Professor Emeritus of Medicine
Division of Digestive Disease and
Gastroenterology and Hepatology
Scott Celinski, MD Nutrition
Mayo Clinic College of Medicine and
Surgical Oncologist University of North Carolina
Science
Department of Surgery President
Rochester, Minnesota, United States
Baylor University Medical Center Center for Education and Practice of
Dallas, Texas, United States Brian G. Czito, MD Biopsychosocial Care
Professor Chapel Hill, North Carolina
Francis K.L. Chan, MBChB(Hons), MD,
Radiation Oncology President
DSc
Duke University Medical Center Drossman Gastroenterology PLLC
Durham, North Carolina, United States Durham, North Carolina, United States
Department of Medicine and
Therapeutics
Chinese University of Hong Kong
Hong Kong, China
viii Contributors
Kerry B. Dunbar, MD, PhD Michael B. Fallon, MD Alexander C. Ford, MBChB, MD

Section Chief, VA Gastroenterology Professor of Medicine Professor of Gastroenterology
Section Gastroenterology, Hepatology, and and Honorary Consultant
Department of Medicine– Nutrition Gastroenterologist
Gastroenterology and Hepatology University of Arizona Leeds Institute of Medical Research
VA North Texas Healthcare System– Chair St. James’s University of Leeds
Dallas VA Medical Center Department of Internal Medicine Leeds Gastroenterology Institute
Associate Professor of Medicine University of Arizona—Phoenix Leeds Teaching Hospitals Trust
Department of Medicine–Division of Phoenix, Arizona, United States Leeds, West Yorkshire, United Kingdom
Geoffrey C. Farrell, MD John S. Fordtran, MD
Professor, Hepatic Medicine Internal Medicine, Division of
Medical School
Australian National University Gastroenterology
Senior Staff Hepatologist Baylor University Medical Center
John E. Eaton, MD The Canberra Hospital Dallas, Texas, United States
Assistant Professor of Medicine Australian Capital Territory, Australia
Chris E. Forsmark, MD
Jordan J. Feld, MD, MPH Professor and Chief
Associate Professor of Medicine Division of Gastroenterology,
Hepatology
University of Toronto Hepatology, and Nutrition
Mayo Clinic
Research Director University of Florida
Toronto Centre for Liver Disease Gainesville, Florida, United States
Steven A. Edmundowicz, MD Senior Scientist
Lawrence S. Friedman, MD
Professor of Medicine Sandra Rotman Centre for Global
Interim Director, Division of Health
Gastroenterology and Hepatology Toronto General Hospital
University of Colorado Anschutz Toronto, Ontario, Canada
Tufts University School of Medicine
Medical Campus
Mark Feldman, MD Boston, Massachusetts
Aurora, Colorado, United States
Chairman of Internal Medicine The Anton R. Fried, MD, Chair
David E. Elliott, MD, PhD Texas Health Presbyterian Hospital Department of Medicine
University of Iowa Carver College of Dallas Newton-Wellesley Hospital
Medicine Clinical Professor of Internal Medicine Newton, Massachusetts
Department of Internal Medicine University of Texas Southwestern Assistant Chief of Medicine
Division of Gastroenterology and Medical School Massachusetts General Hospital
Hepatology Dallas, Texas, United States Boston, Massachusetts, United States
Iowa City VAHCS
Nielsen Q. Fernandez-Becker, MD Scott Fung, MD
Clinical Associate Professor of Medicine Associate Professor
Veterans Administration Health Care
Division of Gastroenterology and Department of Medicine
System
Hepatology University of Toronto
Iowa City, Iowa, United States
Stanford University Staff Hepatologist
B. Joseph Elmunzer, MD, MSc Redwood City, California, United States University Health Network
Peter B. Cotton Professor of Medicine Toronto General Hospital
Paul Feuerstadt, MD
and Endoscopic Innovation Toronto, Ontario, Canada
Attending Physician
Gastroenterology Vadivel Ganapathy, PhD
Hepatology
Gastroenterology Center of Connecticut Professor
Medical University of South Carolina,
Hamden, Connecticut Cell Biology and Biochemistry
Charleston
Assistant Clinical Professor of Medicine Texas Tech University Health Sciences
Charleston, South Carolina, United
Gastroenterology Center
States
Yale University School of Medicine Lubbock, Texas, United States
Charles O. Elson, MD New Haven, Connecticut, United States
Professor of Medicine and Microbiology John J. Garber, MD
Peter Fickert, Prof Instructor in Medicine
Basil I. Hirschowitz Chair in
Division of Gastroenterology and Harvard Medical School
Gastroenterology
Hepatology Assistant in Medicine
University of Alabama at Birmingham
Medical University of Graz Division of Gastroenterology
Birmingham, Alabama, United States
Graz, Austria Massachusetts General Hospital
Grace H. Elta, MD Boston, Massachusetts, United States
Robert E. Fleming, MD
Professor Emeritus
Professor of Pediatrics Praveen Ramakrishnan Geethakumari,
Formerly the H. Marvin Pollard
Saint Louis University School of MD, MS
Collegiate Professor
Medicine Assistant Professor
St. Louis, Missouri, United States Division of Medical Oncology
University of Michigan
Ann Arbor, Michigan, United States Department of Internal Medicine
Medical Center
Contributors ix
Marc G. Ghany, MD, MHSc David J. Hass, MD M. Nedim Ince, MD

Liver Diseases Branch Associate Clinical Professor of Medicine University of Iowa Carver College of
National Institute of Diabetes and Division of Digestive Diseases Medicine

Digestive and Kidney Diseases Yale University School of Medicine Iowa City, Iowa, United States
National Institutes of Health New Haven, Connecticut, United States Department of Internal Medicine
Bethesda, Maryland, United States Division of Gastroenterology and
David M. Hockenbery, MD
Hepatology
Pere Ginès, MD, PhD Member
Iowa City VAHCS
Chairman Clinical Research
Liver Unit Fred Hutchinson Cancer Research
Veterans Administration Health Care
Hospital Clinic Barcelona Center
System
Full Professor of Medicine Professor of Medicine
Iowa City, Iowa, United States
University of Barcelona Division of Gastroenterology
Principal Investigator University of Washington Rachel B. Issaka, MD, MAS
Institut d’Investigacions Biomediques Seattle, Washington, United States Assistant Member
August Pi i Sunyer (IDIBAPS) Clinical Research and Public Health
Christoph Högenauer, MD
Barcelona, Spain Science Divisions
Fred Hutchinson Cancer Research Center
Robert E. Glasgow, MD Department of Internal Medicine
Assistant Professor
Professor and Vice Chairman Medical University of Graz
Department of Medicine, Division of
Surgery Graz, Austria
Gastroenterology
University of Utah
Jacinta A. Holmes, MBBS, PhD University of Washington
Salt Lake City, Utah, United States
Division of Gastroenterology Seattle, Washington, United States
Gregory J. Gores, MD Massachusetts General Hospital
Johanna C. Iturrino, MD
Executive Dean for Research, Professor Boston, Massachusetts, United States
of Medicine Gastroenterology
Division of Gastroenterology and St. Vincent’s Hospital
Beth Israel Deaconess Medical Center
Hepatology University of Melbourne
Mayo Clinic Fitzroy, Victoria, Australia
Rochester, Minnesota, United States Theodore W. James, MD
Colin W. Howden, MD
Fellow
Peter H.R. Green, MD Hyman Professor of Medicine
Phyllis and Ivan Seidenberg Professor of Division of Gastroenterology
University of North Carolina
Medicine University of Tennessee Health Science
Chapel Hill, North Carolina, United
Columbia University Medical Center Center
States
New York, New York, United States Memphis, Tennessee, United States
Harry L.A. Janssen, MD, PhD
David A. Greenwald, MD Patrick A. Hughes, PhD
Director of Clinical Gastroenterology Centre for Nutrition and
and Endoscopy Gastrointestinal Diseases
University of Toronto
Division of Gastroenterology Adelaide Medical School
Toronto, Ontario, Canada
Mount Sinai Hospital University of Adelaide
New York, New York, United States South Australian Health and Medical Dennis M. Jensen, MD
Research Institute Professor of Medicine
C. Prakash Gyawali, MD, MRCP
Nutrition and Metabolism Professor of Medicine–Gastrointestinal
Adelaide, South Australia, Australia David Geffen School of Medicine at
UCLA
Department of Medicine Sohail Z. Husain, MD
Staff Physician
Washington University in St. Louis Professor of Pediatrics
Medicine-Gastrointestinal
St. Louis, Missouri, United States Division of Gastroenterology,
VA Greater Los Angeles Healthcare
Hazem Hammad, MD System
Stanford University School of Medicine
Assistant Professor of Medicine Key Investigator
Stanford, California, United States
Division of Gastroenterology and Director, Human Studies Core and
Hepatology Christopher D. Huston, MD Gastrointestinal Hemostasis Research
University of Colorado Anschutz Professor Unit
Medical Campus Medicine, Microbiology, and Molecular CURE Digestive Diseases Research
Aurora, Colorado, United States Genetics Center
University of Vermont College of Los Angeles, California, United States
Heinz F. Hammer, MD
Medicine
Associate Professor of Medicine Pamela J. Jensen, MD
Attending Physician
Department of Internal Medicine Department of Pathology
Medicine and Infectious Diseases
Medical University Texas Health Presbyterian Hospital
Fletcher Allen Health Care
Graz, Austria Dallas
Burlington, Vermont, United States
Stephen A. Harrison, MD
Visiting Professor of Hepatology
Radcliffe Department of Medicine
University of Oxford
Oxford, United Kingdom
x Contributors
D. Rohan Jeyarajah, MD Jonathan D. Kaunitz, MD Brian E. Lacy, MD, PhD

Chair of Surgery Professor of Medicine and Surgery Senior Associate Consultant
Assistant Chair of Clinical Sciences UCLA School of Medicine Division of Gastroenterology
Head of Surgery Attending Gastroenterologist Mayo Clinic
TCU and UNTHSC School of West Los Angeles Veterans Affairs Jacksonville, Florida, United States
Medicine Medical Center
Anne M. Larson, MD
Fort Worth, Texas Los Angeles, California, United States
Director, Gastrointestinal Services
Laurie Keefer, PhD Division of Gastroenterology/
Methodist Richardson Medical Center
Professor Hepatology
Director, HPB/UGI Fellowship
Medicine and Psychiatry University of Washington
Associate Program Director, General
Icahn School of Medicine at Mount Sinai Seattle, Washington, United States
Surgery Residency Program
Methodist Richardson Medical Center James Y.W. Lau, MD
Richardson, Texas, United States Ciarán P. Kelly, MD Professor of Surgery
Professor of Medicine Department of Surgery
Peter J. Kahrilas, MD
Gastroenterology The Chinese University of Hong Kong
Gilbert H. Marquardt Professor of
Harvard Medical School Director
Medicine
Fellowship Program Director Endoscopy Centre
Feinberg School of Medicine
Gastroenterology Prince of Wales Hospital
Northwestern University
Beth Israel Deaconess Medical Center Hong Kong, China
Northwestern Medicine Ryan Law, DO
Chicago, Illinois, United States Sahil Khanna, MBBS, MS Assistant Professor
Associate Professor of Medicine Division of Gastroenterology
Vishal Kaila, BS, MD
Gastroenterology and Hepatology University of Michigan
Resident
Mayo Clinic Ann Arbor, Michigan, United States
Internal Medicine
Texas Health Presbyterian Benjamin Lebwohl, MD, MS
Dallas, Texas, United States Arthur Y. Kim, MD Assistant Professor of Medicine and
Associate Professor of Medicine Epidemiology
Patrick S. Kamath, MD
Harvard Medical School Columbia University Medical Center
Division of Infectious Diseases New York, New York, United States
Hepatology Anthony J. Lembo, MD
Consultant Professor of Medicine
Gastroenterology and Hepatology Kenneth L. Koch, MD Department of Medicine
Mayo Clinic College of Medicine and Professor of Medicine Beth Israel Deaconess Medical Center
Science Department of Medicine Boston, Massachusetts, United States
Rochester, Minnesota, United States Section on Gastroenterology and
Cynthia Levy, MD
Hepatology
Gilaad G. Kaplan, MD, MPH Professor of Medicine
Wake Forest University School of
Professor of Medicine Division of Hepatology
Medicine
University of Calgary University of Miami
Winston-Salem, North Carolina, United
Calgary, Alberta, Canada Miami, Florida, United States
States
Purna Kashyap, MBBS Blair Lewis, MD
Benjamin Kulow, MD
Associate Professor of Medicine Medical Director
Colon and Rectal Surgeon
Physiology and Biomedical Engineering Carnegie Hill Endoscopy
Saint Luke’s Health System
Mayo Clinic Clinical Professor of Medicine
Kansas City, Missouri, United States
Rochester, Minnesota, United States Mount Sinai Medical Center
Rekha B. Kumar, MD, MS New York, New York, United States
Jennifer Katz, MD
Assistant Professor of Medicine James H. Lewis, MD
Endocrinology, Diabetes, and
Division of Gastroenterology Professor of Medicine
Metabolism
Montefiore Medical Center Director of Hepatology
Weill Cornell Medical College
Bronx, New York, United States Division of Gastroenterology
Attending Physician
Georgetown University Medical Center
David A. Katzka, MD Endocrinology, Diabetes, and
Washington, DC, United States
Professor of and Consultant in Medicine Metabolism
Gastroenterology New York Presbyterian Hospital Rodger A. Liddle, MD
Mayo Clinic New York, New York, United States Professor of Medicine
Rochester, Minnesota, United States Department of Medicine
Vidhya Kunnathur, MD
Duke University Medical Center
Debra K. Katzman, MD, FRCPC Assistant Professor
Durham, North Carolina, United States
Professor of Pediatrics Division of Digestive Diseases
Department of Pediatrics University of Cincinnati Steven D. Lidofsky, MD, PhD
The Hospital for Sick Children and Cincinnati, Ohio, United States Professor of Medicine
University of Toronto University of Vermont
Joann Kwah, MD
Toronto, Ontario, Canada Director of Hepatology
University of Vermont Medical Center
Albert Einstein College of Medicine
Burlington, Vermont, United States
Gastroenterology
Bronx, New York, United States
Contributors xi
Keith D. Lindor, MD Ricard Masia, MD, PhD Frederick H. Millham, MD, MBA
Senior Advisor and Professor Associate Director, Translational Chair, Surgery
Office of the University Provost Pathology South Shore Hospital

