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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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should be made. To the fullest extent of the law, no responsibility is assumed by Elsevier, authors, editors
or contributors for any injury and/or damage to persons or property as a matter of products liability,
negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas
contained in the material herein.
Previous editions copyrighted 2016, 2010, 2006, 2002, 1998, 1993, 1989, 1983, 1978, and 1973.
Library of Congress Control Number: 2020934045
Senior Content Strategist: Nancy Duffy

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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
RNAs (siRNAs) by the protein Dicer. These siRNAs bind to its mesenchymal cells, its vasculature, a variety of immune cells
complementary mRNA sequences, and this binding determines recruited to the tumor and particularly in tumors of the intes-
the specificity for RNA targets. Long noncoding RNAs may per- tinal tract, and tumor-associated microbiota which contribute
form diverse functions like gene silencing, splicing, and extension significantly to the tumor microenvironment. In addition, these
of telomeres. elements acting in concert lead to a metabolic environment, such
as the oxygen and nutrient supply of the tumor, that often plays
a significant role in the evolution of the tumor at the primary site
Oncogenic Signaling Pathways and its potential for distant metastasis.
Individual oncogenes or tumor suppressor genes do not necessar-
ily induce cellular transformation directly but typically function
in concert with one another as components of larger oncogenic
TUMOR METABOLISM
signaling pathways already discussed. Some of the pathways that Tumor cells exhibit abnormal metabolic profiles to facilitate their
are particularly relevant for GI tumorigenesis include the Wnt growth and anabolic needs. Observations in 1924 from Nobel
and Ras signaling pathways. These are pathways that regulate Laureate Otto Heinrich Warburg revealed that tumor cells dis-
normal tissue homeostasis but become oncogenic when the sig- played dramatic increases in aerobic glycolysis and diminished
nals are transduced in an aberrant or amplified manner. The key mitochondrial respiration. This metabolic state, known as the
features of Wnt signaling are illustrated in Fig. 1.3. α-Catenin is Warburg effect, has been validated and is a hallmark feature of
translocated from the inner plasma membrane to the cytoplasm. most malignancies.66 It is becoming increasingly clear that inte-
There, it forms a macromolecular complex with the APC pro- gration of the genetic lesions that characterize cancer formation
tein Axin and glycogen synthase kinase-3α. Phosphorylation of is responsible for the changes in cellular metabolism that accom-
α-catenin by glycogen synthase kinase-3α triggers its degradation. pany cellular transformation. Many of the genes implicated in GI
In the presence of an active Wnt signal, α-catenin is stabilized cancers (p53, K-Ras, PI3K, mTOR, HIF, Myc) can in fact regulate
and enters the nucleus, where it interacts with the transcription metabolic pathways. Moreover, germline mutations in metabolic
factor Tcf-4 to up-regulate a number of key target genes, includ- regulators (e.g., subunits of succinate dehydrogenase) that are not
ing c-Myc, cyclin D1, and vascular endothelial growth factor (VEGF). classical oncogenes or tumor suppressor genes have been associ-
As discussed earlier, Wnt signaling is essential for regulating ated with a high risk of tumorigenesis (pheochromocytoma and
proliferation of normal intestinal epithelium, and dysregulated paraganglioma).67,68 The selection advantage of increased glycol-
Wnt signaling is an almost universal feature of all colorectal can- ysis in cancer cells may include greater tolerance to hypoxic envi-
cers. The latter can result from a mutation in the APC, Axin, or ronments and shunting of metabolic byproducts (e.g., lactate) to
α-catenin genes, although alterations in the APC tumor suppres- other biosynthetic pathways. These altered metabolic pathways
sor gene are the most common. An alteration in just one of these are promising new targets for therapy.
components is sufficient to activate the entire pathway. Thus, it is
essential to consider individual genetic alterations in the context
of the overall signaling pathway in which they function.
Inflammation and Cancer
Because pathways are typically not linear, additional levels of Immune cells recruited to the tumor microenvironment can result
complexity arise. There is frequent overlap among pathways, and in a variety of effects. On the one hand, tumor immune surveil-
the distinction between pathways can be somewhat arbitrary. For lance is well recognized and immunosuppressed states increase
example, mutations in the K-ras oncogene result in activation of the risk of cancer development. On the other hand, a number of
multiple distinct signaling pathways, including Raf/ERK/MAPK, cellular elements of hematopoietic origin can promote primary
PI3K/Akt, and nuclear factor-κB, all of which play an important tumor growth, prevent effective immune surveillance, or pro-
role in tumorigenesis (see Fig. 1.5). Crosstalk between these mote the acquisition of features of neoplastic cells that facilitate
effector pathways serves to modulate the cellular responses fur- metastasis. Myeloid cells with immature characteristics, so-called
ther. For example, Akt, a target of PI3K, can phosphorylate Raf myeloid-derived suppressor cells, are an important example of
and thereby regulate signaling through the MAPK pathway.63 this phenomenon.69
Finally, each of these signaling pathways regulates multiple bio- In addition, a number of chronic inflammatory conditions
logical processes related to tumorigenesis,64 including cell cycle increase the site-specific risk of cancer; examples of this include
progression, apoptosis, senescence, angiogenesis, and invasion. ulcerative colitis (see Chapter 115), chronic gastritis (see Chap-
Another pathway that plays a particularly important role ter 52), chronic pancreatitis (see Chapter 59), Barrett’s esopha-
in GI tumors is the cyclooxygenase-2 (COX-2) pathway. The gus (see Chapter 47), and chronic viral hepatitis (see Chapters
enzyme COX-2 is a key regulator of prostaglandin synthesis that 79 and 80). The influences of inflammation on the development
is induced in inflammation and neoplasia. Although no mutations of neoplasia are multifaceted and complex. Cytokines produced
of COX-2 have been described, overexpression of COX-2 in by inflammatory cells can lead to activation of antiapoptotic and
colonic adenomas and cancers is associated with tumor progres- pro-proliferative signals in tumor cells mediated by transcrip-
sion and angiogenesis (see Fig. 1.4), primarily through induction tion factors such as nuclear factor-κB and STAT3.70,71 Immune
of prostaglandin E2 synthesis. Inhibition of COX-2 with a vari- cells may also promote remodeling of the vascular network and
ety of agents (aspirin, nonsteroidal anti-inflammatory drugs, or promote angiogenesis (discussed later). Inflammation may also
COX-2 selective inhibitors such as celecoxib) is associated with a induce DNA damage from cytokine-stimulated production of
reduced risk of colorectal adenomas and cancer.65 reactive oxygen species.
TUMOR MICROENVIRONMENT Microbiome

Cancer is ultimately a complex tissue consisting not only of neo- The human body possesses over 100 trillion microbes and the
plastic cells harboring a number of genetic lesions, as outlined largest concentration of these organisms are present in the GI
previously, but the composite of a number of cellular components tract. The interaction between these organisms and the host is
that endow the tumor with all of its properties. Indeed, the conan area of great interest, particularly for a broad range of autoim-
tribution of non-neoplastic cells to the behavior and evolution mune, metabolic, and neoplastic disorders.72 Interestingly, colonic
of a tumor is increasingly recognized. Cellular elements with tumors are associated with specific subsets of bacteria, and the
recognized contributions to the behavior of the tumor include tumor associated microbial species have the capacity of inducing
Another random document with
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gorras de terciopelo morado con
cintas blancas atadas.
Las damas de la señora Reyna
que salieron con ella, son: la
señora doña Costantina toda
vestida de terciopelo negro
forrado de damasco negro,
acuchillada toda la seda de
encima, atada con madexa de
seda negra con cabos de oro.
Vna gorra de terciopelo negro con
muchos joyeles e pieças de oro
muy ricas.
Sacó la señora duquesa de
Grauisa vna saya de brocado rico
a la lombarda, forrada de
damasco blanco con vna mantilla
de damasco blanco forrada de
raso carmesi guarnecida de tres
tiras del mesmo brocado sobre
pestañas de raso carmesi: vna
gorra de raso blanco forrada de
raso carmesi acuchillado lo
blanco con vnas g. g. de oro
esmaltadas. Vn rico collar hecho
de las mismas letras muy rico.
La señora Porfisana sacó vna
saya de raso blanco con vna
gelosia de fresos de oro encima
d'ellos puestos sobre pestañas de
tafetan leonado, con vn collar muy
rico hecho a manera de vna
gelosia. Vna gorra de raso blanco
con muchas pieças de oro fechas
como gelosia.
La señora doña Merlesa de Ricart
sacó vna saya de brocado blanco
a la francesa, con vnas
cortaduras de terciopelo morado a
manera de vnas espinas de
pescado, forrada la saya de raso
morado. Estauan las cortaduras
de alto a baxo de manera que la
obra que hazia la seda hazia el
brocado, con vn collar de la
manera de la cortadura. Vna
gorra de terciopelo morado con
muchas pieças como las del
collar.
La señora Angelera de Agustano
sacó vna saya de terciopelo negro
con muchos fresos de plata
puestos en tornos a manera de
ondas, muy espessos a manera
de puntas, sobre pestañas de
tafetan amarillo. Vna gorra de
raso blanco con muchos cabos de
oro. Vn collar de oro hecho a
puntas.
La señora Caronisa sacó vna
saya de brocado e terciopelo
morado hecha a quartos, abierta
por la delantera e costados,
forrada de damasco naranjado
con las mangas de la misma
manera, con vnos torçales de oro
e morado que atauan las
aberturas, con vnas lisonjas
cortadas de brocado en el
terciopelo e del terciopelo en el
brocado. Vn collar de lisonjas de
oro e de rochicler; vna gorra de
raso morado llena de lisonjas.
La señora Cantoria Dortonisa
sacó vna saya de raso blanco con
vna reja de fresos de oro cubierta
que hazia toda la saya centellas;
en medio de cada centella vna
estrella de oro martillo
estampada. La gorra dela mesma
manera. La saya forrada de
damasco morado. Vn collar de
centellas de oro grandes, en
medio de cada vna, vna estrella
de rochicler.
La señora Violesa de Aguster
sacó vna saya de brocado de oro
tirado con vnas faxas angostas de
terciopelo morado por encima
sobre pestañas blancas, vna
mantilla de raso morado forrado
de damasco blanco con faxas
anchas del brocado, guarnecida
la mantilla con vna gorra de
terciopelo carmesi; con muchas
pieças de oro. Vn collar muy rico.
Muchas otras damas salieron con
la señora reyna, que por abreuiar
aqui no se escriuen aunque muy