Arizona State University Medicine Surface Oncology Weymouth, Massachusetts
Gastroenterology and Hepatology Cambridge, Massachusetts, United States Associate Professor of Surgery (Part
Mayo Clinic Hospital Time)
Joel B. Mason, MD
Phoenix, Arizona, United States Harvard Medical School
Professor of Medicine and Nutrition
Mark E. Lowe, MD, PhD Divisions of Gastroenterology and
Harvey R. Colton Professor of Pediatric Clinical Nutrition Ginat W. Mirowski, DMD, MD
Science and Vice Chair Tufts University Adjunct Clinical Professor
Department of Pediatrics Director Department of Oral Pathology,
Washington University School of Vitamins and Carcinogenesis Laboratory Medicine, and Radiology
Medicine USDA Human Nutrition Research Indiana University School of Dentistry
St. Louis, Missouri, United States Center at Tufts University Professor of Clinical Dermatology
Boston, Massachusetts, United States (Clinical Track)
Cara L. Mack, MD
Department of Dermatology
Professor of Pediatrics Jeffrey B. Matthews, MD
Indiana University School of Medicine
University of Colorado School of Dallas B. Phemister Professor and
Indianapolis, Indiana, United States
Medicine Chairman
Children’s Hospital Colorado Department of Surgery Joseph Misdraji, MD
Aurora, Colorado, United States The University of Chicago Medicine Associate Professor of Pathology
Chicago, Illinois, United States Harvard Medical School
Ryan D. Madanick, MD
Associate Pathologist
Assistant Professor of Medicine Craig J. McClain, MD
Division of Gastroenterology and Professor of Medicine and Pharmacology
Hepatology and Toxicology
University of North Carolina School of Vice President for Health Affairs and Daniel S. Mishkin, MD, CM
Medicine Research Chief of Gastroenterology
Chapel Hill, North Carolina, United University of Louisville Atrius Health
States Director Boston, Massachusetts, United States
Gastroenterology
Willis C. Maddrey, MD Bijal Modi, MD
Robley Rex VA Medical Center
Special Assistant to the President Department of Internal Medicine
Louisville, Kentucky, United States
Professor of Internal Medicine Division of Hematology and Oncology
Arnold N. and Carol S. Ablon Stephen A. McClave, MD Texas Health Presbyterian Hospital
Professorship in Biomedical Science Professor and Director of Clinical Dallas
Adelyn and Edmund M. Hoffman Nutrition Dallas, Texas, United States
Distinguished Chair in Medical Department of Medicine
John Magaña Morton, MD, MPH, MHA
Science University of Louisville School of
Vice Chair for Quality
University of Texas Southwestern Medicine
Department of Surgery
Medical Center Louisville, Kentucky, United States
Chief
Shilpa Mehra, MD Bariatric and Minimally Invasive Surgery
Matthias Maiwald, MD, PhD Assistant Professor of Medicine Yale School of Medicine
Senior Consultant in Microbiology Department of Medicine Department of Surgery
Department of Pathology and Division of Gastroenterology New Haven, Connecticut, United States
Laboratory Medicine Albert Einstein College of Medicine
William Conan Mustain, MD
KK Women’s and Children’s Hospital, Bronx, New York, United States
Assistant Professor of Surgery
Singapore
Megha S. Mehta, MD Division of Colon and Rectal Surgery
Adjunct Associate Professor
Assistant Professor of Pediatrics University of Arkansas for Medical
Department of Microbiology and
University of Texas Southwestern Sciences
Immunology
Medical Center Little Rock, Arkansas, United States
Yong Loo Lin School of Medicine
National University of Singapore Filipe Gaio Nery, MD
Adjunct Associate Professor Shivang S. Mehta, MD Physician
Duke-NUS Graduate Medical School Pediatric Gastroenterology Fellow Departamento de Anestesiologia,
Singapore, Singapore Department of Pediatric Cuidados Intensivos e Emergência
Gastroenterology Centro Hospitalar do Porto–Hospital
Lawrence A. Mark, MD, PhD
University of Texas Southwestern Santo António, Porto
Associate Professor of Clinical
Medical Center Researcher, EPIUnit
Dermatology
Dallas, Texas, United States Instituto de Saúde Pública, Universidade
Department of Dermatology
do Porto, Porto
Indiana University School of Medicine Joanna M.P. Melia, MD
Researcher, Ciências Médicas
Indianapolis, Indiana, United States Assistant Professor of Medicine
Instituto de Ciências Biomédicas de Abel
Johns Hopkins University School of
Paul Martin, MD, FRCP, FRCPI Salazar
Medicine
Chief, Division of Gastroenterology and Porto, Portugal
Baltimore, Maryland, United States
Hepatology
University of Miami
Miami, Florida, United States
xii Contributors
Siew C. Ng, MBBS (Lond), PhD (Lond) Patrick R. Pfau, MD Christopher K. Rayner, MBBS, PhD
Professor of Medicine Professor, Chief of Clinical Professor
Department of Medicine and Gastroenterology Adelaide Medical School
Therapeutics Section of Gastroenterology and University of Adelaide
State Key Laboratory of Digestive Hepatology Consultant Gastroenterologist
Disease University of Wisconsin School of Department of Gastroenterology and
LKS Institute of Health Science Medicine and Public Health Hepatology
The Chinese University of Hong Kong Madison, Wisconsin, United States Royal Adelaide Hospital
Hong Kong, China Adelaide, South Australia, Australia
Angela K. Pham, MD
Mark L. Norris, BSc (Hon), MD Clinical Assistant Professor Ahsan Raza, MD
Associate Professor of Pediatrics Gastroenterology, Hepatology, and General and Colorectal Surgery
Pediatrics Nutrition Rapides Surgical Specialists
Children’s Hospital of Eastern Ontario University of Florida Alexandria, Louisiana, United States
University of Ottawa Gainesville, Florida, United States
Miguel D. Regueiro, MD
Ottawa, Ontario, Canada
Kimberly L. Pham, MD Chair and Professor of Medicine
John O’Grady, MD, FRCPI St. George’s University Grenada Department of Gastroenterology and
Professor West Indies, Grenada Hepatology
Institute of Liver Studies Cleveland Clinic, Digestive Disease and
Daniel S. Pratt, MD
King’s College Hospital Surgery Institute
Clinical Director, Liver Transplantation
London, United Kingdom Cleveland, Ohio, United States
Manisha Palta, MD Massachusetts General Hospital John F. Reinus, MD
Associate Professor Assistant Professor of Medicine Professor of Medicine
Radiation Oncology Harvard Medical School Department of Medicine
Duke University Boston, Massachusetts, United States Albert Einstein College of Medicine
Durham, North Carolina, United States Medical Director of Liver
David O. Prichard, MB, BCh, PhD
Transplantation
Stephen J. Pandol, MD Gastroenterologist
Montefiore-Einstein Center for
Professor Gastroenterology and Hepatology
Transplantation
Medicine Mayo Clinic
Cedars-Sinai Medical Center Rochester, Minnesota
Bronx, New York, United States
Los Angeles, California, United States
Michael Quante, PD, Dr
David A. Relman, MD
John E. Pandolfino, MD, MSCI Technische Universität München
Thomas C. and Joan M. Merigan
Hans Popper Professor of Medicine II Medizinische Klinik
Professor
Feinberg School of Medicine Klinikum rechts der Isar
Departments of Medicine and
Northwestern University München, Germany
Microbiology and Immunology
Division Chief
Eamonn M.M. Quigley, MD Stanford University
Professor of Medicine and Chief, Stanford, California
Northwestern Medicine
Gastroenterology and Hepatology Chief of Infectious Diseases
Chicago, Illinois, United States
David M. and Lynda K. Underwood Veterans Affairs Palo Alto Health Care
Darrell S. Pardi, MD, MS Center for Digestive Disorders System
Vice Chair Houston Methodist Hospital Palo Alto, California, United States
Division of Gastroenterology and Weill Cornell Medical College
Arvind Rengarajan, MD
Hepatology Houston, Texas, United States
Barnes-Jewish Hospital
Associate Dean
Balakrishnan S. Ramakrishna, MBBS, Department of Internal Medicine
Mayo School of Graduate Medical
MD, DM, PhD Washington University in St. Louis
Education
Head St. Louis, Missouri, United States
Mayo Clinic
Institute of Gastroenterology
Rochester, Minnesota, United States Joel E. Richter, MD
SRM Institutes for Medical Science
Professor and Director
Michelle Pearlman, MD Chennai, Tamil Nadu, India
Division of Digestive Diseases and
Mrinalini C. Rao, PhD Nutrition
Department of Internal Medicine,
Professor University of South Florida
Division of Digestive and Liver
Department of Physiology and Director
Diseases
Biophysics Joy McCann Culverhouse Center for
University of Illinois at Chicago Swallowing Disorders
Chicago, Illinois, United States University of South Florida
Vyjeyanthi S. Periyakoil, MD Tampa, Florida, United States
Satish S.C. Rao, MD, PhD
Director, Palliative Care Education and
Professor of Medicine Sumera H. Rizvi, MD
Training
Harold J. Harrison, MD, Distinguished Assistant Professor of Medicine
University Chair in Gastroenterology Division of Gastroenterology and
Stanford University School of Medicine
Medicine-Gastroenterology/Hepatology Hepatology
Stanford, California, United States
Augusta University Mayo Clinic
Augusta, Georgia, United States Rochester, Minnesota, United States
Contributors xiii
Syed Mujtaba Rizvi, MD Jayashree Sarathy, PhD Vijay H. Shah, MD

Assistant Professor Associate Professor Professor
Division of Medical Oncology Department of Biological Sciences Medicine, Physiology, and Cancer Cell
Department of Internal Medicine Program Director of Master of Science Biology
UT Southwestern Medical Center in Integrative Physiology Chair
Dallas, Texas, United States Benedictine University Division of Gastroenterology and
Lisle, Illinois Hepatology
Eve A. Roberts, MD, PhD
Visiting Research Professor Associate Chair of Research Medicine
Adjunct Professor
Department of Physiology and Mayo Clinic College of Medicine and
Pediatrics, Medicine, and Pharmacology
Biophysics Science
and Toxicology
University of Illinois at Chicago Rochester, Minnesota, United States
University of Toronto
Adjunct Scientist G. Thomas Shires, MD
Genetics and Genome Biology Program George S. Sarosi Jr., MD John P. Thompson Chair
Hospital for Sick Children Research Robert H. Hux MD Professor and Vice Surgical Services
Institute Chairman for Education Texas Health Presbyterian Hospital
Associate Department of Surgery Dallas
Division of Gastroenterology, University of Florida College of Dallas, Texas, United States
Hepatology, and Nutrition Medicine
Maria H. Sjogren, MD, MPH
The Hospital for Sick Children Staff Surgeon
Senior Hepatologist
Toronto, Ontario, Canada Surgical Service
Associate Fellow NF/SG VAMC
Walter Reed National Medical Center
History of Science and Technology Gainesville, Florida, United States
Bethesda, Maryland, United States
Program
Thomas J. Savides, MD
University of King’s College Phillip D. Smith, MD
Professor of Clinical Medicine
Halifax, Nova Scotia, Canada Professor of Medicine and Microbiology
University of Alabama at Birmingham
Martin D. Rosenthal, MD University of California San Diego
Birmingham, Alabama, United States
Assistant Professor La Jolla, California, United States
Surgery Elsa Solà, MD, PhD
Lawrence R. Schiller, MD
University of Florida Liver Unit
Attending Physician
Gainesville, Florida, United States Hospital Clinic
Gastroenterology Division
Associate Professor
Marc E. Rothenberg, MD, PhD Baylor University Medical Center
University of Barcelona
Professor of Pediatrics Dallas, Texas, United States
Researcher
Cincinnati Children’s Hospital Medical
Mitchell L. Schubert, MD Institut d’Investigacions Biomediques
Center
Professor of Medicine and Physiology August Pi i Sunyer (IDIBAPS)
Cincinnati, Ohio, United States
Virginia Commonwealth University Barcelona, Spain
Jayanta Roy-Chowdhury, MBBS Health System
Rhonda F. Souza, MD
Professor Chief, Division of Gastroenterology,
Co-Director, Center for Esophageal
Departments of Medicine and Genetics Hepatology, and Nutrition
Diseases
Director, Genetic Engineering and Gene McGuire Veterans Affairs Medical
Therapy Core Facility Center
Baylor University Medical Center
Albert Einstein College of Medicine Richmond, Virginia, United States
Cynthia L. Sears, MD Research
Namita Roy-Chowdhury, PhD Professor of Medicine and Oncology Baylor Scott and White Research
Professor Johns Hopkins University School of Institute
Departments of Medicine and Genetics Medicine Dallas, Texas, United States
Albert Einstein College of Medicine Baltimore, Maryland, United States
Cedric W. Spak, MD, MPH
Joseph H. Sellin, MD Clinical Assistant Professor
David T. Rubin, MD Professor Emeritus Infectious Diseases
Joseph B. Kirsner Professor of Medicine Division of Gastroenterology Baylor University Medical Center
Chief, Section of Gastroenterology, Baylor College of Medicine Staff Physician
Hepatology, and Nutrition Chief of Gastroenterology Infectious Diseases
Department of Medicine Ben Taub General Hospital Texas Centers for Infectious Disease
University of Chicago Houston, Texas, United States Associates
Chicago, Illinois, United States Dallas, Texas, United States
M. Gaith Semrin, MD, MBBS
Associate Professor Stuart Jon Spechler, MD
Pediatric Gastroenterology and Chief, Division of Gastroenterology
Nutrition Co-Director, Center for Esophageal
UT Southwestern Medical Center Research
Children Medical Center Dallas Department of Medicine
Dallas, Texas, United States Baylor University Medical Center at Dallas
Research
Baylor Scott and White Research Institute
xiv Contributors
James E. Squires, MD, MS Jan Tack, MD, PhD Dominique Charles Valla, MD
Assistant Professor Head, Division of Gastroenterology and Professor of Hepatology
Department of Pediatrics Hepatology Liver Unit
UPMC Children’s Hospital of Leuven University Hospitals Hôpital Beaujon, APHP,
Pittsburgh Professor of Medicine Clichy-la-Garenne
Pittsburgh, Pennsylvania, United States Translational Research Center for France
Gastrointestinal Disorders (TARGID) CRI, UMR1149
Neil H. Stollman, MD
Department of Clinical and Inserm and Université de Paris
Associate Clinical Professor
Experimental Medicine Paris, France
Department of Medicine, Division of
University of Leuven
Gastroenterology John J. Vargo II, MD, MPH
Leuven, Belgium
University of California San Francisco Associate Professor of Medicine
San Francisco, California Nicholas J. Talley, MD, PhD Gastroenterology and Hepatology
Chief Distinguished Laureate Professor Cleveland Clinic
Division of Gastroenterology Faculty of Health and Medicine Cleveland, Ohio, United States
Alta Bates Summit Medical Center University of Newcastle, Australia
Santhi Swaroop Vege, MD
Oakland, California, United States Newcastle, New South Wales, Australia
Professor of Medicine and Director
Sarah E. Streett, MD Jarred P. Tanksley, MD, PhD Pancreas Group
Clinical Associate Professor Resident Gastroenterology and Hepatology
Director IBD Education Radiation Oncology Mayo Clinic
Division of Gastroenterology and Duke University Rochester, Minnesota, United States
Hepatology Durham, North Carolina, United States
Axel von Herbay, MD
Stanford University
Narci C. Teoh, MD Professor of Pathology
Redwood City, California, United States
Professor of Medicine Faculty of Medicine
Jonathan R. Strosberg, MD Australian National University University of Heidelberg
Associate Professor Senior Staff Hepatologist Heidelberg Hans Pathologie
Gastrointestinal Oncology The Canberra Hospital Hamburg, Germany
Moffitt Cancer Center Australian Capital Territory, Australia
Margaret von Mehren, MD
Tampa, Florida, United States
Dawn M. Torres, MD Professor
Frederick J. Suchy, MD Program Director GI Fellowship Department of Hematology/Oncology
Children’s Hospital Colorado Department of Medicine Fox Chase Cancer Center
Professor of Pediatrics and Associate Walter Reed National Military Medical Philadelphia, Pennsylvania, United
Dean for Child Health Research Center States
Pediatrics Associate Professor of Medicine
David Q.-H. Wang, MD, PhD
University of Colorado School of Department of Medicine
Medicine Uniformed Services University of the
Departments of Medicine and Genetics
Aurora, Colorado, United States Health Sciences
Director, Molecular Biology and Next
Bethesda, Maryland, United States
Aravind Sugumar, MD Generation Technology Core
Instructor Kiran Turaga, MD, MPH Marion Bessin Liver Research Center
Gastroenterology and Hepatology Associate Professor Albert Einstein College of Medicine
Cleveland Clinic Foundation Department of Surgery Bronx, New York, United States
Cleveland, Ohio, United States The University of Chicago
Sachin Wani, MD
Shelby Sullivan, MD Associate Professor of Medicine
Associate Professor of Medicine Richard H. Turnage, MD Division of Gastroenterology and
Director, Gastroenterology Metabolic Executive Associate Dean for Clinical Hepatology
and Bariatric Program Affairs University of Colorado Anschutz
Division of Gastroenterology and Professor of Surgery Medical Campus
Hepatology University of Arkansas for Medical Aurora, Colorado, United States
University of Colorado Anschutz Sciences Medical Center
Frederick Weber, MD
Medical Campus University of Arkansas for Medical
Clinical Professor
Aurora, Colorado, United States Sciences
Little Rock, Arkansas, United States
Gyongyi Szabo, MD, PhD Hepatology
Mitchell T. Rabkin, MD Chair Michael F. Vaezi, MD, PhD, MS University of Alabama Birmingham
Chief Academic Officer Professor of Medicine and Birmingham, Alabama, United States
Beth Israel Deaconess Medical Center Otolaryngology
Barry K. Wershil, MD
and Beth Israel Lahey Health Division of Gastroenterology and
Professor
Faculty Dean for Academic Affairs Hepatology
Pediatrics
Harvard Medical School Vanderbilt University
Northwestern University Feinberg
Boston, Massachusetts, United States Director
School of Medicine
Center for Swallowing and Esophageal
Chief, Division of Gastroenterology,
Disorders
Vanderbilt University Medical Center
Pediatrics
Director
Ann & Robert H. Lurie Children’s
Clinical Research
Hospital of Chicago
Vanderbilt University Medical Center
Nashville, Tennessee, United States
Contributors xv
David C. Whitcomb, MD, PhD Christopher G. Willett, MD Anahit A. Zeynalyan, MD