atauiadas fuessen.
Salidas estas tres señoras vino la
señora visoreyna, que es una
muy hermosa dama, e con ella su
hermana qu'es desposada con el
hijo del principe de Salusana, e
muchas señoras de titulo con
ellas.
La señora visoreyna sacó vna
saya francesa cubierta todas de
vnas alcarchofas de oro de
martillo, vna gorra de la misma
manera, vn rico collar de
alcarchofas, vna guarnicion de
vna mula de terciopelo carmesi
con vnos fresos de oro en lugar
de franjas, chapada de vnas
alcarchofas de plata e muchos
batientes dorados encima. Diez
moços d'espuelas vestidos de
morado, de grana e azul
turquesado.
Sacó su hermana vna saya de oro
de martillo escacado forrada de
raso carmesi con vna mantilla de
damasco azul guarnecida de vnas
pieças de oro de martillo muy
ricas a manera de vnas penas.
Vna gorra del mismo raso con las
mismas pieças.
Salio con la señora visoreyna, la
condesa de Camposalado con
vna saya de altibaxo carmesi
abierta por los costados e
delantera, forrada de damasco
blanco con vnos fresos de plata e
sembrada con vnas visagras de
oro; vna gorra de raso carmesi
con las pieças; vn rico collar de lo
mismo; vna guarnicion de vna
mula chapada de las mismas
pieças de plata. Los moços
d'espuelas con jubones de raso
carmesi e sayos de paño
naranjado guarnecidos de
terciopelo negro, calças coloradas
e blancas.
La condesa de Auertino, su hija,
sacó vna saya hecha a puntas de
brocado rico e raso morado
forrada de raso blanco, hauia
sobre el morado vnos cardos de
oro sembrados; una gorra morada
de las mesmas pieças, vn collar
rico de lo mismo, la guarnicion de
la mula de la misma manera; los
moços vestidos de morado e
blanco.
La señora princesa de Salusana
llego venida la visreyna e con ella
su hija Candina e la duquesa de
Altamura. Sacó la señora
princesa vna saya de terciopelo
negro cubierta de vnos alacranes
de oro forrada de brocado blanco;
vna gorra de raso blanco con las
mismas pieças, vn collar de lo
mismo, vna hacanea con vna
guarnicion rica de lo mismo. Los
moços d'espuelas con sayos de
terciopelo negro e los jubones de
brocadelo morado; vna calça
negra, otra morada e blanca.
La señora Candina su hija sacó
una saya de terciopelo morado
cubierta de chaperia de oro con
vnas faxas de brocado assi por la
cortapisa y aberturas de la
delantera e costados forrada de
raso leonado; vna gorra leonada
con las pieças mesmas
guarnecida; vn collar de bueltas;
la guarnicion de la hacanea muy
rica, los moços vestidos de raso
leonado e terciopelo morado.
La duquesa de Altamura salio en
angarillas con vna saya de raso
carmesi, vna loba de brocado
negro forrada de damasco blanco.
La mula guarnecida de terciopelo
carmesi, los moços vestidos de
terciopelo negro e grana.
Salio con la marquesa de
Persiana la señora Mariana de
Seuerin, la señora marquesa de
Guariano. La marquesa de
Persiana sacó vna saya de
terciopelo carmesi con vnos
fresos de oro de tres dedos de
ancho passados por la saya a
escaques, de manera que estaua
hecha vn tablero; hauia en cada
escaque del carmesi vna coluna
de oro, la gorra de la misma
manera, vn rico collar de colunas,
la guarnicion de vn cauallo dela
manera de la saya, los moços
vestidos todos de amarillo.
La marquesa de Guariano salio
vestida de negro. Sacó vna saya
de plata tirada escacada con vnas
tiras de terciopelo carmesi de tres
en tres angostas, e sobre las
faxas vnas palmas pequeñas de
oro, la saya forrada de raso
encarnado, con vn collar de oro
muy rico hecho de dos palmas,
vna guarnicion de vna hacanea
de raso morado con muchas
palmas de plata doradas e
blancas como batientes.
La marquesa del Lago sacó vna
saya francesa, las mangas
forradas de oro tirado e por de
fuera cubierta de fresos de oro
tan espessos que casi cobrían
mas de la mitad de la saya; vn
rico collar hecho a manera de
vnas carrancas, vna guarnicion de
vna mula cubierta de plata a
manera de collar; los moços
vestidos todos de leonado.
Salio con ella la señora Laurencia
con vna saya de brocado y raso
encarnado hecha a lisonjas, hauia
en cada lisonja vna cruz de sant
Juan trocada de lo vno en lo otro.
Vna gorra de raso amarillo con
muchas lisonjas de oro en cada
vna, vna cruz blanca esmaltada,
vn collar de las mismas pieças,
vna guarnicion de vna mula con la
obra de la saya.
Salio la señora de la Isla Elpania
que primero fue princesa de
Saladino e con ella salio la señora
Casandra de Beluiso e la señora
Ipolisandra. La señora de la Isla
sacó vna saya de terciopelo
carmesi e raso carmesi hecho a
triangulos no grandes e por
encima delas costuras vnos
fresos de oro angostos; dentro en
cada triangulo hauia un triangulo
de oro bien releuado, algo mas
pequeño; vna muy rica gorra llena
de pedreria, vn collar de balaxos
muy rico; vna muy rica guarnicion
de vna hacanea; doze moços
vestidos de morado e amarillo.
La señora Casandra de Baluiso
sacó vna saya de raso blanco con
mucha chaperia sembrada por
ella, eran vnas eles de plata
bruñida, forrada la saya de
brocado azul. Vna gorra de lo
mismo; vn collar de perlas muy
rico, vna guarnicion de vna mula
como la suya.
Sacó la señora Ipolisandra vna
saya de brocado leonado forrada
de raso negro, con vnas
cortaduras de terciopelo negro
sobre el brocado de tiras
angostas, cubierta la saya a
manera de vna reja, hazian en los
vazios del brocado vnas rosas, en
las juntas de la trepa hauia mas
vnas pieças pequeñas de oro que
hazian la obra del brocado. Vna
gorra de raso leonado con
muchas pieças de las de la suya;
vn collar de pieças de las mismas
de bueltas.
Salieron la condesa dela Marca e
la marquesa de la Chesta juntas.
La condessa sacó vna saya de
raso azul e cubierta toda de vnas
escamas de brocado tan grandes
como vna mano sobrepossadas
sobre la saya que la cubrian,
atadas sobre vnos torçales de
plata vnas con otras; vn rico collar
d'escamas, vna guarnicion de vna
hacanea de lo mismo.
La marquesa de la Chesta sacó
vna saya a girones de oro tirado y
de plata tirada escacado, los
girones estauan sueltos sobre vna
forradura de damasco carmesi
atados vnos con otros con cintas
azules; vn collar e gorra muy rica
de muchas piedras de precio.
Salieron la condessa de Trauiso e
madama de Andria e las dos
Carlinas de Rosseller. La condesa
sacó vna saya de brocado negro
e raso carmesi a quartos, e los
quartos estauan forrados de lo
vno en lo otro e lo de encima
acuchillado a todas las cortaduras
con cintas blancas con cabos de
oro; vna gorra de lo mismo, vn
cauallo con vna rica guarnicion
estradiota, vn rico collar.
La señora madama de Andia sacó
vna saya de terciopelo negro e de
raso negro de la manera de la
condessa, saluo que las cintas
eran de hilos de perlas e la seda
estaua cubierta de chaperia de
oro.
Las dos hermanas Carlinas
salieron vestidas con dos sayas
lombardas de raso amarillo
forradas de damasco blanco e
sobre lo amarillo muchas
madexas de hilo de plata tan
espessa que apenas lo amarillo
se mostraua.
Muchas otras damas en aquella
fiesta muy atauiadas salieron que
por abreuiar el autor no las pone,
saluo que quenta de los
caualleros que con el señor
visorey salieron aquel dia, en los
quales no quenta los que justaron
ni a la noche vinieron galanes que
tiraron al precio del rubi, porque
en su lugar se hablará de cada
vno dellos.
El señor visrey sacó vna ropa de
terciopelo carmesi forrada en raso
carmesi con vnas alleluyas de oro
sembradas por ella; vna
guarnicion de lo mismo con
muchos batientes, vn jubon de
raso carmesi, vn sayo de brocado
blanco con faxas de raso carmesi
con las mismas alleluyas, vn muy
rico collar de las mismas. Sacó
treynta alabarderos vestidos de
grana blanca, doze moços de
espuelas con sayos e calças de
grana, jubones de raso blanco.
Sacó vnas letras por las alleluyas
que dezia:
Son pocos los que en tal dia
les contenta ell'alegria.
Salio el almirante señor de