Professor Professor and Chairman Resident
Medicine, Cell Biology and Molecular Radiation Oncology Internal Medicine

Physiology, and Human Genetics Duke University Baylor University Medical Center
University of Pittsburgh and UPMC Durham, North Carolina, United States Dallas, Texas, United States
Pittsburgh, Pennsylvania, United States
Joseph C. Yarze, MD
C. Mel Wilcox, MD, MSPH Assistant Professor of Medicine
Division of Gastroenterology and Harvard Medical School
Hepatology Associate Physician
University of Alabama at Birmingham Division of Gastroenterology
Birmingham, Alabama, United States Massachusetts General Hospital
Foreword
Even attempting to write a Foreword for the 11th edition been in the recent past and what we hope (and expect) to achieve
of Sleisenger and Fordtran’s Gastrointestinal and Liver Disease: in the future.
Pathophysiology/Diagnosis/Management, a textbook that has served A trusted book provides a helpful guide that is readily available
for many decades to prepare readers to respond to challenges at moments of uncertainty. A comparison of an individual chapter
presented by patients with gastrointestinal and liver disease, is from a past edition and what we have now further validates the
a daunting task and yet a great pleasure. Just having achieved an conclusion that progress is being made, and the future of our spe-
11th edition of a textbook is, in and of itself, a remarkable accom- cialty is encouraging. The three senior editors and three associate
plishment. Generations of gastroenterologists and hepatologists editors of the 11th edition are foremost authorities and widely
have relied on Sleisenger and Fordtran to provide comprehensive, recognized for their abilities to identify topics of interest and
up-to-date, reliable information. to persuade experts in these areas to share their knowledge. To
The 11th edition is a welcome addition to the previous editions, write an updated review of one’s field can be a Herculean task that
which have been widely acclaimed as important go-to sources requires not only knowledge but also courage. The editors have
of information regarding the broad array of disorders affecting surely succeeded. The careful selection of authors of individual
the gastrointestinal tract and the liver. Over the past half cen- chapters allows each to bring his or her own style regarding what
tury, these volumes have been mainstays in the libraries of those to emphasize; to lay out what we know, as well as what we need to
engaged in these fields. Since its inception 10 editions ago, this know, to diagnose and effectively treat specific problems; and to
now classic textbook has tracked the evolution of thinking in mul- provide suggestions and guidance as to how to manage patients
tiple areas and has served readers well. These days, there are ever- while integrating new observations into practice.
expanding ways for those of us interested in gastroenterology and With regard to the liver section, the current state of knowl-
hepatology to be stimulated, informed, educated, and refreshed. edge about hepatitis-inducing viruses and drug-induced liver dis-
Lectures, conversations with colleagues, and attendance at local, eases and the tsunami of interest in the many consequences of the
regional, and national meetings have their roles, and we all learn effects of excessive fat in the liver in the causation of chronic liver
from our patients. Perusal of relevant articles in medical journals diseases are breathtaking. These achievements have been well-
is increasingly difficult in an era in which the number of available chronicled journeys with opportunities (and hope) for even more
journals has increased remarkably. The practicing clinician, given effective therapeutic agents in the near future. Just one edition
present-day time constraints, will more than ever find this text- ago, we were on the threshold of having effective, widely appli-
book reliable, informative, and useful. In these two volumes are cable treatments for the several types of viral hepatitis; much of
overviews of what is known now and glimpses of what the future what we hoped for has been achieved. It is now likely that there
is likely to bring. A blend of skill, knowledge, practical experi- will be discovery of therapeutic approaches that will favorably
ence, and the ability to teach is required of the authors in order affect the broad array of fat-related liver injuries, including their
to achieve these goals. Overall, these efforts have been successful association with cardiovascular disorders. Widely available access
in presenting accurate and comprehensive updates in our fields of to advanced endoscopy has changed the approach to the evalua-
interest and serve us well as a look to our past, provide reflections tion and treatment of many disorders of the gastrointestinal tract,
regarding our present, and delineate problems yet to be solved. bile ducts, and pancreas. Furthermore, who could have foreseen
We are fortunate to live in exciting and rapidly changing just a few years ago how advances in biological therapies and
times in gastroenterology and hepatology. The sheer volume minimally invasive surgery would so redirect our treatments of
of new ideas presented in multiple journals is stimulating and a broad array of disorders or how important the gut microbiome
often overwhelming. Each of us must evaluate and assimilate would be in the pathogenesis of many disorders. Once we under-
new information while making efforts to appropriately incor- stand how to favorably alter the gut microbiome, major leaps for-
porate the new advances into our practices. To stay up to date ward can be expected.
and achieve our goals requires considerable effort and dedica- What is next? Gene editing and an understanding of intesti-
tion (Even COVID-19 is mentioned several times throughout nal microbiota, now in their infancy, will receive much deserved
the book.). There is comfort in having available a reliable and attention in the next few years. With each passing year, advances in
trusted guide to refresh and stimulate us. manipulation of the human genome and intestinal microbiota are
The 11th edition of Sleisenger and Fordtran provides a firm, becoming more precise and require constant, thoughtful oversight
authoritative platform regarding what is established knowledge to ensure that we do what we should do and not just what we can
and identifies where progress is being made to prepare us to do. In this edition, we have blueprints and predictions of the future
be better armed for the foreseeable future. We all need to be for many aspects of our specialty. It is important to discard old
informed of the likely validity and usefulness of new observa- ideas that have not proved effective while constantly re-examining
tions. It is vital that we recognize the degree of certainty of the the basis for what we think we know and appropriately altering
data that led to our conclusions. There have been (and will be) what we do.
definite game-changing advances and also many seemingly good We all marvel when we see what has been (and is) happening
ideas and approaches that turn out to be sidesteps. New concepts in medicine and the effects of these advances in gastroenterology
must be recognized, double-checked, processed, and then incor- and hepatology. Surely, the best is yet to come, and we all hope
porated into our thinking, subsequently affecting our actions. that what we are learning and applying now will stimulate us to
The breadth of subjects covered in depth in these two vol- create an even better future.
umes is impressive. I had the honor to write the Foreword to the
9th edition published in 2010. When comparing the expansion of Willis C. Maddrey, MD
knowledge from then to now, one can appreciate where we have Dallas, Texas
xvi
The Sleisenger and Fordtran Editors
Mark Feldman, MD Lawrence S. Friedman, MD Lawrence J. Brandt, MD
Editions 5-11 Editions 7-11 Editions 8-11
Raymond T. Chung, MD David T. Rubin, MD C. Mel Wilcox, MD
Edition 11 Edition 11 Edition 11
Marvin H. Sleisenger, MD John S. Fordtran, MD Bruce F. Scharschmidt, MD
Editions 1-7 Editions 1-5 Editions 5-6
xvii
Preface
Nearly a half century ago, in the summer of 1971, Drs. Marvin As one looks back 50 years, the advances made in our field
H. Sleisenger in San Francisco and John S. Fordtran in Dallas as a result of rigorous basic science and clinical research have
embarked on a new venture: planning, writing, and editing the been truly remarkable, and the future holds even greater prom-
inaugural edition of a new textbook for gastroenterologists. ise of discovery. Featured advances discussed in the 11th edition
The book received widespread praise for incorporating state- include improved diagnosis and treatment of chronic hepatitis B
of-the-art descriptions of the pathophysiology of the d isorders and C; evolution in the diagnosis and treatment of Helicobacter
discussed—a first for a medical textbook. Since the a uspicious pylori infection and the resulting benefits on the prevention and
debut of Gastrointestinal Disease: Pathophysiology/Diagnosis/ treatment of peptic ulcer disease and gastric neoplasia; improve-
Management, subsequent editions have been published every ments in the prevention of colorectal cancer through screening
4 to 5 years, and we are pleased that the 11th edition of this and surveillance; new approaches to the recognition and treat-
venerable textbook continues the tradition and standards set ment of Barrett esophagus and consequent prevention of esopha-
by the founding editors. To be sure, innumerable enhance- geal adenocarcinoma; the expanding use of biologic agents and
ments have been made since the 1st edition, such as the addi- novel small molecules to treat and prevent recurrences of IBD;
tion of chapters on liver diseases, the availability of the book recognition of an increasing number of immune and autoimmune
online and on hand-held devices, the introduction of monthly diseases affecting not only the stomach and hepatobiliary system
updates to bring attention to important new developments but also the pancreas and intestine; improvements in the ability
that occur between editions, the incorporation of videos of to risk stratify and treat patients with GI bleeding; and continuing
new diagnostic and therapeutic procedures, and the participa- progress in hepatic, pancreatic, and small bowel transplantation.
tion of authors from around the world to give the book a truly There have been remarkable advances in our understanding the
international flavor. gut microbiome, which is becoming the focus of interest in diverse
In the summer of 2017, the current editors met with the fields, such as IBS, IBD, obesity, hepatic encephalopathy, and oth-
publisher and reviewed the prior (10th) edition of the book ers, including non-GI disorders. We are particularly pleased to
in great detail. Most importantly, the core group of 3 senior have completely redesigned the section on IBD by reorganizing
editors invited 3 associate editors (Drs. Raymond T. Chung, and updating the discussions of pathophysiology, clinical presen-
David T. Rubin, and C. Mel Wilcox) to join them in order to tation, and management, all of which are evolving rapidly.
facilitate critical review of the chapters, to help select the most Sadly, the original co-founder of this textbook, Dr. Marvin H.
expert authors, and to provide greater content expertise. Each Sleisenger, passed away on October 19, 2017, at the age of 93.
associate editor worked closely with a senior editor. The result, Marvin will be greatly missed, and we trust that this 11th edition
we hope, is an easily readable, carefully edited, highly accurate, would have met with his approval and commendation.
and thorough review of the state of the art of gastrointestinal
and liver disease. The target audience is primarily practicing Mark Feldman, MD
gastroenterologists and hepatologists (adult and pediatric) and Lawrence S. Friedman, MD
trainees in gastroenterology. We hope the book will also be Lawrence J. Brandt, MD
useful to general internists, other specialists, and students at
all levels.
xviii
Acknowledgments
The editors and associate editors of the 11th edition of Sleisenger thank Dr. Willis C. Maddrey of the University of Texas South-
& Fordtran’s Gastrointestinal and Liver Disease are most grateful western for his eloquent Foreword, the second time he has been
to the more than 230 authors from countries in North America, called on to do this honor for Sleisenger & Fordtran. We remem-
Europe, Asia, and Australia who contributed their knowledge, ber with affection Dr. Marvin H. Sleisenger, who passed away as
expertise, and wisdom to the pages of the book. We are also the 11th edition of the book he co-created was being prepared,
appreciative of the talented staff at Elsevier who helped bring and pay tribute to Dr. John S. Fordtran for his continuing inspi-
this book to life, particularly Nancy Duffy, Dolores Meloni, and ration and contributions. We are deeply appreciative of the love
Deidre Simpson. A special call out goes to Cindy Thoms, who and support of our spouses: Barbara Feldman, Mary Jo Cappuc-
oversaw production of the book. We are most thankful to our cilli, Lois Brandt, Kim Wilcox, Diane Abraczinskas, and Rebecca
assistants, Sherie Strang, Alison Sholock, Amy Nash, and Amy Rubin. Finally, we thank our readers, to whom the book is dedi-
Majkowski, for outstanding secretarial support. We want to cated, for their confidence and trust in this textbook.
xix
Abbreviation List
AASLD American Association for the Study of Liver ESR Erythrocyte sedimentation rate
Diseases EUS Endoscopic ultrasonography
ACG American College of Gastroenterology FDA U.S. Food and Drug Administration
ACTH Corticotropin FNA Fine-needle aspiration
AE Angioectasia GAVE Gastric antral vascular ectasia
AFP Alpha fetoprotein GERD Gastroesophageal reflux disease
AGA American Gastroenterological Association GGTP Gamma glutamyl transpeptidase
AIDS Acquired immunodeficiency syndrome GI Gastrointestinal
ALF Acute liver failure GIST GI stromal tumor
ALT Alanine aminotransferase GU Gastric ulcer
AMA Antimitochondrial antibodies H & E Hematoxylin and eosin
ANA Antinuclear antibodies H2RA Histamine-2 receptor antagonist
ANCA Antineutrophil cytoplasmic antibodies HAV Hepatitis A virus
APACHE Acute physiology and chronic health HBV Hepatitis B virus
examination
HCC Hepatocellular carcinoma
APC Argon plasma coagulation
HCG Human chorionic gonadotropin
ASGE American Society for Gastrointestinal Endoscopy
HCV Hepatitis C virus
AST Aspartate aminotransferase
HDL High-density lipoprotein
ATP Adenosine triphosphate
HDV Hepatitis D virus
BICAP Bipolar electrocoagulation
HELLP Hemolysis, elevated liver enzymes, low platelets
BMI Body mass index
HEV Hepatitis E virus
BRBPR Bright red blood per rectum
Hgb Hemoglobin
CBC Complete blood count
HHT Hereditary hemorrhagic telangiectasia
CCK Cholecystokinin
HIV Human immunodeficiency virus
CEA Carcinoembryonic antigen
HLA Human leukocyte antigen
CDI Clostridioides difficile infection
HPV Human papillomavirus
CF Cystic fibrosis
HSV Herpes simplex virus
CFTR Cystic fibrosis transmembrane conductance
regulator Hp Helicobacter pylori
CMV Cytomegalovirus IBD Inflammatory bowel disease
CNS Central nervous system IBS Irritable bowel syndrome
CO2 Carbon dioxide ICU Intensive care unit
COX Cyclooxygenase IMA Inferior mesenteric artery
CT Computed tomography IMT Intestinal microbiota transplantation
CTA Computed tomography angiography INR International normalized ratio
DAA Direct-acting antiviral agent IV Intravenous
DIC Disseminated intravascular coagulation IVIG Intravenous immunoglobulin
DILI Drug-induced liver injury LDH Lactate dehydrogenase
DNA Deoxyribonucleic acid LDL Low-density lipoprotein
DU Duodenal ulcer LGI Lower gastrointestinal
DVT Deep vein thrombosis LGIB Lower gastrointestinal bleed
EBV Epstein-Barr virus LLQ Left lower quadrant
EGD Esophagogastroduodenoscopy LT Liver transplantation
EGF Epidermal growth factor LUQ Left upper quadrant
EMG Electromyography MELD Model for end-stage liver disease
ERCP Endoscopic retrograde cholangiopancreatography MEN Multiple endocrine neoplasia
xxv
xxvi Abbreviation List
MHC Major histocompatibility complex SBP Spontaneous bacterial peritonitis

MRA Magnetic resonance angiography SIBO Small intestinal bacterial overgrowth
MRCP Magnetic resonance cholangiopancreatography SLE Systemic lupus erythematosus
MRI Magnetic resonance imaging SOD Sphincter of Oddi dysfunction
NAFLD Nonalcoholic fatty liver disease TB Tuberculosis
NASH Nonalcoholic steatohepatitis TG Triglyceride(s)
NG Nasogastric TIPS Transjugular intraheptic portosystemic shunt
NPO Nil per os (nothing by mouth) TNF Tumor necrosis factor
NSAID(s) Nonsteroidal anti-inflammatory drug(s) TNM Tumor node metastasis
O2 Oxygen TPN Total parenteral nutrition
PBC Primary biliary cholangitis UC Ulcerative colitis
PCR Polymerase chain reaction UDCA Ursodeoxycholic acid
PET Positron emission tomography UGI Upper gastrointestinal
PPI Proton pump inhibitor UGIB Upper gastrointestinal bleed
PSC Primary sclerosing cholangitis UGIS Upper gastrointestinal series
PSE Portosystemic encephalopathy UNOS United Network for Organ Sharing
PUD Peptic ulcer disease US Ultrasonography
RA Rheumatoid arthritis USA United States of America
RLQ Right lower quadrant VLDL Very-low-density lipoprotein
RNA Ribonucleic acid WBC White blood cell
RUQ Right upper quadrant WHO World Health Organization
SBO Small bowel obstruction ZES Zollinger-Ellison syndrome
PART
I Biology of the Gastrointestinal Tract
1 Cellular Growth and Neoplasia

Ezra Burstein
CHAPTER OUTLINE MECHANISMS OF NORMAL TISSUE HOMEOSTASIS

MECHANISMS OF NORMAL TISSUE HOMEOSTASIS . . . . . . . 1 Cellular Proliferation
Cellular Proliferation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Tissue homeostasis is maintained by the delicate balance of cel-
Apoptosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 lular proliferation and differentiation, which provide new cellular
Senescence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 elements to replace dying cells as part of normal tissue function
Signaling Pathways That Regulate Cellular Growth . . . . . . . 3 or during tissue repair. At a fundamental level, neoplasia arises
INTESTINAL TUMOR DEVELOPMENT . . . . . . . . . . . . . . . . . . . 5 when cell proliferation escapes the homeostatic mechanisms
Multistep Formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 that maintain this process in balance with senescence and pro-
Clonal Expansion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 grammed cell death. Cell proliferation occurs as cells divide, a
process that occurs through an orderly set of steps referred to as
Cancer Stem Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 the cell cycle (Fig. 1.1). In preparation for cell division, there is a
Epithelial-Mesenchymal Transition . . . . . . . . . . . . . . . . . . . 5 period of biosynthetic activity called the G1 phase that is typically
NEOPLASIA-ASSOCIATED GENES . . . . . . . . . . . . . . . . . . . . . 6 associated with an increase of cell size. This phase is followed by
Oncogenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 precise duplication of the genome, designated the S phase. After
Oncogenic Growth Factors and Growth Factor Receptors . . . 7 an intervening gap period designated as the G2 phase, mitosis
Nuclear Oncogenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 occurs during the M phase.
Tumor Suppressor Genes . . . . . . . . . . . . . . . . . . . . . . . . . . 8 The commitment to proceed to DNA replication occurs at
the G1/S checkpoint or restriction (R) point. Cells may exit this
DNA Repair Genes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 cycle of active proliferation before reaching the R point and enter
Noncoding RNAs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 a quiescent phase known as G0. Cells can subsequently reenter
Oncogenic Signaling Pathways . . . . . . . . . . . . . . . . . . . . . 10 the cell cycle from the G0 state (see Fig. 1.1). Another checkpoint
TUMOR MICROENVIRONMENT . . . . . . . . . . . . . . . . . . . . . . . 10 exists at the boundary between the G2 and M phases. The G2/M
checkpoint ensures that mitosis does not proceed prior to the
TUMOR METABOLISM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 repair of any damaged DNA after genome replication. Impaired
Inflammation and Cancer . . . . . . . . . . . . . . . . . . . . . . . . . 10 function of these checkpoints is frequently observed in cancers.
Microbiome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 Regulation of cell cycle progression is achieved principally by
BIOLOGICAL FEATURES OF TUMOR METASTASIS . . . . . . . . 11 a set of proteins known as cyclins and cyclin-dependent kinases
Angiogenesis and Lymphangiogenesis . . . . . . . . . . . . . . . 11 (CDKs). These proteins are expressed in specific parts of the cell
cycle and regulate the G1/S and G2/M checkpoints. During the
ENVIRONMENTAL INFLUENCES . . . . . . . . . . . . . . . . . . . . . . 11 G1 phase, cyclins D and E are most active.1 Overexpression of
Chemical Carcinogenesis . . . . . . . . . . . . . . . . . . . . . . . . . 11 cyclin D1 in fibroblasts results in more rapid entry of cells into
Dietary Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 the S phase, and, consistent with a role in cancer, cyclin D1 is fre-
MOLECULAR MEDICINE: CURRENT AND FUTURE quently overexpressed in a number of GI and non-GI malignan-
APPROACHES IN GASTROINTESTINAL ONCOLOGY . . . . . . . 12 cies.2 During the S phase, cyclin A is predominantly expressed,
Next Generation Sequencing . . . . . . . . . . . . . . . . . . . . . . . 12 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 cata-
Molecular Diagnostics . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 lysts 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,
Normal cellular proliferation and differentiation are essential to cyclin D1–dependent progression from G1 to S phase is the result
tissue homeostasis in all organs, including the digestive tract. The of cyclin D1/CDK4 phosphorylation of the tumor suppression
neoplastic process involves a fundamental disruption of these mech- pRb, the product of the retinoblastoma gene, as well as the Rb
anisms, which can give rise to cancer development and metastasis family members p130 and p107.3 These proteins sequester E2F
with the additional acquisition of other hallmarks of cancer. As a transcription factors that promote expression of factors required
group, malignancies of the GI tract are the leading cause of cancer- for S phase, and their phosphorylation by CDK4 leads to their
associated mortality, and it is therefore essential to understand the functional inhibition. Thus, loss of Rb expression also accom-
underlying biology that gives rise to tumor formation. This chapter plishes more rapid progression to S phase and is another genetic
reviews mechanisms of normal cell growth and the fundamental lesion seen in many tumors. An analogous circuit is found in the
cellular and molecular alterations that facilitate malignant transfor- G2/M transition, where cyclin A/CDK2 mediates the activation
mation. The basic concepts discussed in this chapter provide the of another transcriptional regulator, FoxM1, required for the
framework for discussion of specific GI neoplasms in later chapters. expression of factors involved in mitosis.4
1
2 PART I Biology of the Gastrointestinal Tract
Ink4A CDK4
Cyclin D1
P
pRb pRb P
P
E2F
G1/S
checkpoint
E2F
G0 G1 S
Cyclin D/E Cyclin A
Cyclin B
M G2
P
FoxM1
P
G2 /M
checkpoint
P
FoxM1 FoxM1
P
Cyclin A
Cip/Kip CDK2
Fig. 1.1 Regulation of the cell cycle by (cycs), cyclin-dependent kinases (cdks), and cdk inhibitors. In the
normal cell cycle, DNA synthesis (in which chromosomal DNA is duplicated) occurs in the S phase, whereas
mitosis (in which nuclei first divide to form a pair of new nuclei, followed by actual cellular division to form a
pair of daughter cells) takes place in the M phase. The S and M phases are separated by two gap phases: the
G1 phase after mitosis and before DNA synthesis, and the G2 phase following the S phase. During these gap
phases, the cell is synthesizing proteins and metabolites, increasing its mass, and preparing for the S phase
and M phase. Cell cycle progression is regulated primarily at two points, the G2/M and G1/S checkpoints,
through the coordinated activities of cyclins and CDKs, which in turn are negatively regulated by CDK inhibitors
(Ink4 and Cip/Kip families).
The cell cycle is also regulated by multiple CDK inhibi-

tors, which are classified into various classes and are referred by
Apoptosis
multiple names.5 CDK4 and CDK6 are inhibited by members Apoptosis is a form of programmed cell death that is geneti-
of the Ink4 family of inhibitors known as p16INK4a (encoded cally programmed and executed by specific proteases known
by the Cdkn2a gene), p15INK4b (Cdkn2b), p18INK4c (Cdkn2c), as caspases.9 Similar to other protease cascades, such as the
and p19INK4d (Cdkn2d)].6 Thus these factors also impinge on coagulation system, caspases become active upon cleavage of
Cyclin D1/CDK4 regulation of pRb, and consequent E2F activ- an inactive pro-form, typically through the action of another
ity and S phase entry. p16INK4A loss in cancer results in greater caspase or as a result of focal accumulation of inactive caspases.
activation of CDK4 and is frequently inactivated in GI cancers, a Apoptosis is an important mechanism that counterbalances cell
finding consistent with its function as a tumor suppressor gene.7,8 proliferation; thus, escape from normal apoptotic mechanisms
Members of the Cip/Kip family of CDK inhibitors are known plays a critical role in oncogenesis. Morphologically, apoptosis
as p21Cip1 (Cdkn1a), p27Kip1 (Cdkn1b), and p57Kip2 (Cdkn1c)] and is characterized by distinctive features that include chromatin
are more promiscuous and interfere with multiple cyclin/CDK compaction, condensation of the cytoplasm, nuclear fragmenta-
complexes, including CDK2. tion, and marked alterations at the plasma membrane, resulting
CHAPTER 1 Cellular Growth and Neoplasia 3
Death
Receptors 1
(TNFR1, Fas, etc.)
Bax
Cyto c Bak
Caspase-8 Cellular Stress
(Radiation,
chemotherapy, etc.)
Bcl-2
Caspase-9 Apaf-1
Bcl-xL Mitochondria
Mcl-1
Executioner Downstream
Caspases Targets leading to
(Casp-3, Casp-7) 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 desta-
bilize 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.
Senescence
Apoptosis may be triggered by internal or external stimuli. Senescence is the process by which cells permanently lose their
Internal stimuli of apoptosis may include nutrient deprivation, ability to divide. Senescence may occur in response to the stress
hypoxia, DNA damage, or other stressors, including specific tox- induced by activation of oncogenes or DNA damage or after a fixed
ins, chemical signals, and pathogens. Apoptosis routinely occurs number of cellular divisions (replicative senescence). Associated
during normal development to facilitate tissue patterning. Simi- with the exit from the cell cycle, senescence is associated with a
larly, a number of stress situations, including tissue inflammation, secretory phenotype that includes a variety of proinflammatory
can trigger apoptosis. Apoptosis may also be stimulated by spe- factors. As a physiologic event, senescence limits dysregulated or
cific cell surface receptors belonging to the tumor necrosis factor excessive proliferation. However, when dysregulated, senescence
receptor superfamily, including tumor necrosis factor R1 and Fas, can also contribute to aging and depletion of stem cells.11 During
which are referred to as death receptors (Fig. 1.2). carcinogenesis, senescence is frequently bypassed or lost.
At the intracellular level, the last common event in all forms Replicative senescence is triggered shortening of telomeres,
of apoptosis is the activation of so-called executioner caspases, repetitive sequences at the end of chromosomes that protect
caspase 3 and 7, which mediate the cleavage of a large number genomic integrity. Telomeres shorten with each cell division,
of downstream targets that eventually precipitate cell death. and when they reach a critically short length, they initiate DNA
Proapoptotic signals frequently converge at the level of the damage signaling and cellular senescence. This phenomenon can
mitochondria, where they destabilize the mitochondrial mem- be routinely seen in vitro when primary cells undergo repeated
brane and collapse the electrical gradient required for aerobic rounds of replication, eventually acquiring critically short telo-
respiration (see Fig. 1.2). Besides the effects that result in cel- meres.12 To prevent senescence from being triggered by sus-
lular energetics, this process leads to the release into the cyto- tained replication, cancer cells activate the telomerase enzyme,
sol of proteins normally present in the intermembrane space which adds additional telomeres to the end of chromosomes.13
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,
Signaling Pathways That Regulate Cellular Growth
which contains Apaf1 and facilitates the activation of caspase 9, Cellular proliferation is achieved through transition of cells from
which can directly activate caspases 3 and 7. On the other hand, G0 arrest into the active cell cycle (see Fig. 1.1). Although pro-
death receptors activate executioner caspases through receptor gression through the cell cycle is controlled by the regulatory
initiated intracellular signaling events that result in the upstream mechanisms just described, overall proliferation is also modulated
activation of caspase 8. by external stimuli. Growth factors that bind to specific trans-
The mitochondrial membrane permeabilization events that membrane receptors on the cell surface are especially important.
lead to apoptosome formation are controlled by proteins of the Also acting through transmembrane cell surface receptors, extra-
Bcl-2 family. On the one hand, Bax and Bak help form the pore, cellular matrix and cell-cell adhesion molecules (i.e., integrins,
whereas Bcl-2, Bcl-xL, and Mcl-1 inhibit pore formation. The cadherins, selectins, proteoglycans) can also have a significant
stoichiometric ratio between proapoptotic and antiapoptotic impact on cell proliferation. Alterations in cell-matrix or cell-
members of the Bcl-2 family can determine the balance between cell interactions are particularly important in contributing to the
cell survival and cell death.10 In cancer, alterations in the balance invasive phenotype of malignant cells.
of proapoptotic and antiapoptotic factors, including member of After ligand binding, the cytoplasmic tails of these transmem-
the Bcl-2 family, are common events. brane receptor proteins activate intracellular signaling cascades
that alter gene transcription and protein expression. Based on the Many receptors are members of the so-called 7-membrane–
nature of the intracellular signaling cascades that these recep- spanning receptor family. These receptors are coupled to guanine
tors initiate, they can be classified into three major categories: nucleotide binding proteins, also known as G proteins, and thus,
(1) tyrosine kinases, (2) serine and threonine kinases, and (3) G the receptors are referred to as G protein–coupled receptors. G
protein–coupled receptors (GPCRs). proteins undergo a conformational change that is dependent on
The receptors for many peptide growth factors contain intrin- the presence of guanosine phosphates.15 Activation of G proteins
sic tyrosine kinase activity within their intracellular tail. After can trigger a variety of intracellular signals, including stimula-
ligand binding, tyrosine kinase activity is stimulated, leading to tion of phospholipase C and the generation of phosphoinositides
phosphorylation of tyrosine residues in target proteins within (most importantly, inositol 1,4,5-triphosphate) and diacylglycerol
the cell. Most receptors also autophosphorylate tyrosine residues through hydrolysis of membrane phospholipids, as well as modu-
present in the receptors themselves to magnify signaling, and, in lation of the second messengers cyclic adenosine monophosphate
some cases, this also causes attenuation of their own activity to and guanosine monophosphate.16 Somatostatin receptors exem-
effect an intramolecular feedback regulatory mechanism. The plify a GPCR prevalent in the GI tract.
receptors for many peptide growth factors, including the receptor Binding of growth factors and cytokines to cell surface recep-
for EGF and related growth factors, belong to this receptor class. tors typically produces alterations in a variety of cellular functions
Other receptors on the cell surface possess kinase activity that influence growth. These functions include ion transport,
directed toward serine or threonine residues rather than tyrosine. nutrient uptake, and protein synthesis. However, the ligand-
These receptors also phosphorylate a variety of cellular proteins, receptor interaction must ultimately modify one or more of the
leading to a cascade of biological responses. Multiple sites of ser- homeostatic mechanisms discussed to affect cellular proliferation.
ine and threonine phosphorylation are present on many growth The Wnt pathway is one important example of a signaling
factor receptors, including the tyrosine kinase receptors, suggest- pathway that regulates a diverse number of homeostatic mecha-
ing the existence of significant interactions among various recep- nisms to control proliferation of intestinal epithelial cells (Fig.
tors present on a single cell.14 The transforming growth factor 1.3). Evolutionarily conserved among several species, Wnt sig-
(TGF)-α receptor complex is one important example of a serine- naling, as a rule, regulates proliferation in the stem cell niche
threonine kinase–containing transmembrane receptor. and is essential for epithelial homeostasis in the GI tract. From a
Wnt
Frizzled Receptor Plasma Membrane
β-catenin
Pi
GSK-3β
GSK-3β
Axin Axin
APC Dishevelled
APC
Pi
Cytosolic
β-catenin
Proteosome
Nucleus c-Myc
Cyclin D1
VEGF
Tcf4
Fig. 1.3 The Wnt signaling pathway is an important regulator of intestinal epithelial cell proliferation and tumori-
genesis. In the absence of a Wnt signal (left top), cytosolic β-catenin is regulated by the destruction complex,
consisting of APC, Axin, and glycogen synthase kinase-3β (GSK-3β). The destruction complex phosphorylates
α-catenin and targets it for degradation via the ubiquitin-proteosome pathway. In the presence of an active
Wnt signal (right top), α-catenin degradation is prevented and the protein is stabilized, leading to excess 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.
signaling perspective, its actions are largely the result of the accu- silencing. Other forms of epigenetic change involve the chemi-
mulation of α-catenin in the nucleus, where it binds with the tran- cal modification of the histone proteins that are required for the 1
scription factor Tcf-4 to activate a set of target genes.17 In normal assembly of the nucleosome and that control chromatin compac-
cells, α-catenin is largely associated with adherens junctions, and tion and DNA access. Although mutations in histones themselves
the cytoplasmic pool of this protein is rapidly degraded through are rare in cancer, mutations in the enzymes that modify histones
a phosphorylation and ubiquitination pathway. This is mediated are emerging as an important group of tumor-associated muta-
by the so-called destruction complex, which includes the tumor tions. It is important to note that involvement by these pathways
suppressor APC. When secreted Wnt ligands bind to cell surface is not mutually exclusive.
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
Clonal Expansion
activation of genes that promote cell proliferation. Inhibition of Clonal expansion is essential to tumor development.25 The acqui-
the Wnt signal in mice can be achieved by deletion of Tcf-4 or sition of a mutation that may provide a growth or survival advan-
overexpression of the Wnt inhibitor Dickkopf1, which results in tage to a cell is followed by clonal expansion of these mutated cells.
dramatic hypoproliferation of the intestinal epithelium.18,19 Wnt As this population grows, and particularly with the acquisition of
signaling is most active in the base of the crypt, and as differentia- genetic/epigenetic instability, a second round of clonal expansion
tion ensues, tissue homeostasis is maintained by growth-inhibit- occurs as a cell within this population sustains still another genetic
ing signals that counterbalance proliferative signals and promote alteration that further enhances its growth properties. This itera-
differentiation, including members of the TGF-α family such as tive process of selection, with accumulating genetic alterations,
BMP4.20 Specific members of this family have unique functions results in malignancy. Because of the nature of the clonal expan-
is tissue homeostasis, including promoting a differentiated and sion process, once frank malignancy has developed, it is often the
fibrogenic phenotype of mesenchymal cells, induction of specific case that multiple clones are present in the same tumor, with a
T cell subtypes, and myriad other activities. In broad terms, the different catalog of mutations harbored among various cancer
effects of TGF-α family members are mediated intracellularly cells. Referred to as tumor heterogeneity, this ongoing process may
through the Smad family of proteins, which are transcription fac- give certain cells selection advantages.26 Metastasis may be facili-
tors that are activated in response to ligand-receptor binding.21 tated by the evolution of a subset of tumor cells that acquire the
TGF-α induces transcription of the cell cycle inhibitors p15INK4B capability of traversing the circulatory system and thriving in a
and p21CIP1/WAF1 and is a potent growth-inhibiting factor that new environment.
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
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
INTESTINAL TUMOR DEVELOPMENT cells that have stem cell–like properties. CSCs are believed to be
the tumor-initiating cells from which clonal expansion occurs.
Multistep Formation Moreover, it is hypothesized that eradication of these cells is a key
Multiple sequential genetic alterations are required for the trans- therapeutic goal because failure to do so may result in relapse of
formation of normal intestinal epithelium to neoplasia. This mul- disease. Within this CSC hypothesis, there are 2 models.27 The
tistep nature of tumorigenesis is most directly illustrated by the first is a hierarchical model in which CSCs serve as progenitors
changes that accrue in the development of colonic neoplasia (see for all cells in in a given tumor, whereas other cells have limited
Chapter 127). The progression from normal epithelium through long-term reproductive potential. The basic evidence for this
adenomatous polyps to malignant neoplasia is paralleled by the model is the finding that only cells with specific surface markers
accumulation of genetic alterations that change key pathways can repopulate the tumor in xenotransplantation experiments. In
that control proliferation and tissue homeostasis. Studies on the the GI tract, analysis of putative CSCs demonstrate transcrip-
molecular pathogenesis of colon cancer have served as a paradigm tional programs and markers shared with normal intestinal stem
for the elucidation of genetic alterations in other GI cancers, cells, such as Lgr5 and EphB2, which identify and purify colon
including gastric and pancreatic cancer. CSCs.28 The second stochastic model posits that each cancer
Genomic instability is observed in almost all cancers in the GI cell has the same potential to be a CSC, but this determination
tract. This genetically unstable environment promotes the accu- is stochastically based on internal factors in addition to external
mulation of the multiple alterations that characterize GI cancers. environmental cues.
Instability of the genome may result from several mechanisms,
including changes in the genome DNA sequence or through mod-
ifications of the nucleotides to alter their functionality, a process
Epithelial-Mesenchymal Transition
called epigenetic change. In colon cancer, there are now 3 well- It has been noted that within tumors of epithelial origin, some
recognized forms of genetic/epigenetic instability that promote cells acquire features of mesenchymal cells. A similar process
carcinogenesis (Fig. 1.4), and they have been termed chromosomal occurs during normal embryogenesis, when polarized epithelial
instability, microsatellite instability (MSI), and CpG island methylator cells no longer recognize the boundaries imposed by adjacent
phenotype (CIMP).23,24 Chromosomal instability refers to altera- epithelial cells or their basement membrane and adopt features of
tions in chromosomal structure resulting in large chromosomal migratory mesenchymal cells. This phenomenon, designated epi-
deletions, duplications, and translocations, which in aggregate thelial-mesenchymal transition (EMT), endows cells with the ability
result in a state of aneuploidy. In contrast, MSI refers to frequent to move through tissue planes that normally serve as boundar-
alterations in tracts of repetitive DNA sequences (referred to ies for epithelial cells, such as the basement membrane, a dense
microsatellite DNA) and are often diploid or near-diploid on a matrix of collagen, glycoproteins, and proteoglycans. The trans-
chromosomal level (see later discussion on DNA repair). CIMP migration of tumor cells through the basement membrane likely
refers to the accumulation of an epigenetic modification, meth- involves production of key proteolytic activities. Alternatively,
ylation of guanine residues in so-called CpG-islands, areas rich the tumor cell may produce factors capable of activating pro-
in cytidine and guanine in gene promoter sites. This modifica- enzymes present in the extracellular matrix. For example, the
tion has a potent effect on gene transcription and results in gene tumor may produce urokinase, itself a protease, or plasminogen
7-10 years
Chromosomal Hyperproliferative Early Late