Camposalado con vna ropa de
altibaxo carmesi, vn jubon de
brocado rico, un sayo de vellutado
morado, vn collar de vueltas muy
rico. Seys moços de espuelas con
sayos de Perpiñan y jubones de
damasco pardillo.
Salio el principe de Salusana con
vna ropa de brocado raso negro
forrada en raso blanco, vn sayo
de vellutado morado, vn jubon de
oro de martillo, vn collar muy rico
de piedras, los moços de
espuelas con jubones de brocado,
calças moradas e blancas, vn
cauallo con vna rica guarnicion.
Estos fueron juezes del precio de
los caualleros e por esto se
nombran primero.
Salieron con el señor visorey los
dos cardenales de Brujas e
Felernisa, en su habito.
Salio con el conde de Leonis, el
duque de Terminado, el conde de
Ponte Forto con muchos otros
caualleros e cincuenta continos
del rey que le aguardan, todos
mancebos e gentiles caualleros,
todos muy bien atauiados. De lo
qual no se cuenta mas.
Salieron con la reyna e con la
duquesa el gran Antolino, el qual
sacó vna ropa de raso carmesi
forrada en brocado blanco, vn
jubon de brocado rico, vn muy
rico collar, doze moços de
espuelas con jubones de brocado
e terciopelo carmesi e calças
moradas e pardillas; vna hacanea
ricamente guarnecida.
Salio con ellas el señor Fabricano
con vna ropa de altibaxo morada
forrada de raso blanco, vn jubon
de brocado morado rico forrado
de lo mismo. Los moços de
espuelas vestidos de las mismas
sedas e colores, con vn rico collar
de bueltas, vn cauallo guarnecido
de lo mesmo.
Salio con ellas el duque de
Altamira con vna ropa de
terciopelo leonado faxada toda de
fresos anchos e angostos de oro
escacados, vn sayo de raso
leonado de lo mesmo guarnecido,
con vn jubon de oro tirado. Los
moços vestidos de terciopelo
leonado e raso pardillo.
Salio con ellas el duque de Belisa
con vna ropa de raso negro
colchada a ondas bordada de oro,
vn sayo de brocado rico, un jubon
de raso carmesi con muchas
pieças de oro de martillo.
Salio con ellas el duque de
Fernissa con vna ropa de raso
blanco forrada de damasco
morado faxada de brocado, un
sayo de lo mismo, un jubon de
raso carmesi guarnecido de
pieças de oro de martillo. Estos
señores salieron con muchos
caualleros que los acompañaron.
COMO LOS MANTENEDORES E