Normal Carcinoma
instability epithelium Adenoma Adenoma
APC COX2 KRAS TP53

overexpression
2-3 years
Microsatellite Hyperproliferative Early Late

Normal Carcinoma
instability epithelium Serrated Polyp Sessile Serrated Adenoma
Mutations in genes with polynucleotide tracks

Germline mutations in IGF2R, BAX, TGFB2R, etc. TP53
MMR genes followed
'second hit' (˜5%)
MLH1 promoter
methylation and
silencing (˜10%)
Unclear duration
CIMP Hyperproliferative Early Late

Normal Carcinoma
epithelium Serrated Polyp Sessile Serrated Adenoma
CpG island methylation and silencing of tumor

KRAS suppressor genes TP53
or BRAF
mutations
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 on-
cogenes (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 microsatel-
lite instability model (middle pathway), mutations in DNA mismatch repair (MMR) genes create a mutator phe-
notype 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 muta-
tion 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 chro-
mosomal instability to become microsatellite stable tumors.
activator. Having gained access to the interstitial stromal com- DNA repair genes, which prevent accumulation of new muta-
partment, tumor cells can then enter lymphatic and blood vessels tions. Activation of oncogenes or inactivation of tumor suppres-
and metastasize. sor genes contributes to malignant transformation. Although
In addition to these properties, it has been recognized that most of these genes encode for proteins, many cancer-promoting
cells that undergo EMT acquire not only invasive features but genes that harbor oncogenic and tumor suppressive functions
also CSC-like features.29 do not encode for proteins but rather for RNAs that modulate
One key feature of EMT is the loss of adherens junctions genomic function, so-called noncoding RNAs.
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
Oncogenes
Mutations in E-cadherin are common in many GI cancers, par- According to the Catalog of Somatic Mutations in Cancer
ticularly gastric cancer, where germline mutations in E-cadherin (COSMIC),31 there are close to 80 oncogenes with strong evidence
are also linked to hereditary diffuse gastric cancer. of involvement in cancer. Genes that encode a normal cellular pro-
tein, whose function may promote the neoplastic process (e.g., anti-
apoptotic function, cell proliferation stimulation, etc.), may function
NEOPLASIA-ASSOCIATED GENES as oncogenes when they are expressed at inappropriately high levels.
Genes that become altered during the neoplastic process belong A typical mechanism for this phenomenon is gene amplification,
to two distinct groups: (1) oncogenes, which actively confer a when tumors acquire multiple copies of a normal gene resulting in a
growth-promoting property, or (2) tumor suppressor genes, the dosage effect that leads to increased gene expression.
products of which normally restrain growth or proliferation. In other cases, a variety of mutations may lead to inappropri-
An important category within tumor suppressor genes includes ately high activity of a normal gene, leading to cancer-promoting
activities. Point mutations or large gene rearrangements result- Growth factor

ing in fusion proteins are examples of mutations that can lead receptors 1
to oncogene activation. For example, several genes that encode
tyrosine kinase–containing growth factor receptors become
oncogenes after a mutation results in unregulated tyrosine kinase
activity that is no longer dependent on the presence of the appro-
K-ras
priate ligand (e.g., EGF). Because of their tumor-promoting
activity, these mutations tend to be recurrent among specific can-
cer classes. The normal cellular genes from which the oncogenes
derive are designated proto-oncogenes. Most of these genes are
widely expressed in many different types of tumor cells. PI3K B-raf
Finally, another source of oncogenes are virally encoded pro-
teins that may affect cellular growth or survival.32 These factors,
while evolved to favor the viral cycle, may in some instances favor
neoplastic development and this is the reason why specific viruses AKT MEK
are associated with increased cancer risk. In addition, in the case
of retroviruses, the ability of the viral genome to insert itself in
the genome of the host can lead to disruptions in the expression
of genes in the vicinity of insertion sites, which at times, may have mTOR ERK
oncogenic activities.
The proteins encoded by oncogenes may affect any of the
hallmarks of cancer, such as stimulate growth factor pathways,
promote tumor invasion, prevent cell death, or have other tumor- Cell growth
promoting actions. With regards to promoting growth factor Proliferation
pathways, oncogenes may encode for (1) growth factors or their Survival
receptors, or for (2) intracellular signal transduction molecules
downstream of the receptor itself, including transcription factors
that mediate the actions of the growth factor at the level of the
nucleus. Fig. 1.5 Signal transduction downstream of growth factor receptors,
where K-ras plays a major role. Oncogenic K-ras can activate multiple
signaling pathways. Molecules that are frequently mutated in colorectal
Oncogenic Growth Factors and Growth Factor cancer are noted by a red arrow and include K-ras (40%), B-raf (10%),
Receptors and PI3K (15%). AKT, Cellular homolog of v-Akt oncogene; ERK,
The transforming effects of enhanced expression of a variety of extracellular signal regulated kinase; MEK, MAPK/ERK kinase; mTOR,
growth factors have been demonstrated both in vitro and in vivo. mammalian target of rapamycin; PI3K; phosphoinositide-3 kinase.
Several growth factor–related proteins encoded by oncogenes
have now been recognized, including the family of Wnt and Sis
proteins, which encodes the α chain of platelet-derived growth To date, almost all ras mutations in GI malignancies occur in
factor. Cancer cells may engage in autocrine signaling to promote the K-ras oncogene. The highest mutation frequency is found in
their growth, or coax the adjacent stroma to hypersecrete such tumors of the exocrine pancreas (>90%).33 Ras genes activated
growth-stimulating factors. More frequently, a variety of recep- through point mutation have been identified in approximately
tors are upregulated in expression or dysregulated leading to con- 50% of colonic cancers as well as a subset of serrated tumors (see
stitutive action. Among them, are receptor tyrosine kinases of the Fig. 1.4).34
EGF receptor family (ERBB1-4), which are frequently upregu- Most oncogenic mutations in ras cause biochemical changes
lated in a variety of GI cancers. that maintain it in the active, guanosine triphosphate–bound state
by reducing guanosine triphosphatase activity or by destabiliz-
ing the inactive guanosine diphosphate–bound form. However,
Signal Transduction–Related Oncogenes several ras mutants retain significant guanosine triphosphatase
Intermediate steps that effectively translate ligand-receptor activity; therefore, other mechanisms that convert ras to a trans-
binding to an intracellular signal are essential in mediating func- forming protein may be involved.35
tional responses of the cell. Mutations in genes that encode key A functional consequence of ras activation is the phosphoryla-
proteins that participate in signal transduction can also lead to tion and activation of key downstream serine/threonine kinases.
cellular transformation (Fig. 1.5). In this regard, the largest fam- One important target of ras is B-raf. In colon cancers without
ily of oncogenes encodes proteins with protein kinase activity. an identifiable K-ras mutation, 20% possess an activating B-raf
Many members of this large oncogene group are expressed by mutation,36 consistent with the concept that activation of an
neoplasms of the GI tract, and these include the Src nonrecep- oncogenic pathway can be achieved through an alteration in any
tor tyrosine kinase that associates with the inner surface of the of several sequential components of a particular pathway (see
plasma membrane. Fig. 1.5).
G proteins regulate signaling of the large family of GPCRs
through the exchange of guanosine triphosphate with guano-
sine diphosphate. In this regard, the ras family of genes, which
Nuclear Oncogenes
encodes a family of proteins related to the G proteins, are among Many cellular oncogenes encode proteins that localize to the
the most commonly detected oncogenes in GI tract cancers. The nucleus. In essence, these nuclear oncogene products are the final
ras family contains 3 genes: H-ras, K-ras, and N-ras. These factors mediators of signal transduction pathways that are also affected
are essential to transduce signals from various growth receptor by cytoplasmic and plasma membrane–bound oncoproteins,
signaling cascades and point mutations that result in activating because they act as transcription factors that regulate expression
amino acid substitutions at critical hot spot positions convert the of certain genes that enhance cellular proliferation and suppress
normal gene into an oncogene. normal differentiation.
The role of nuclear oncogenes is illustrated by the myc family. only one additional hit is required, leading to the younger age of
The c-Myc protein product is involved in critical cellular func- onset and the potential for tumor multiplicity that accompanies
tions like proliferation, differentiation, apoptosis, transformation, these syndromes.
and transcriptional activation of key genes.37 Frequently, c-Myc Although this 2-hit model has been generally observed, there
is overexpressed or amplified in many GI cancers. c-Myc has been are exceptions. Some tumor suppressors may function to increase
found to be a transcriptional target of the α-catenin/TCF-4 com- cancer risk when only one allele is mutated. Moreover, some
plex in colorectal cancers (see Fig. 1.3), which may explain the cancer genetic syndromes display somatic recessive mode of
overexpression of c-Myc observed in this cancer type.38 inheritance because genetic risk is conferred only when biallelic
inactivating mutations are present. Another important feature of
tumor suppressor genes is that they do not function identically
Tumor Suppressor Genes in every tissue type. Consequently, inactivation of a particular
Mutations of tumor suppressor genes are associated with all GI tumor suppressor gene is tumorigenic only in certain tissues. For
cancers, and a number of these genes and their products have example, the tumor suppressor genes RB1 and VHL play crucial
been identified and characterized (Table 1.1). Unlike gain-of- roles in retinoblastomas and renal cell cancer, respectively, but
function mutations, which are characteristic of oncogenes, muta- are rarely mutated in GI malignancies. Tumor suppressor genes
tions in tumor suppressor genes are loss-of-function mutations shown to have a critical role in the pathogenesis of GI malignan-
and are therefore biallelic. cies, APC, TP53, and SMAD4, are described later. Furthermore,
Initial recognition of the existence of tumor suppressor genes we will discuss DNA repair pathways that, when lost, can give rise
was derived from genetic analyses of cancer-prone families. In to neoplasia and therefore function as tumor suppressor factors.
the GI tract, hereditary colon cancer, gastric cancer, and pancre-
atic cancer syndromes are the best described and are discussed
elsewhere in this text (see Chapters 54, 60, and 127). In these
Adenomatous Polyposis Coli Gene
syndromes, there is a marked increase in risk for a particular Genetic linkage analysis revealed markers on chromosome 5q21
tumor in the absence of other predisposing environmental fac- that were tightly linked to polyp development in affected mem-
tors. Tumors arise typically at a younger age than they do in the bers of kindreds with familial adenomatous polyposis (FAP) and
general population, and multiple primary tumors may develop Gardner’s syndrome.40 Further work led to identification of the
within the target tissue. gene responsible for FAP, the APC gene.41-43 The full spectrum
From a genetic standpoint, cancer genetic syndromes most of adenomatous polyposis syndromes attributable to APC is dis-
often have an autosomal dominant mode of mendelian inheri- cussed in detail in Chapter 126. Somatic mutations in APC have
tance. Based on observations in hereditary retinoblastoma, also been found in most sporadic colon polyps and cancers.44,45
Knudson proposed the “2-hit” hypothesis,39 which explains Mutations in APC are characteristically identified in the earliest
the relationship between sporadic and familial forms of cancer. adenomas, indicating that APC plays a critical role as the gate-
Whereas sporadic tumors are initiated by somatic biallelic inac- keeper in the multistep progression from normal epithelial cell to
tivating mutations of a tumor suppressor gene, tumors in familial colon cancer (see Fig. 1.4).
cancer syndromes are accelerated by the inheritance of a monoal- The APC gene comprises 15 exons and encodes a predicted
lelic mutation of a tumor suppressor gene present in all cells in protein of 2843 amino acids, or approximately 310 kDa. Most
affected family members. When this germline mutation is fol- germline and somatic APC gene mutations result in a premature
lowed by a somatic mutation in the remaining normal allele of stop codon and therefore a truncated APC protein product and
the tumor suppressor gene, this gives rise to the development of loss of function. As discussed earlier, APC is a negative regulator
a neoplastic clone that eventually gives rise to a tumor (Fig. 1.6). of the Wnt signaling pathway and its inactivation results in a state
Because of the germline mutation, the likelihood of full inactiva- that resembles constitutive activation of Wnt. Intracellularly,
tion of the tumor suppressor is diminished substantially because
Acquired
Germline somatic
TABLE 1.1 Mutations Associated with Hereditary Gastrointestinal mutation mutation
Cancer Syndromes
TSG X
Disorder Gene(s) Mutated Inherited