AVENTUREROS
SALIERON Á LA TELA
Salieron los mantenedores juntos.
Sacó Flamiano vn cauallo con vn
paje con el que traya unos
paramentos de brocado blanco,
vnas cortapisas encarnadas sobre
las cuales auia vnas letras de
plata grandes que dezia:
Quien á lo blanco tirare

donde guarda lo encarnado
por demas haurá tirado.
Salio el mismo con vnos

paramentos de raso encarnado
chapados con vna obra relevada
de plata muy rica, la cual hazia
vnos vacios en el raso en los
quales hauia dos viboras de oro
en cada vno. La cimera de las
mismas viboras. Veynte moços
vestidos a la tudesca de
terciopelo encarnado e raso
blanco, con otro cauallo en que
hauia de justar, con vna
guarnicion de lo mismo. Vn paje
vestido de lo mismo. Dezia la letra
de las viboras:
Cuando llega al coraçon

su herida,
no hay mas remedio en la
vida.
Sacó Vasquiran vnos paramentos

de terciopelo negro, y su persona
vestida de negro. Vn paje en otro
cauallo con una guarnicion negra,
vestido de negro; veynte moços
vestidos de negro, vna cimera con
vna muerte que dezia:
Pequeño mal es tenella

pues qu'es mayor mal
querella.
Sacó vn otro paje con vn cauallo

que traya vnos paramentos de
terciopelo verde oscuro e raso
verde claro que son esperança
perdida e cobrada, con vnas
letras por la cortapisa que dezia:
Perdiose la de la vida
pero la del morir queda
porqu'el dolor viuir pueda.
Salio el conde Sauriano con vnos
paramentos de raso naranjados
cubiertos de vnas jaolas de plata,
con otro cauallo con vna
guarnicion de lo mismo, con vn
paje vestido de blanco e
naranjado; doze moços de las
mismas colores, vna cimera de
vna jaola con una calandria de
plata. Dezia la letra de la
calandria: (Está en el çaguer
verso el nombre de la dama).
Pues que de mi vida poca

su silencio da señal,
calle el bien e cante el mal.
Sacó el señor marques de

Carlerin vnos paramentos de
plata texida cubiertos de
ymagineria de oro, con vna
cimera hecha de portales y en
cada vno vna imagen; eran todas
las ymagines de rostro de damas.
Dezia la letra de las ymagines:
No está en estas vuestra

ymagen
porque es tal
que ninguna l'es ygual.
Sacó Alarcos de Reyner vnos

paramentos de brocado rico de
pelo, con vn paje vestido de
negro, en otro cauallo con vnos
paramentos de terciopelo negro,
con una reja de plata que los
cobria. Hauian en los vacios de
las rejas vnas erres doradas.
Traya por cimera un relox. Decia
la letra:
No fuera fino mi mal

porque mi ventura es tal.
Sacó el marques de Persiana

vnos paramentos de terciopelo
leonado con vnas palmeras de
plata chapadas de todos. Vn otro
cauallo con vn paje con vna
guarnicion de lo mesmo. Vna
palmera por cimera. La letra:
Ha sembrado mi ventura
mi querer e mi querella
e no espero fruto della.
Sacó el conde de la Marca vnos

paramentos de terciopelo carmesi
cubiertos de chaperia de plata de
vnos llobres o señuelos, con otro
cauallo con vn paje, con vnos
paramentos de brocado negro e
brocado blanco con vnas faxas de
terciopelo morado que partia los
quartos, con una cimera de los
mismos señuelos, con vna letra
que dezia:
Mi pensamiento ha subido
do no le calle llamar
pues que no cabe baxar.
Sacó Lisandro de Xarqui vnos
paramentos de terciopelo negro
cubierto de lagrimas de plata con
vna cortapisa ancha de vnas
peñas bordadas de oro llenas de
lagrimas que las rompian todas, e
la cimera de lo mismo. Vn paje
con vna guarnicion de brocado en
otro cauallo. Dezia la letra:
Mis tristes lagrimas viuas

en estas hazen señal,
y en vos nunca por mi mal.
Sacó el prior de Albano vnos

paramentos de brocado
encarnado; otro cauallo con vna
guarnicion de lo mismo, los
paramentos e la guarnicion con
vnas lamparas de plata que
mostrauan estar muertas, con una
cimera de las mismas lamparas
con una letra que dezia:
Muertas estan, pues la vida

de males viue encendida.
Sacó el marques de Villatonda

vnos paramentos de raso carmesi
cubiertos de otros de brocado,
cortados todos de manera de
unas clarauoyas, estauan
releuados los unos de los otros,
encima dél el brocado, estauan
cubiertos de vnos pesales de
plata; la cimera de lo mismo con
vna letra que dezia:
No hay con qué puedan

pesarse
mis querellas
sino con el pesar dellas.
Sacó el prior de Mariana unos

paramentos de oro tirado
escacado a girones, con otros de
raso encarnado, chapado el raso
de vnos marmoles de plata, e la
cimera de lo mismo; otros tres
cauallos sacó pero ni dél ni de los
otros, por acortar no se cuenta,
sino de uno. Los marmoles de los
paramentos e cimera eran
quebrados. La letra dezia:
No hay quien pueda

sostener
de mis males su pesar
que no le haga quebrar.
Sacó el duque de Felernisa vnos

paramentos de raso blanco
cubiertos de vnos manojos de
masiega hechos de plata con
muchos batientes dorados de las
espigas de la masiega, sacó por
cimera un mundo. Dezia la letra:
Menester fuera crecerse

para dalle complimiento
a vuestro merecimiento.
Sacó Francalver vnos paramentos
de terciopelo negro cubiertos de
puntas de plata como vn erizo
espesas y en cada punta un
batiente de plata blanca; sacó por
cimera las arpias de Fineo. Dezia
la letra:
Mi codicia es más terrible

pues desseo lo impossible.
Sacó el conde de Torremuestra

vnos paramentos de terciopelo
leonado cubiertos todos de vna
obra de plata enrrejada; hauia en
los espacios vna cosa de los
martirios de la passion; sacó por
cimera todos los martirios. La
letra dezia:
Si con la fe e con sofrillos

los martires se han saluado,
yo soy bien auenturado.
Sacó el duque de Grauisa vnos

paramentos de brocado rico
blanco con unas pieças de armas
como trofeos de vitoria o de
triunfo sembradas por ellos, con
la cimera de las mismas pieças
con una letra que dezia:
Pues no quise defenderme

de ser el mejor perdido
yo triunfo de bien vencido.
Sacó Rosseller el pacifico vnos

paramentos de brocado negro
con vnas ruedas de fortuna
sembradas de plata, con vna
rueda de la fortuna quebrada por
cimera, con vna letra que dezia.
Si anduuiera como suele

despues que yo ando en ella
cabo houiera mi querella.
Sacó el marques de la Chesta

vnos paramentos de brocado
blanco e terciopelo leonado
cubiertos de vidrios de muchas
maneras hechos de plata, e por
cimera un aparador de los que
tienen los que venden vidrios, con
muchas pieças de vidrio. Dezia la
letra:
Peligrosa está la vida

do ventura
no tiene cosa segura.
Sacó el marques del Lago vnos

paramentos de raso azul con
vnos niueles de plata muy ricos, e
por cimera un niuel de niuelar con
vna letra que dezia:
No es possible que mi bien

venga al niuel de mis males

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EDITORS ASSOCIATE EDITORS

LAWRENCE S. FRIEDMAN, MD DAVID T. RUBIN, MD

SLEISENGER AND FORDTRAN’S GASTROINTESTINAL AND LIVER DISEASE,

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

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Editions 5-11 Editions 7-11 Editions 8-11

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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

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

TUMOR MICROENVIRONMENT Microbiome

Salio el almirante señor de

COMO LOS MANTENEDORES E

Quien á lo blanco tirare

Salio el mismo con vnos

Cuando llega al coraçon

Sacó Vasquiran vnos paramentos

Pequeño mal es tenella

Sacó vn otro paje con vn cauallo

Pues que de mi vida poca

Sacó el señor marques de

No está en estas vuestra

Sacó Alarcos de Reyner vnos

No fuera fino mi mal

ebook download Sleisenger and Fordtran's Gastrointestinal and Liver Disease 11th Edition Mark Feldman - eBook PDF all chapter

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