cancer Tumor
FAP, AFAP, Gardner syndrome APC syndrome
Lynch syndrome (HNPCC) MLH1, MSH2, PMS2, MSH6, Acquired Second
EPCAM (through disruption of the somatic somatic
neighboring MSH2 gene) mutation mutation
MAP MUTYH X X
Peutz-Jeghers syndrome STK11 Sporadic

Tumor
cancer
Cowden’s disease PTEN
Juvenile polyposis SMAD4, BMPR1A
Hereditary diffuse gastric cancer CDH1 Time
Hereditary pancreatic cancer ATM, BRCA1, BRCA2, PALB2, , Tumor suppressor gene.
PALLD, CDKN2A, PRSS1,
Fig. 1.6 Knudson’s 2-hit hypothesis. In an inherited cancer syndrome,
SPINK1, PRSS2, CTRC, CFTR
one chromosome has an inactive tumor suppressor gene (TSG) locus
MEN1 Menin because of a germline mutation. The counterpart TSG on the remaining

AFAP, Attenuated FAP; APC, adenomatous polyposis coli; FAP, familial paired chromosome is subsequently inactivated by a somatic mutation,
adenomatous polyposis; HNPCC, hereditary nonpolyposis colorectal leading to tumor formation. In contrast, in a sporadic cancer, the two
cancer; MAP, MUTYH-associated polyposis; MEN1, multiple alleles of the TSG need to become inactivated through two indepen-
endocrine neoplasia, type 1; MUTYH, mutY homolog. dent somatic mutations, an event that is less likely to occur within a
single cell.

this is manifested by stabilization of α-catenin, which mediates DNA fragment, fill in the gap with the correct nucleotide, and
the transcriptional effects of Wnt activation and the subsequent finally reseal the remaining nick. The family of DNA mismatch 1
oncogenic phenotype (see Fig. 1.3). Interestingly, another mecha- repair genes includes two basic molecular components, a mis-
nism to achieve this signaling outcome are mutations in α-catenin match recognition complex composed of MSH2 and MSH6, and
itself that render the protein impervious to APC-dependent deg- an excision inducing complex composed of MLH1 and PMS2.
radation. Mutations in any of these genes result in defective mismatch
repair, and when inherited due to a germline mutation, they
give rise to Lynch syndrome, also known as hereditary nonpolypo-
TP53 Gene sis colorectal cancer.55,56 Complete loss of a mismatch repair factor
This is the most commonly mutated gene in human cancer,46 and leads to very high rates of DNA mutations, and mismatch repair
point mutations in TP53 are found with high frequency in all can- defective tumors accumulate a high burden of cancer somatic
cers of the GI tract.47 In fact, point mutations in TP53 have been mutations, typically over 2000 somatic mutations, resulting in a
identified in as many as 50% to 70% of sporadic colon cancers large number of tumor-specific neoantigens.57 Affected cells are
(see Fig. 1.4). Interestingly, these mutations arise relatively late called replication error positive, in contrast to the replication error–
in the oncogenic process as the gene is mutated in only a small negative phenotype.58,59 Because microsatellite DNA sequences
subset of colonic adenomas.48 are primarily affected by this type of genetic instability, the tumor
Named for a 53-kDa-sized gene product, p53 is a nuclear cells display insertions or deletions in these stretches of DNA
phosphoprotein that plays a key role in cell cycle regulation and when compared to nontumor tissue, a phenomenon referred to
apoptosis.47 In the nucleus, p53 functions as a transcription fac- as microsatellite instability. Mechanistically, the absence of DNA
tor which can be induced by conditions of cellular stress, such as repair does not directly cause cancer but creates a milieu that per-
ionizing radiation, growth factor withdrawal, or cytotoxic ther- mits accumulation of mutations in a variety of genes that contain
apy. Induction of p53 arrests cells at the G1 phase to facilitate repetitive DNA sequences, such as the TGF-α type II receptor,
DNA repair, senescence, or trigger apoptosis. These responses IGF type II receptor, BAX, and E2F-4, among others.
are mediated in part by its transcriptional targets such as the Loss of mismatch repair genes represents an important
p21CIP1/WAF1 inhibitor of the cell cycle or the proapoptotic gene, mechanism for the accumulation of mutations within a tumor
PUMA.49 Interestingly, it is often the case that TP53 mutations (see Fig. 1.4). While 5% of colon cancer are due to Lynch syn-
occur as the combination of a genomic deletion encompassing drome, i.e., germline mutations in the mismatch repair system,
one allele, together with a missense mutation in the second allele twice as many tumors (10%) display similar molecular charac-
that targets specific hotspots within the protein. Recent evidence teristics without a germline mutation in any of the mismatch
indicates that the genomic deletions function not only by remov- repair genes. These tumors are most often driven by somatic
ing TP53 but through the loss of adjacent genes with tumor sup- loss of function in this system, most often as a result of silencing
pressive activities.50 Furthermore, the second type of mutations, of MLH1 gene expression as a result of an epigenetic change
resulting in specific missense mutations are thought to contribute in the promoter region of this gene called DNA methylation.
gain-of-function tumorigenic activities.51 In addition to the TP53 MLH1 promoter hypermethylation is most often observed in
point mutations in sporadic cancers, germline TP53 mutations lesions that are serrated adenomas by histology and that also
have been observed in the Li-Fraumeni syndrome, an autosomal carry B-Raf mutations (see Fig. 1.4). Finally, it has been recog-
dominant familial disorder in which breast carcinoma, soft tissue nized that another mechanism that can lead to a state of high
sarcoma, osteosarcoma, leukemia, brain tumor, colon cancer, and mutation burden is the loss of exonuclease proofreading activity
adrenocortical carcinoma can develop in affected persons.52 of the replicative DNA polymerase Pol-ε or Πολ–δ, through a
variety of missense mutations.60
Another important DNA repair pathway involved in carci-
SMAD4 Gene nogenesis is mediated by the MUTYH gene. It encodes a DNA
SMAD4 is a tumor suppressor gene located on chromosome 18q glycosylase that participates in the repair of oxidized guanine
and is deleted or mutated in most pancreatic adenocarcinomas nucleotides, such as 8-oxoguanine residues, that may inappropri-
and a subset of colon cancers. Smad4, the protein encoded by this ately pair with adenines, ultimately leading to somatic G:C→T:A
gene is an essential intracellular mediator of factors belonging to mutations if uncorrected. Biallelic mutations in MUTYH results
the TGF-α superfamily. Smad4 functions as a transcription fac- in an adenomatous polyposis syndrome that resembles FAP,
tor and is an obligate partner of other members of the Smad pro- except that its mode of inheritance is autosomal recessive (see
tein family.53 Mutant Smad4 lacks these properties and among Chapter 126).61,62 Interestingly, G:C→T:A mutations in the APC
other effects, leads to loss of TGF-α inhibition of proliferation. gene were almost universally found in the polyps of patients with
Germline mutations in SMAD4 result in the juvenile polyposis germline MUTYH mutations, indicating that there are impor-
syndrome (see Chapter 126). tant similarities in the molecular pathogenesis of polyps in the
MUTYH and FAP syndromes.
DNA Repair Genes
DNA replication itself and various types of DNA damaging agents
Noncoding RNAs
can introduce errors into the genome. These errors include spon- Our genomes harbor a variety of genes whose products are RNAs
taneous mismatching of nucleotides during normal DNA replica- that do not encode for a protein. The RNA products, termed non-
tion, oxidative damage of nucleotides, and complete double-strand coding RNAs, consist of a broad category of active RNA molecules
breaks. Therefore, a variety of cellular mechanisms have evolved that can mediate a variety of effects. The categories of noncoding
to prevent or correct DNA errors. One type of error that devel- RNAs are rapidly expanding and include so-called microRNAs
ops during replication may occur in repetitive mononucleotide or and long noncoding RNAs, which are frequently dysregulated in
dinucleotide stretches of DNA, so-called microsatellite regions.54 cancers. The microRNAs play a critical role in silencing of other
These repetitive regions are prone to DNA mismatches, which if RNA transcripts via RNA degradation or translational inhibition
not resolved, can result in short insertions or deletions. The cel- and typically regulate dozens of target RNAs at a time. Their
lular machinery devoted to correct these errors is referred to the biogenesis involves conventional gene transcription, followed by
mismatch repair system. The enzymes bind mismatched DNA, processing of the resulting RNA by a variety of nuclease cleavage
cut the DNA strand with the mismatched nucleotide, unwind the events, resulting ultimately in the generation of small interfering
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At Linz I stopped long enough to thank Anderson and his colonel
for the escort vehicles they had produced on a moment’s notice that
morning in response to a call from Colonel Sheehan. This third pair
of jeeps were very conscientious about their escort duties. The one
in the vanguard kept well in the lead and would signal us whenever
he came to a depression in the road. This got on Leclancher’s
nerves, for I heard him muttering under his breath every time it
happened. But I was so glad to have an escort of any kind that I
pretended not to notice his irritation.
When we reached Lambach, midway between Linz and Salzburg,
we lost this pair of guardians but acquired two sent on from the latter
city. While waiting for them to appear, I scrounged lunch for myself
and the drivers at a local battery. As soon as the new escorts arrived
we started on again and pulled into Salzburg at two-thirty. This time
there were no delays and we threaded our way through the dripping
streets and out on to the Autobahn without mishap.
I now had only one remaining worry—the bad detour near
Rosenheim. Again, perhaps thanks to the weather, we were in luck
and found this treacherous by-pass free of traffic. As we rolled into
Munich, the rain let up and by the time we turned into the
Königsplatz, the sun had broken through the clearing skies.
My first major evacuation job was finished. As soon as I got my
drivers fixed up with transportation back to their camp and the
members of our escort party fed and billeted I could relax with a
clear conscience. It was a little after five-thirty, and Third Army’s
inflexible habits about the hour at which all enlisted men should eat
didn’t make this problem such an easy one. Third Army
Headquarters was a good twenty minutes away, so I took the men to
the Military Government Detachment where the meal schedule was
more elastic. Afterward I shepherded them to their billets and went
off to my own. I would have to write up a report of the expedition for
Captain Posey, but that could wait.
(5)
SECOND TRIP TO HOHENFURTH
The first order of business the next morning was a conference with
Captain Posey. I gave him a complete account of the Hohenfurth trip
and presented my recommendations for a second and final visit to
complete the evacuation. It was my suggestion that I return to the
monastery with the same trucks—as soon as they could be unloaded
and serviced—and that he send up another officer with at least eight
additional trucks, the second convoy to arrive by the time I had
completed the loading of my own. I proposed taking four packers this
time instead of two, the idea being that two of the packers could help
me with the loading while the others were building cases for the
fragile objects which would have to be crated. I mentioned also the
impending withdrawal of our troops from Hohenfurth, which would
make later operations of such nature impossible.
This was of course no news to Captain Posey as, presumably, it
had been the determining factor in the removal of the Hohenfurth
things in the first place. He approved my plan and advised me to get
my trucks lined up, and said he would see what he could do about
sending an additional officer. I didn’t like the sound of that. Too often
I had used those same words myself when confronted with a difficult
request. Furthermore, it had been my experience with the Army in
general thus far—and with Third Army in particular—that “out of
sight, out of mind” was a favorite motto. I had no intention of going
back to Hohenfurth until I had a definite promise that reinforcements
would be forthcoming. I think that my insistence piqued the captain a
bit. But at that point I was feeling exceedingly brisk and businesslike
—a mood which I found new and stimulating. It would be better to
have a clear understanding now as to who would join me in
Hohenfurth; as I explained to Captain Posey, I would like to give the
officer some detailed instructions, preferably oral ones, before I
started off.
I spent the rest of that day and most of the following one at the
Verwaltungsbau supervising the unloading of the ten trucks from
Hohenfurth and making trips out to the trucking company
headquarters to conclude arrangements for continued use of the
vehicles. Also, I had to put in a request for eight others. It was
gratifying to find that every piece we had packed at Hohenfurth came
through without a scratch. My two packers, to whom all credit for this
belonged, were equally elated. My request for the services of four
packers was met with black looks, but when I promised that we’d not
be gone more than four or five days, Craig acquiesced.
Late in the afternoon of the second day, I went again to Posey’s
office. He was not there but I found Lincoln, as usual hunched
morosely over his typewriter. He said he had good news for me.
Captain Posey had pulled a fast one and snatched a wonderful guy
away from Jim Rorimer, Monuments Officer at Seventh Army—a
fellow named Lamont Moore. Moore was already, he thought, on his
way down to Munich to make the trip to Hohenfurth. When I said I
didn’t know Moore, Lincoln proceeded to tell me about him.
“Lamont was director of the educational program at the National
Gallery in Washington before he went into the Army. Before that he
had a brilliant record at the Newark Museum. The two of you ought
to get along famously. Lamont’s got a wonderful sense of humor.
He’s exceedingly intelligent and he’s had a lot of experience in
evacuation work.”
“Where did you know him?” I asked.
“We were in France last winter. That was before he was
commissioned. He’s a lieutenant now,” Lincoln said.
“That sounds perfect. But I want to ask you a question about
something else and I want a truthful answer. I have a sneaking
notion that you knew all the time what was in that monastery at
Hohenfurth. How about it?”
“Furniture and sculpture, you mean, instead of paintings?” he
asked. “Of course I didn’t.”
“Well, maybe you didn’t, but perhaps you can imagine how I felt
when I found that the Mannheimer collection alone contained more
than two thousand items, and that the Rothschild pieces totaled up
to a similar figure.”
Lincoln’s chuckle belied his protestations. “I’ve got another piece
of news for you,” he said. “John Nicholas Brown and Mason
Hammond are arriving tomorrow. I thought you might like to see
them before you return to Hohenfurth.”
“You told me once that Captain Posey, like many another officer,
doesn’t relish visitors from higher headquarters,” I said. “Am I to infer
a connection between his absence from the office and the impending
arrival of these two distinguished emissaries from the Group Control
Council?”
He assured me that I was not, but I left the office wondering about
it all the same.
That evening George Stout paid one of his rare and fleeting visits
to Munich. On these occasions he stayed either with Craig or Ham
Coulter. This time the four of us—all “strays” from the Navy—
gathered in Ham’s quarters.
“The work at the mine,” George said, “is going along as rapidly as
can be expected in the circumstances. But it’s got to be stepped up. I
came down to find out how soon you could join me.”
“I’m going back to Hohenfurth again,” I said. “Lamont Moore is to
meet me there.”
George was glad to hear this and said that he and Lamont had
worked together at the Siegen mine in Westphalia. He confirmed all
of the good things Lincoln had told me about Lamont and said that
he’d like to have both of us at Alt Aussee. He promised to have a talk
with Posey about it, because he was of the opinion that these big
evacuation jobs should be handled by a team rather than by a single
officer. According to George, a team of at least three—and
preferably four—officers would be the perfect setup. Then the work
could be divided up. Each officer would have specific duties,
assigned to him on the basis of his particular talents. But all
members of the team would have responsibilities of equal
importance. It would be teamwork in the real sense of the term.
Like all of George’s proposals, this one sounded very sensible. At
the same time, when I recalled the haphazard way I had been
obliged to conduct operations thus far myself, I wondered if it weren’t
Utopian. That didn’t discourage George. When he had a good idea
he never let go of it. And, if we had only been a larger group, I am
convinced that his brain child about teams would have had wonderful
results. As it was, the events of the next few weeks were to
demonstrate how effective the scheme was on a small scale.
When I got out to Third Army Headquarters the next morning,
George had already come and gone. I would have liked to ask Posey
about their conversation but he didn’t seem to be in a chatty mood—
at least not on that subject. However, he did have a few caustic
things to say about “people from high headquarters who have
nothing better to do than travel around and interrupt the work of
others.”
Knowing that he was referring to Messrs. Brown and Hammond—
Lincoln’s assurance of the night before to the contrary
notwithstanding—I piously observed that high-level visitors to the
field might do quite a lot of good. For one thing, the fact that they had
taken the trouble to visit it emphasized the importance of the work
they had come to inspect; and, for another, it pleased the officer in
the field to have his job noticed by the boys at the top. I thought I
sounded pretty convincing, but sensing that I was not, I turned to
other topics.
About that time John and Mason arrived. Our last meeting had
taken place in the vaults of the Reichsbank at Frankfurt several
weeks before. Mason referred to that and jokingly accused me of
having run out on him. When I told him that I was about to return to
Hohenfurth he announced loudly that that was perfect—he and John
would drop in to see me there. I said that would be fine but, when I
noted the expression on Captain Posey’s face, I added to myself,
“fine, if they get the clearance.” Before coming up to see me, they
expected to visit one or two places south of Munich, so they wouldn’t
reach Hohenfurth before the end of the week.
Captain Posey was a great believer in the old theory that the Devil
finds work for idle hands, at least as far as I was concerned. That
same afternoon he casually suggested that I take a “little run down
into the Tyrol” for him and inspect a castle about which he had been
asked to make a report. He proposed the trip with such prewar
insouciance that it sounded like a pleasant holiday excursion. As a
matter of fact it was an appealing suggestion, despite my plans for
an early morning start to Hohenfurth.
It was a beautiful summer day and my jeep driver asked if a friend
of his, a sergeant who was keen about photography, might come
along. I agreed and the three of us headed out east of Munich on the
Autobahn. It was fun to be riding in an open jeep instead of an
enclosed truck.
We reached Rosenheim in record time and there struck south into
the mountains. Our objective was the little village of Brixlegg,
between Kufstein and Innsbruck. We were on the main road to the
Brenner Pass. Italy was temptingly close. We stopped from time to
time so that the sergeant could get a snapshot of some particularly
dramatic vista. But there was an embarrassment of riches—every
part of the road was spectacularly beautiful.
Brixlegg was a tiny cluster of picturesque chalets, but it had not
been tiny enough to elude the attentions of the air force. On the
outskirts we saw the shattered remains of what had been an
important factory for the manufacture of airplane parts. Happily, the
bombers had concentrated their efforts on the factory. The little
village had suffered practically no damage at all.
We located our castle without difficulty. It was Schloss Matzen,
one of the finest castles of the Tyrol—the property of a British officer,
Vice-Admiral Baillie-Grohman. This gentleman had requested a
report on the castle from the American authorities. We found
everything in perfect order. The admiral’s cousin—a Hungarian
baron named Von Schmedes who spoke excellent English—was in
residence. He showed us over the place. The castle was an example
of intelligent restoration. According to the inscription on a plaque
over the entrance, the aunt of the present owner had devoted her life
to this task.
Although an “Off Limits” sign was prominently displayed on the
premises, the baron was fearful of intruders. As the castle stood
some distance from the main highway, I thought he was being
unduly apprehensive. He said that an official letter of warning to
unwelcome visitors would be an added protection. To please him I
wrote out a statement to the effect that the castle was an historic
monument, the property of a British subject, etc., and signed it in the
name of the Commanding General of the Third U. S. Army.
On our way out we were shown two rooms on the ground floor
which were filled with polychromed wood sculpture from the museum
at Innsbruck. The baron said that additional objects from the
Innsbruck museum were stored in a near-by castle, Schloss
Lichtwert.
It was but a few minutes’ drive from Schloss Matzen, so I decided
to have a look at it. Schloss Lichtwert, though not nearly so
picturesque either in character or as to site, was the more interesting
of the two. It stood baldly in the middle of a field and was actually a
big country house rather than a castle.
We were hospitably received by a courtly old gentleman, Baron
von Iname, to whom I explained the reason for our visit. One of his
daughters offered to do the honors, saying that her father was
extremely deaf. We followed her to a handsome drawing room on
the second floor, where several other members of the family were
gathered in conversation around a large table set with coffee things.
In one of the wall panels was a concealed door, which the daughter
of the house opened by pressing a hidden spring. Leading the way,
she took us into a room about twenty feet square filled with violins,
violas and ’cellos. They hung in rows from the ceiling, like hams in a
smokehouse. Fräulein von Iname said that the collection of musical
instruments at Innsbruck was a very fine one. We were standing in a
Stradivarius forest.
When we passed back into the drawing room, the father
whispered a few words to his daughter. She turned to us smiling and
said, “Father asked if I had pointed out to you the thickness of the
walls in this part of the castle. He is very proud of the fact that they
date from the fourteenth century and that our family has always lived
here. He also asks me to invite you to take coffee with us.”
Knowing that coffee was valued as molten gold, I declined the
invitation on the grounds that we had a long trip ahead of us.
Thanking her for her courtesy, we left. It was after eleven when we
got back to Munich. We had driven a little more than three hundred
miles.
Bad weather and bad luck attended us all the way to Hohenfurth
the next day. Less than an hour out on the Autobahn, we came upon
a gruesome accident—an overturned jeep and the limp figures of
two GIs at one side of the road, the mangled body of a German
soldier in the center of the pavement. An ambulance had already
arrived and a doctor was ministering to the injured American
soldiers. The German was obviously beyond medical help. As soon
as the road was cleared, we continued—but at a very sober pace.
On the other side of Salzburg we had carburetor trouble which
held us up for nearly two hours. It was after five thirty when we
reached Linz. We stopped there for supper and I had a few words
with the colonel who had looked after us so well a few days before.
He seemed surprised to see me again, and rather agitated.
“You can get through this time,” he said, “but don’t try to come
back this way.”
“What do you mean, sir?” I asked, puzzled by his curt admonition.
Apparently annoyed by my query, he said brusquely, “Don’t ask
any questions. Just do as I say—don’t come back this way.”
At supper I saw Lieutenant Anderson again and I broached the
subject to him. “Does the colonel mean that the Russians are
expected to move up to the other side of the Danube?” I asked.
“Take a good look at the bridge when you cross over tonight,” he
said.
It was my turn to be nettled now. “Look here, I don’t mean to be
intruding on any precious military secret, but I am expecting a
second convoy to join me at Hohenfurth in two days; if the other
trucks aren’t going to be able to get through I ought to let the people
at Third Army Headquarters know.”
“Well, frankly I don’t know just what the score is, but the colonel
probably has definite information,” he said. “What I meant about the
bridge is that it’s jammed with people and carts, all coming over to
the west side of the Danube. It’s been like that for the past two days
and it can mean only one thing—that the Russians aren’t far behind.”
This wasn’t too reassuring, but I decided to take a fatalistic attitude
toward it. If I had to find some other route back from Hohenfurth, I’d
worry about it when the time came. I did, however, try to get through
to Third Army Headquarters on the phone. Posey’s office didn’t
answer, so I asked Anderson to put in a call for me in the morning.
It was slow going over the bridge, but we finally forced our way
through the welter of carts and wagons. Once we were in open
country, the traffic thinned out and we moved along at a faster pace.
The Czech and American officers at the frontier recognized us and
waved us through without formality. We arrived in Hohenfurth a little
before nine. I knew the ropes this time, so it was a simple matter to
get the men billeted in the monastery. After that I went on to my own
former billet. When I reached the house, I found a group of officers in
the recreation room. They were holding an informal meeting. Colonel
Sheehan was presiding and motioned to me to join the group. He
had just returned from the headquarters at Budweis with important
news. His own orders had come through, so he would be pulling out
for home in a few days. But of greater concern to me was the news
that the Czechs would definitely take over at the end of the week.
We would still have some troops in the area, but their duties would
be greatly curtailed. I would have to finish the job at the monastery
as fast as possible and head back to Munich.
We resumed our work at the monastery with surprisingly few
delays. It was almost as if there had been no interruption of our
earlier operations. This time I had double the number of PWs, so I
did not have to call on the drivers to help with the loading. During my
absence, Dr. Mutter had put a stonemason to work on the pieces
which had been set into the wall, and these now lay like parts of a
puzzle in a neat pattern on the floor of the reception hall, ready to be
packed. He had also procured lumber and nails, so my two extra
packers were able to get to work on the cases which had to be built.
By evening, seven of the trucks were loaded, leaving only one more
to do the next day.
That night I consulted one of the officers, who had a wide
knowledge of the roads in that area, about an alternate route to
Munich. He showed me, on the map, a winding back road which
would take me through Passau—instead of Linz and Salzburg—to
Munich. It was, he said, a very “scenic route” but longer than the way
I had come. He felt sure, though, that I could get my trucks through,
that there were no bad detours, etc. It was comforting to know that
this route existed as a possibility—just in case. But I still had hopes
of being able to go back by way of Linz, in spite of the colonel’s
warning.
The next day was the Fourth of July—not that I expected either my
French or German associates to take special notice of the fact. Still I
was glad that I had only one truck to load on the holiday. I took
advantage of the later breakfast hour, knowing that my faithful
German packers would be on the job at seven o’clock as usual.
When I arrived at the monastery at nine-thirty, I found that the last
truck was already half loaded. There was enough room to add the
two cases containing the Della Robbia plaque and the Renaissance
fireplace taken out of the wall; and, if we were careful, we might find
a place for the fifteenth century Florentine relief which the
stonemason had also painstakingly removed. Once that was done,
there was nothing to do but wait for the arrival of Lieutenant Moore
and the additional trucks.
I called the workmen together. In halting German, I explained the
significance of the Fourth of July and announced that there would be
no more work that day. It was providentially near the lunch hour. I
could send the PWs back to their camp as soon as they had eaten.
The German packers, intent on returning to Munich as soon as
possible, chose to get on with the cases they were building. Dr.
Mutter and I retired to his study to take stock of the receipts we had
thus far made out. As for the French drivers, they had disappeared
to their quarters.
After lunching at the officers’ mess, I decided to celebrate the
Glorious Fourth in my own quiet way. Major Whittemore had lent me
a car, so I set out on an expedition of my own devising. Ever since
the night of our trip to Krummau, I had wanted to explore the castle
of Rosenberg, and this seemed the logical time to do it. Rosenberg
was only eight kilometers away.
It was a sleepy summer afternoon. Not a leaf was stirring as I
followed the winding Moldau into the pretty village with its storybook
castle. The road to the castle was rough and tortuous, reminding me
of a back road in the Tennessee mountain country. Just as I was
beginning to wonder if the little sedan were equal to the climb, the
road turned sharply into a level areaway before the castle courtyard.
I parked the car and went in search of the caretaker. When I found
no one, I ascended a flight of stone steps which led from the
courtyard to the second floor. The room at the head of the stairs was
empty, but I heard voices in the one adjoining. Two cleaning women
were scrubbing the floor, chattering to each other as they worked.
They were startled to see me, but one of them had the presence of
mind to scurry off and return a few minutes later with the archetype
of all castle caretakers. He had been custodian for the past fifty-six
years. Lately there hadn’t been many visitors.
He took me first to the picture gallery—a long high-ceilinged room
with tall windows looking out over the river. There were a dozen full-
length canvases around the rough plaster walls, past Dukes of
Rosenberg and their sour-faced Duchesses. The clou of the
collection was a tubercular lady in seventeenth century costume.
The caretaker solemnly informed me that she was the ill-fated
duchess who paced the ramparts of the castle every night just before
twelve. She had lived, he told me, in the fourteenth century. When I
mentioned as tactfully as possible that her gown indicated she had
been a mere three hundred years ahead of the styles, he gave me a
dirty look as much as to say, “a disbeliever.” I did my best to erase
this unfortunate impression and proceeded to the next series of
apartments. They included a weapon room, a sumptuous state
bedchamber reserved for royal visitors, several richly furnished
reception rooms, and a long gallery called the Crusaders’ Hall—a
copy, the caretaker said, of a room in the Palace at Versailles. Here
hung full-length portraits of such historic personages as Godefroy de
Bouillon, Robert Guiscard and Frederick Barbarossa—all done by an
indifferent German painter of the last century. Notwithstanding its
ostentatious atmosphere, the gallery had a dignity quite in keeping
with the musty elegance of the castle.
I thanked the old man, gave him a couple of cigarettes and
returned to the car. It was time for me to be getting back to the
monastery.
I gauged my arrival nicely. As I pulled up to the entrance, the
guard at the archway came over to the car to tell me that eight trucks
had just driven through. When I reached the courtyard the last of
them was backing up against the chapel wall.
A tall, rangy lieutenant, wearing the familiar helmet liner prescribed
by Third Army regulations, walked up to the car as I was getting out
and said, “Good afternoon, sir. Dr. Livingstone, I presume?”
So this was Lamont Moore. Just as Lincoln had predicted, I liked
him at once. There was a quiet self-possession about him, coupled
with a quizzical, humorous expression, which was pleasantly
reassuring. I have never forgotten the impression of Olympian calm I
received at that first meeting. In succeeding months, there were
many times when Lamont got thoroughly riled, but his composure
never deserted him. His even temper and his sense of humor could
always be depended upon to leaven the more impetuous actions of
his companions.
Without wasting breath on inconsequential conversation, he
suggested that we “case the joint.” After introducing him to Dr.
Mutter, who was still hovering around like a distracted schoolmaster,
we made a tour of the premises. By the time we had finished I had
the comforting, if somewhat unflattering, feeling that he had a clearer
understanding of the work there than I, notwithstanding the time I
had spent at the monastery.
On our way down to the village afterward, I asked Lamont if he
had had any difficulty coming up through Linz. He said no, but that
he also had been warned not to return that way.
As soon as he had found a billet, we settled down to talk over the
loading of his trucks. “The colonel says that we’ll have to finish the
job in a hurry. The Czechs are taking over at the end of the week,” I
said. “And if the Russians move up to the Danube, we won’t be able
to go back by way of Linz. We’ll have to return by way of Passau.”
“I understand that there isn’t any bridge over the Danube at
Passau,” Lamont said quietly. At that I got excited, but in the same
quiet voice Lamont said, “Don’t worry. We’ve got more important
things to think about—something to drink, for example.”
We went over to the officers’ club, arriving just in time to be offered
a sample of the Fourth of July punch which two of the officers had
been mixing that afternoon. From the look of things, they had perfect
confidence in their recipe, which called for red wine, armagnac and
champagne. After the first sip I didn’t have to be told there would be
fireworks in Hohenfurth that evening.
Lamont and I began to discuss mutual friends and acquaintances
in the museum world, a habit deeply ingrained in members of our
profession. We agreed that a mutual “hate” often brought people
together more quickly than a mutual admiration. Then inconsistently
—it was probably the punch—we started talking about Lincoln,
whom we both liked very much.
“It was Lincoln who told me what a fine fellow you are, Lamont,” I
said.
“That’s interesting,” he said with a noiseless laugh. “He said the
same thing about you.”
Comparing notes, we found that Lincoln had given us identical
vignettes of each other.
“Tell me something about the work you’ve been doing in MFA&A.
This is my first real job, so I’m still a neophyte,” I said.
Lamont rolled his eyes wearily and said, “Oh, I’ve been evacuating
works of art for the past four months, and I wonder sometimes if it’s
ever going to end. Siegen was my big show. It was the foul and
dripping copper mine in Westphalia where the priceless treasures
from the Rhineland museums were stored. The shaft was two
thousand feet deep and some of the mine chambers were more than
half a mile from the shaft. Walker Hancock of First Army and George
Stout had inspected it originally and advised immediate evacuation.
But no place was available. First Army was pushing eastward, so all
Walker could do was to reassure himself from time to time that the
contents were adequately guarded.
“Shortly before VE-Day, I received a cryptic telegram at Ninth
Army Headquarters stating that, as of midnight that particular night,
Siegen was my headache. Then followed weeks of activity in which
Walker, Steve and I were involved.”
“Who is Steve?” I asked.
“Steve Kovalyak of Punxsutawney, Pennsylvania,” said Lamont. “I
think he’s with George at Alt Aussee now. I hope you’ll meet him.
He’s a great character.
“A bunker at Bonn was approved as a new repository for the
Siegen treasures. I surveyed the roads to Bonn and found them
impossible for truck transport. George was called to Alt Aussee.
Walker went off to see about setting up a collecting point at Marburg.
“Then I was called back to Ninth Army Headquarters. The
evacuation of Siegen was momentarily at a standstill.
“Later I returned and, with Walker’s and Steve’s assistance,
completed the evacuation. We moved everything to Marburg, except
the famous Romanesque doors from the church of Santa Maria im
Kapitol. Walker took them to the cathedral at Cologne, along with the
Aachen crown jewels.
“Siegen was the second major evacuation—perhaps you could
say it was the first carried out by a team of MFA&A officers.”
“What was the first?” I asked.
“The Merkers mine, where the Nazi gold and the Berlin Museum
things were stored. That was the most spectacular of the early
evacuations—that and Bernterode.”
“What about Bernterode?” I asked. I had read Hancock’s official
report of the operation and had seen some snapshots taken in the
mine, so I was curious to have a firsthand account.
“Walter Hancock was the officer in charge of the evacuation,” said
Lamont. “Like Siegen, it was a deep-shaft mine, so the contents had
to be brought up by an elevator. It was a hell of a job to get the
elevator back in working order. The dramatic thing about Bernterode
was the discovery of a small chapel, or shrine, constructed in one of
the mine chambers and then completely walled up.
“In this concealed shrine, the Nazis had placed the bronze
sarcophagi of Frederick the Great, Frederick William—the Soldier
King—and those of Von Hindenburg and his wife. On the coffins had
been laid wreaths, ribbons and various insignia of the Party. Around
and about them were some two hundred regimental banners, many
of them dating from the early Prussian wars.
“When Walker was ready to take the coffins out of the mine, he
found they were so large and heavy that they’d have to come up one
at a time. He was standing at the top of the shaft as the coffin of
Frederick the Great rose slowly from the depths. As it neared the
level, a radio in the distance blared forth the ‘Star-Spangled Banner.’
And just as the coffin came into view, the radio band struck up ‘God
Save the King.’ The date,” Lamont added significantly, “was May the
eighth.”
If I thought I was going to get much sleep that night, I reckoned
without the patriotic officers of the Yankee Division, who were hell-
bent on making it a really Glorious Fourth. It had been my mistake in
the first place to move into quarters directly over the recreation room.
It wasn’t much of a bedroom anyway—just an alcove with an
eighteenth century settee for a bed. I was resting precariously on this
spindly collector’s item when the door was flung open and Major
Thacher shouted that I was wanted below. I told him to go away. To
my surprise he did—but only to return a few minutes later with
reinforcements. I must come down at once—colonel’s orders, and if I
wouldn’t come quietly, they’d carry me down. Before I could get off
my settee, it was pitched forward and I sprawled on the floor. What
fun it was for everybody—except me! I put on a dressing gown and
was marched down the stairs. I had been called in, as a naval officer,
to settle an argument: Who had won the Battle of Jutland? The
Battle of Jutland, of all things! At that moment I wasn’t at all sure in
what war it had been fought, let alone who had won it. But assuming
an assurance I was far from feeling I declared that it had been a
draw. My luck was with me that night after all, for that had been the
colonel’s contention. So I was allowed to return to my makeshift bed.
Lamont took some of the wind out of my sails by assuring me the
next morning that the British had defeated the German fleet at
Jutland in 1916.
But we were having our own battle of Hohenfurth that morning, so
I was too preoccupied to give Jutland more than a passing thought.
Just before noon, as we finished our fourth truck, John Nicholas
Brown and Mason Hammond arrived. Mason, as was his custom
when traveling about Germany, was bundled up in a great sheepskin
coat—the kind used by the Wehrmacht on the Russian front—and
looked like something out of Nanook of the North. John, less
arctically attired, hailed us gaily from the back seat of the command
car.
Lamont and I suspended operations to show them around. We
were pleased by their comments on our work—how admirably it was
being handled and so on—but we struck a snag when we showed
them Canova’s marble Muse. Lamont and I had just about decided
to leave her where she was. Our two visitors thought that would be a
pity, a downright shame. We pointed out that to transport the statue
would be a hazardous business, even if we succeeded in getting it
onto a truck in the first place. We had no equipment with which to
hoist anything so heavy. On our inspection tour they kept coming
back to the subject of the Canova, and Lamont gave me an irritated
look for having called their attention to it at all.
At lunch, which we had with the colonel, they fixed us. When the
subject of the statue was brought up, the colonel instantly agreed to
provide us with a winch and also two extra trucks. We needed the
trucks all right, but we weren’t particularly happy about the winch.
As soon as we got back to the monastery, we broke the news to
Dr. Mutter. The Muse was about to take a trip. He held up his hands
in dismay and said it would take us half a day to get the statue
loaded. When we told the German packers what we had in mind,
they made a few clucking noises, and then began the necessary
preparations. The first thing they did was to get hold of two logs,
each about six feet in length and five inches in diameter. With the
help of a dozen PWs, they got them placed beneath the base of the
statue. From that point on, it was a matter of slowly rolling the statue
as the logs rolled. It was arduous work. A distance of well over four
hundred yards was involved, and the last half of it was along a
sloping ramp where it was particularly difficult to keep the heavy
marble under control.
Once the truck was reached, it was necessary to set up a stout
runway from the ground to the bed of the truck. This done, the next
move was to place heavy pads around the base of the statue, so that
the cable of the winch would not scratch the surface of the marble. It
was a tense moment. Would the winch be strong enough to drag its
heavy burden up the runway? It began to grind, and slowly the Muse
slid up the boards, paused for a quivering instant and then glided
majestically along the bed of the truck. There were cheers from the
PWs who had gathered around the truck to watch. We all sighed with
relief, and then congratulated the little packers who had engineered
the whole operation. Dr. Mutter kept shaking his head in disbelief. He
told us that when the statue had been brought to the monastery in
the first place, it had taken three hours to unload it. The present
operation had taken forty-five minutes.
After this triumph, the loading of the remaining trucks seemed an
anticlimax, but we kept hard at it for the next six hours. By seven
o’clock, all ten of them were finished. All told, we would be a convoy
of eighteen trucks.
We were on the point of starting down to the village for supper,
when Dr. Mutter, even more agitated than he had been before,
rushed up and implored us to grant him a great favor. Would we, out
of the kindness of our hearts—oh, he knew he had no right to ask
such a favor—would we take him and his wife and little girl along
with us to Linz the next day? Linz was his home, he had a house
there. He had brought his family to Hohenfurth only because the
Nazis wouldn’t allow him to give up his duties as custodian of the
collections at the monastery. Now the Czechs were going to be in
complete control. He and his family were Austrians and there was no
telling what would happen to them.
How news does get around, I thought to myself. We hadn’t said a
word about the Czechs taking over, but when I expressed the proper
surprise and asked him where he had heard that rumor, he wagged
his head as much as to say, “Oh, I know what I am talking about, all
right!”
My heart wasn’t exactly bleeding for Dr. Mutter, but at the thought
of his little girl, who was about the age of my own, I couldn’t say no. I
told him to be ready to leave at seven the next morning. I didn’t tell
him how uncertain it was that we would ever get to Linz at all.
It was pouring when I crawled out of my bed at six a.m. I seemed
to specialize in bad weather, particularly when starting out with a
convoy! At the monastery everything was in order. At the last minute
I decided to tell Dr. Mutter there was a possibility—even a probability
—that we would not be able to cross over at Linz, and I told him why.
He was terrified when I mentioned the prospect of being stopped by
the Russians. I assured him that we would drop him and his family
off at one of the villages on the other side of the Austrian border, if
we found there was going to be trouble. It was cold comfort but the
best I had to offer.
I climbed into the lead truck, Lamont into the tenth, and
Leclancher, as usual, took over the last truck. Leclancher, with his
customary ability to pull a rabbit out of a hat at a critical juncture, had
found among his drivers one who spoke some Russian, so we had
put him at the controls of the first truck. It might make a good
impression.
Once again we had a jeep escort to the border, and there we
picked up three others to conduct us as far as Linz. The cocky little
sergeant in the jeep that was to lead came over to my truck, squinted
up at me and said, “You look nervous this morning, Lieutenant.”
Well, I thought, if it’s that apparent, what’s the use of denying it? “I
am,” I said. “This is a big convoy and it’s filled with millions of dollars’
worth of stuff. I’d hate to have anything happen to it.”
He whistled at that. Then, rubbing his hands briskly, he retorted,
“And nothing is going to happen to it.”
He took off and we swung in behind him. The first hour was a long
one. There was more traffic than ever before—a steady stream of
carts all moving toward Linz. At last we shifted into low gear, and I
knew that we were on the steep grade leading down to Urfahr. If
there were going to be trouble, we’d know it in a minute. At that
moment, the sergeant in the lead jeep turned around and waved. I
thought, There’s trouble ahead. But he was only signaling that the
road was clear.
We rolled over the rough cobblestones onto the bridge. I saw the
gleaming helmet liners of the new escort awaiting us as we drew up
to the center of the span. I motioned to one of our new guardians
that we would stop at the first convenient place on the other side.
We were such a long convoy that I thought we’d be halfway
through Linz before our escort directed us to pull over to the curb.
There we unloaded the Mutter family and their luggage. The doctor
and his wife were tearfully grateful and the little girl smiled her
thanks.
I was feeling relaxed and happy and wanted to share my relief with
someone, so I suggested to Lamont that we pay our respects to the
colonel who had warned us not to come through Linz. It was a
letdown to find only a warrant officer in the colonel’s anteroom. But
he remembered us and was surprised to see us again. He said we
had been lucky; the latest news was that the Russians would move
up to the opposite side of the Danube by noon. We left appropriate
messages for the colonel and his adjutant, returned to our trucks and
headed west toward Lambach.
As on the previous trip, the escort turned back at that point. A new
one—this time an impressive array of six armed jeeps—shepherded
us from there. We stopped for lunch with a Corps of Engineers outfit
of the 11th Armored Division on the outskirts of Schwannenstadt.
The C.O., Major Allen, and his executive officer, Captain Myers,
welcomed us as warmly as if we had been commanding generals
instead of a motley crew of eighteen French drivers, plus twelve
“noncoms” from the escorting jeeps—a total of thirty-two, including
Lamont and me. We doled out K rations to our four packers, for we
couldn’t take civilians into an Army mess.
After lunch I telephoned ahead to Salzburg to ask for an escort
from there to Munich, requesting that it meet us on the edge of town,
east of the river. The weather had cleared, and drying patches of
water on the road reflected a blue sky. By the time we had sighted
Salzburg it was actually hot. As we rolled into the outskirts we were
enveloped in clouds of dust from the steady procession of military
vehicles. We waited in vain for our new escort. After an hour we
decided to proceed without one. I didn’t like the idea very much, but
it was getting on toward five o’clock, and we wanted to reach Munich
in time for supper. We fell far short of our goal, being forced to stop
once because of a flat tire, and a second time because of carburetor
trouble. These two delays cost us close to two hours. At seven
o’clock we halted by the placid waters of Chiemsee and ate cold C
rations in an idyllic setting. It was after nine when we lumbered into
the parking area behind the Gargantuan depot at the Königsplatz.
Lamont and I had twin objectives—hot baths and bed. It didn’t take
us long to achieve both!
We had had every intention of making an early start the next
morning, not so much because of any blind faith in Benjamin
Franklin’s precepts, but simply because they stopped serving
breakfast in the Third Army mess shortly before eight o’clock. In fact,
the first thing one saw on entering the mess hall was a large placard
which stated peremptorily, “The mess will be cleared by 0800. By

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Gastrointestinal and Liver Disease 11th

Sleisenger and Fordtran's Gastrointestinal and Liver

Gastrointestinal and Liver Pathology: A Volume in the

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EDITORS ASSOCIATE EDITORS

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MHC Major histocompatibility complex SBP Spontaneous bacterial peritonitis

1 Cellular Growth and Neoplasia

CHAPTER OUTLINE MECHANISMS OF NORMAL TISSUE HOMEOSTASIS

Cyclin D/E Cyclin A

The cell cycle is also regulated by multiple CDK inhibi-

in compacted apoptotic bodies that are eventually phagocytosed

Frizzled Receptor Plasma Membrane

Chromosomal Hyperproliferative Early Late

APC COX2 KRAS TP53

Microsatellite Hyperproliferative Early Late

Mutations in genes with polynucleotide tracks

CIMP Hyperproliferative Early Late

CpG island methylation and silencing of tumor

activities. Point mutations or large gene rearrangements result- Growth factor

Disorder Gene(s) Mutated Inherited

Peutz-Jeghers syndrome STK11 Sporadic

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